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239 Cards in this Set
- Front
- Back
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Goldenhar Syndrome
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Extreme end of oculoauriculovertebral (OAV) spectrum (maldevelopment of 1st and 2nd branchial arches)
Mostly sporadic Unilateral microtia Hemifacial microsomia Mandibular hypoplasia Microstomia (cleft at side of mouth) PLUS Epibulbar dermoids Vertebral anomalies (malformed, fused, hemivertebrae) Cardiac anomalies |
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Hemifacial Microsomia (HFM)
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Mild end of oculoauriculovertebral (OAV) spectrum (maldevelopment of 1st and 2nd branchial arches)
Multifactorial, cause unknown Unilateral microtia Mandibular hypoplasia Microstomia (cleft at side of mouth) |
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Townes-Brocks syndrome (TBS)
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mutations in SALL1
Autosomal dominant Triad: Imperforate Anus Dysplastic Ears (preauricular tags, sensorineural and/or conductive hearing loss) Thumb malformations (triphalangial, or duplication of thumb) Renal (horseshoe kidney, hypoplasia, polycystic kidneys, reflux) Heart Intellectual disability in 10% |
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General Traits of Craniofacial Microsomia (CFM)
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Malformation of 1st and 2nd branchial arches
Mostly simplex with unknown etiology Recurrence risks are empiric (2-3% sibs if no family history) Facial asymmetry Maxillary and/or mandibular hypoplasia Preauricular or facial tags Ear malformations (microtia, anotia, aural atresia) Hearing loss (conductive, sensory, or mixed) Cranial nerve anomalies (facial palsy, sensorineural hearing loss, impaired extraocular movements) Respiratory compromise from severe mandibular hypoplasia, Cleft lip and/or palate (macrostomia most common, lateral) Vertebral (malformed, fused, hemivertebrae) Epibulbar dermoids (benign tumor in the cornea) Sometimes: Microphthalmia Cardiac (TOF, VSD, transposition great vessels, aortic arch anomalies) Renal (absent kidney, double ureter, hydronephrosis, etc.) Limb anomalies (radial or ulnar ray) Microcephaly, hydrocephaly, brain malformations (hypoplasia of corpus callosum, Arnold-Chiari malformation, holoprosencephaly) |
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When do neural crest cells migrate to the branchial arches?
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4th week of gestation
Each arch 3 layers: 1) Endoderm 2) Ectomesenchyme with mesoderm 3) Ectoderm Form: muscle, artery, nerve, cartilage |
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Treacher Collins Syndrome (TCS)
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Mutations in TCOF1
60% de novo Autosomal dominant 40-50% have conductive hearing loss (bones of middle ear) Malar (zygomatic) hypoplasia = no cheekbones Mandibular hypoplasia Microtia (external ear abnormalities) Leads to conductive hearing loss Downslanting palpebral fissures Coloboma of lower eyelid Deficient lower eyelashes Scalp hair in sideburn area Normal intelligence Cleft palate Choanal stenosis or atresia |
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Nager Syndrome
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Facial anomalies and PREaxial limb anomalies
Rare, mostly simplex, cause unknown Autosomal dominant (AD, AR reported) Hypoplasia/absence of thumbs Triphalangeal thumbs Hypoplasia/absence of radius Radioulnar synostosis Short forearms Malar hypoplasia Downslanting palpebral fissures Lower eyelid coloboma Absence of lower eyelashes Lowset, posteriorly rotated ears Preauricular tags, atresia of external ear canal Cleft lip +/- palate Severe micrognathia |
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Miller Syndrome
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Facial anomalies and POSTaxial limb anomalies
Autosomal Recessive, Rare Hypoplasia/syndactyly/absence of pinky and 3rd or 4th digits in some cases Hypoplasia of ulna (shortening of forearms) Malar hypoplasia Severe Micrognathia Cleft lip +/- palate Small cup-shaped ears, lowset Conductive hearing loss Lower eyelid coloboma or drooping Supernumerary nipples |
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CHARGE syndrome
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CHD7 mutations in 60-65%
Autosomal Dominant Hearing loss: cochlear or VIII nerve Coloboma (iris, retina, optic nerve) Heart defects Atresia of choanae Retarded growth and development Genital abnormalities Ear anomalies (no lobule)/hearing loss Mondini defect of the chochlea (fewer turns) Absent or hypoplastic semicircular canals Affects balance DO CT OF TEMPORAL BONE for diagnosis Undescended testicles Hypogonadotrophichypogonadism Cranial nerve dysfunction (facial nerve palsy, hearing, swallowing) |
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Branchiootorenal (BOR) syndrome
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Autosomal dominant
EYA1 (BOR1 locus) 40% SIX5 (BOR2) 5% SIX1 <1% Branchial cleft anomalies (fistulae) Malformation of the outer, middle, inner ear structures Conductive, sensorineural or mixed hearing loss Renal malformations Lacrimal duct stenosis (no TEARS) Preauricular ear pits, lop ear (overfolded helix), microtia, anotia |
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Environmental causes of craniofacial microsomia
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Diabetic mother
Multiple gestation Vasoactive drugs (Advil/ibuprofen, aspirin, pseudoephedrine) Accutane during first trimester (abnormal neural crest migration) Thalidamide Associated with: Maternal use of ART Second trimester bleeding |
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VACTERL association
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Vertebral anomalies
Anal atresia Cardiac anomalies TracheoEsophageal atresia Renal anomalies Limb anomalies Polydactyly Proximally place thumb Radial aplasia Humeral hypoplasia No molecular test Do SALL1 sequencing to rule out Townes-Brocks syndrome |
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Most common form of oral clefting associated with Craniofacial Microsomia
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Unilateral macrostomia
(lateral cleft at side of the mouth) All types of cleft lip and/or palate can be observed |
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What genetic changes can cause Craniofacial Microsomia?
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Most cases simplex (single occurrance in the family)
ALSO: Multifactorial inheritance (3-5% recurrence risk) Single-gene mutations (1-2% of families show Autosomal Dominant; AR rare) Familial more likely to be bilateral; Simplex shows more hearing loss and aural atresia Chromosomal causes (deletion 5p, chroms 18, 22 anomalies) |
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What testing to do in Craniofacial Microsomia?
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Hearing testing (even if passed newborn screening)
X-rays of spine (AP and lateral, especially cervical spine) Renal ultrasound Consider Echocardiogram CT scan of temporal bone at 5 years old Karyotype and aCGH if multiple anomalies or developmental delays |
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When does lip close during gestation?
When does palate close? |
Lip closes: 6-7 weeks of gestation
Palate closes 7-8 weeks (by 12) Failure of lip fusion may interfere with closure of palatal shelves |
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Incidence of cleft lip +/- palate
Incidence of cleft palate alone Which differs with ethnicity, sex? |
Cleft lip +/- palate: 1/750
(50% of cleft lip have cleft palate) Differs with ethnicity Native American>Asian>Caucasian>African American Males>Females Cleft palate: 1/2500 Same for males and females More likely to be syndromic Includes bifid uvula Also submucous cleft palate (VPI)-imperfect union of muscles |
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Environmental risk factors for cleft lip +/- cleft palate
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Antiepileptic drugs (phenytoin)
Retinoids Diabetic mother (gestational diabetes) Alcohol Smoking |
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How much of cleft lip +/- palate is isolated versus syndromic?
How about cleft palate? |
Cleft lip +/- palate: 70% isolated
Multifactorial inheritance 30% not isolated, possibly syndromic Cleft palate: 50% isolated 50% syndromic Increased risk of intellectual disabilities |
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Clinical issues associated with oral clefting
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Feeding difficulties
Otitis media Hearing loss Speech difficulties |
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Syndromes with cleft lip +/- palate
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Van der Woude syndrome
CHARGE syndrome Waardenburg syndrome (type 1 and 2A)-examine eyes Ectrodactyly ectodermal dysplasia and clefting syndrome Ankyloblepharon ectodermal dysplasia and clefting syndrome Early amnion rupture sequence OpitzG/BBB syndrome Basal Cell Nevus syndrome |
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Syndromes associated with cleft palate alone
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22q11.2 deletion syndrome (Velocardiofacial syndrome)
Stickler syndrome Pierre-Robin sequence Smith-Lemli-Opitz syndrome Kabuki syndrome Pallister-Hall syndrome Treacher-Collins syndrome Nager syndrome Miller syndrome (rarely cleft lip) Waardenburg syndrome (type 1 and 2A-examine eyes |
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Fanconi anemia
Ataxia Telangiectasia Smith-Lemli-Opitz syndrome Kabuki syndrome Pallister-Hall syndrome Meier-Gorlin syndrome (small, well-formed ears; absent patellae) Velocardiofacial/DiGeorge (22q11.2) Prader-Willi/Angelman (15q11.2) Smith-Magenis (17p11.2) Miller-Dieker (17p13.3) Cri du Chat or 5p- syndrome 5p15) Wolf-Hirschorn or 4p- syndrome (4p16) Williams syndrome (7q11.23) Langer-Giedion (8q24) 1p36 deletion syndrome (not strong phenotype) |
FILL THESE IN
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Recurrence risks for cleft lip +/- palate
Recurrence risks for cleft palate alone |
Up to 50% if is syndromic; rare autosomal dominant families
Otherwise, multifactorial: 3-5% Sibs of cleft lip +/- palate: 4% (2% if no one else affected) If another sib or a parent affected: 10-20% Children of cleft lip +/- palate: 4% Cleft palate: Sibs 1.8% If two sibs affected: 8% Children 3% |
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Prenatal detection/prevention of cleft lip +/- palate?
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Can sometimes detect cleft lip in second trimester Level 2 ultrasound (not usually cleft palate)
Folic acid may reduce clefting |
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Microtia incidence
How varies by ethnicity, sex |
1/10,000
More common in Navajo Indians Male>Female Right ear more affected than left |
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Environmental risk factors for microtia
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Diabetic mother
Born at altitude Alcohol use Isotrentoin Thalidomide |
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What percentage microtia sporadic (first case in family, empiric recurrence risk)
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2/3 or more (2% recurrence risk in sibs and offspring)
May be familial (mostly autosomal dominant) or syndromic |
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Anomalies associated with microtia
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Hearing deficits (may be contralateral)
Facial clefts Cardiac anomalies Vertebral anomalies Limb anomalies Renal anomalies Holoprosencephaly |
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When a patient has microtia, what do you look for on physical exam?
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Facial asymmetry
Epibulbar dermoids (tumors of sclera) Malocclusion Facial nerve weakness Macrostomia (lateral cleft of mouth) |
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When are these repairs done?
Cleft lip Cleft palate Microtia |
Cleft lip:
Cleft palate: Microtia: 4-6 years When pinna is 80% of adult size |
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Syndromes associated with microtia
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Hemifacial Microsomia/Goldenhar
Nager syndrome Miller syndrome Treacher-Collins syndrome |
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If see cleft palate in setting of Pierre-Robin sequence, what 2 syndromes think of?
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22q11.2 deletion syndrome
Stickler syndrome |
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Pierre-Robin Sequence
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Micrognathia
Glossoptosis Cleft palate (U-shaped) Advance jaw if difficulties in airway, feeding Isolated or part of a syndrome 22q11.2, Stickler |
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22q11.2 deletion syndrome
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1/6000 Caucasian, Af-Am, Asians
1/3800 Hispanics 93% new deletion, 7% inherited Autosomal Dominant Impaired T-cell immunity (77%) Conotruncal cardiac malformations (74%) Learning problems (70-90%) Palatal abnormalities (69%) Hypocalcemia (50%) Renal anomalies (37%) Feeding problems (30%) Hypertelorism Lateral buildup on nasal bridge Columnar nose Bulbous nasal tip Small palpebral fissures Micrognathia/Robin sequence Slender fingers and toes Minor ear anomalies |
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Percentage of children with congenital heart disease who have 22q11.2
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1/68 of all congential heart disease
50-80% of interrupted aortic arch 30-40% of truncus arteriosus 16% of Tetralogy of Fallot 5-8% of children with cleft palate |
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Heart defects most common in 22q11.2
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Tetralogy of Fallot (22%)
Interrupted aortic arch (15%) Ventricular septal defect (13%) Truncus arteriosus (7%) Atrial septal defect (3%) |
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Van der Woude syndrome
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Autosomal dominant
Mutations in IRF-6 Cleft lip Cleft palate Lower lip pits or mounds Hypodontia |
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Stickler Syndrome
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Autosomal dominant connective tissue disorder
COL2A1, COL11A1, COL11A2 Majority of cases inherited Incidence 1/10,000 Myopia (nearsightedness), Cataract Retinal detachment Hearing loss (conductive and sensorineural) Underdevelopment of the midface Cleft palate, Robin sequence Premature arthritis Vitreous of the eye: findings Joint hypermobility |
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Recurrence risk: Unilateral, isolated ear anomalies
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Low (although possible autosomal dominant families)
Multifactorial: 3-5% |
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Midline cleft lip-what need to consider?
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Holoprosencephaly
Orofacialdigital syndrome Short rib polydactyly |
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Chiari Malformation
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Type I usually asymptomatic
Type II Arnold-Chiari malformation more severe (usually w/myelomeningocele) Type III worst Bony space at rear of the skull is smaller than normal, Cerebellum and brainstem pushed downward Blocks flow of cerebrospinal fluid (hydrocephalus) Symptoms: Dizziness, muscle weakness, numbness, vision problems, headache, and problems with balance and coordination |
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Least common form of inheritance for genetic conditions?
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Y linked
or mitochondrial |
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What do you never see in X-linked disease?
What will recessive look like when passed from a father? Dominant? |
Male to male transmission
Recessive: Affected father passes it on All girls are carriers, no boys affected Dominant: All girls affected no boys affected |
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Ataxia Telangectasia
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ATM gene
Finds DS breaks in DNA, arrests at checkpoint Recessive CARRIERS AT RISK FOR BREAST CANCER Amish founder mutation See 7;14 translocation in peripheral blood Elevated serum AFP Progressive cerebellar ataxia Oculomotor apraxia Conjunctival telangiectasia Immunodeficiency Choreoathetosis Sensitivity to ionizing radiation Lymphoma, leukemia risk Wheelchair by age 10 |
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Carriers at risk for disease in what conditions?
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Fabry (women at risk for cardiomyopathy, kidney, neuropathy)
DMD (women at risk for dilated cardiomyopathy) Fragile X premutation (FRAXTAS, POF) Ataxia Telangectasia (breast cancer) |
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Fragile X syndrome
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X-linked
FMR1 gene CGG repeats 3' untranslated region Gene methylation, loss of function Expansion through the mother >200 repeats = disease Moderate MR in males; mild in females (50%) Large head, long face, prominent forehead, jaw Protruding ears Joint laxity Large testes after puberty Autism spectrum disorder common (25%) Hyperactivity, hand flapping, hand biting, temper tantrums Delayed milestones (especially speech) |
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Myotonic Dystrophy
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Triplet repeat disease
Expansion through the mother 5-34 normal 35-49 premutation TKTK |
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What is the minimum recurrence risk for a disease?
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New mutation rate
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Prader-Willi
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TKTK
Floppy, hypotonia Feeding difficulties Hypogonadism, undescended testicles |
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Are there autosomal dominant mitochondrial conditions?
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No. All recessive.
Complex 2 has no MT-encoded proteins in it. Only one totally nuclear encoded. |
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With 3 or more miscarriages, what is the chance of carrying a translocation?
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5%
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What do we think of if a baby was delivered by C-section?
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If in the breech position, could be because wasn't moving as much as normal
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Types of microcephaly
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Congenital
Acquired (suggests a metabolic condition) |
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Developmental milestones:
Head control Roll over Sit Crawl Walk Single words String together 2 words |
Head control: 2 months
Roll over: 3-4 months Sit: 6 months Crawl: 9 months Walk: 1 year (to 15 months) Single words: 1 year String together 2 words: 2 years |
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What IQ qualifies as mentally retarded?
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100 is average IQ
MR is <85 TKTK |
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Down syndrome
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Upslanting palpebral fissures
Hypertelorism Epicanthal folds Speckles in iris Flat nasal bridge Low set, retroverted ears Overfolded helices Single palmar crease (sign of less movement) Low muscle tone (tongue lolls) Risk of early Alzheimers Leukemia TKTKTK |
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Trisomy 18
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No creases at outer joint of fingertips
(a sign of less in utero movement) |
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Reasons for delayed motor milestones
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Big heavy head (achondroplasia)
Fat baby |
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Frequency of nonpaternity?
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~10%
TKTK |
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Arskog syndrome
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TKTK
Shawl scrotum Distal swan-neck shape to fingers (can't straighten them) Hypertelorism |
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Cystic Fibrosis genetics
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CFTR gene
When see R117H, reflex test: 5T/7T/9T variant in noncoding region R117H plus 5T = full mutation 5T alone (with mutation on other chromosome) Bilateral absence of the vas deferens, mildest phenotype 23 mutations on panel present in at least 0.1% patients |
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Carrier advantages
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Sickle cell: Malaria-infected cells sickle and are cleared from body
Cystic Fibrosis: CFTR channels won't pick up typhoid fever from intestines |
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Variegate porphyria
TKTK |
Defect in breaking down red blood cells
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Ellis van Crevald TKTKTK
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Skeletal dysplasia prevalent in the Pennsylvania Amish
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Metachromatic leukodystrophy
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Degeneration of white matter in brain
TKTKTK 1/9 carrier frequency in Inuits |
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Type of dwarfism that is recessive
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Diastrophic dysplasia
TKTKTK |
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Risk of birth defects:
-General pop -First cousin mating -Sib mating (or other first-degree) |
Risk of birth defects:
-General pop: 3-4% -First cousin mating: 6% (double) -Sib mating >50% (share half genes) |
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Hemochromotosis
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HFE gene
Autosomal recessive Absorb and store too much iron Builds up in pancreas, heart, liver Diabetes Cardiomyopathy Cirrhosis and liver failure 1/9 are carriers of C282Y TKTKTK Less serious in women (menstruate) VERY LOW PENETRANCE |
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Global distribution of alpha and beta thalassemias
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Alpha: Asia
Alpha + Beta: India Beta: Mediterranean |
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How high a carrier frequency is considered high enough to screen for?
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1/100 as rule of thumb
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What is the benefit of Genzyme's expanded CF panel?
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Additional mutations common in Hispanic and African Americans
If see echogenic bowel and family is Hispanic If already know wife a carrier, SEQUENCING gives best chance of picking up something in the husband |
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Do sickle cell carriers have anemia and a low MCV?
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No. So have to do hemoglobin electrophoresis to screen
African-American carrier frequency = 1/12 TKTK |
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Tay Sachs screening for a pregnant woman
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Mutation analysis
Do enzyme analysis in her partner if not Ashkenazi Jewish (mutation testing has good pickup only for AJ) |
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Which type of hemoglobin rises in Beta-thalassemia trait (carriers)?
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Hbg A2 (alpha2-delta2; usually up to age 6 months) always
Hbg F (alpha2-gamma2; usually fetal hemoglobin) sometimes |
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Fanconi anemia
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One of the AJ disorders
Bone marrow failure Drop in RBC, WBC, platelets TKTKTK |
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Duchenne Muscular Dystrophy
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High rate of new mutations
If no family history, 2/3 mothers are carriers 1/3 de novo 65% deletions 10% duplications 30% small mutations detected by sequencing |
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Common X-linked metabolic disorders
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OTC deficiency (urea cycle)
Hunter syndrome (lysosomal storage disorder, MPS type II) |
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How does a complete mole occur?
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Trisomic rescue
Two sperm fertilize an egg Kick out the female DNA |
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Angelman syndrome characteristics
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"Happy puppet"
No speech at all Severe MR Seizures Jerky gait Large jaw, protruding tongue Inappropriate laughter Postured like a marionette Paternal UPD is on rare mechanism |
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Angelman syndrome mechanisms
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Deletion 68%
UBE3A mutation 11% UPD (paternal) 7% Lower than in Prader-Willi Imprinting defect 0.5% |
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Hearing Loss
Modes of inheritance? |
Autosomal dominant
Autosomal recessive X-linked Mitochondrial |
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Stats on childhood hearing loss
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1/1000 born deaf
1/300 significant hearing impairment 60% is genetic 40% environmental OF genetic: 70% non-syndromic 30% syndromic OF non-syndromic 80% autosomal recessive 20% autosomal dominant |
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Most commonly affected gene for non-syndromic hearing loss?
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GJB2 (Connexin 26)
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Connexin deafness
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10% of all congenital hearing loss
70% of all non-syndromic, recessive hearing loss Carrier frequency 2-3% Caucasians (similar to CF) 4-5% Ashkenazi Jews 1% Japanese |
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Types of mutations in connexins
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Homozygous (AR) point mutations
Frameshift mutations 35delG mutation in Caucasians Means gap junctions can't function (a few dominant mutations like R75W) (V27I is just a polymorphism) |
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GJB2 (connexin 26) gene structure
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A single coding exon
Sequencing primers cover entire sequence |
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Familial Hypercholesterolemia (FH)
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Autosomal dominant
LDLR mutations (Seq; Del/Dup) High LDL "Bad" Cholesterol Receptor can't remove LDL from blood Begins at birth Risk of early heart attack and stroke Homozygotes more severe Locus on Chromosome 19 Fatty skin deposits called xanthomas (elbows, knees, buttocks, tendons, and around the cornea of the eye) Cholesterol deposits in eyelids (xanthelasmas) Chest pain (angina); other signs CAD |
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Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
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Occurs in males (some females): 45%/16%
With Fragile X (FMR1) Premutation 55-200 repeats Late-onset Progressive cerebellar ataxia Intention tremor Cerebellar white matter lesions on MRI |
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FMR1-Related Primary Ovarian Failure (POF)
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Occurs in ~20% females
with a Fragile X (FMR1) Premutation Age < 40 55-200 repeats |
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Fragile X Repeat Lengths
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CGG Repeats
Expansion in the mother Father transmits his allele to ALL daughters (NO sons) 5-44 Normal 45-54 Borderline 55-200 Premutation > 200 Full mutation Interrupting AGG repeats make more stable |
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Conditions caused by chromosome deletions
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Prader-Willi
Miller-Dieker Smith-Magenis Langer-Gideon |
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Beckwith-Wiedemann:
Causes |
Imprinted domain on 11p15.5
Parent of origin effects Growth factors and tumor suppressor genes Maternal methylation errors "Differentially methylated regions" 50% loss of methylation at DMR2 (antisense RNA now inactivates cell cycle regulator gene CDKN1C ) 20% Paternal UPD (Now 2x IGF2 paternally expressed AND DMR2 shut down) usually segmental, mitotic error DMR1 has H19 (noncoding mRNA) and IGF2 10% CDKN1C mutations (gene is normally maternally expressed) 40% IN FAMILIAL CASES, WITH MATERNAL TRANSMISSION (other forms low recurrence risk) |
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Beckwith-Wiedemann:
Features |
Overgrowth syndrome (1/13,700)
Prematurity, polyhydramnios, large placenta Macrosomia Macroglossia Visceromegaly Umbilical hernia/omphalocele Hemihyperplasia Embryonal tumors (7.5%) (Wilms, Renal abnormalities Earlobe creases and helical pits See tops of whites of eyes Newborn hypoglycemia (pancreatic beta-cell hypertrophy) Clitoral/genitalia enlargement Cardiac malformations, cardiomyopathy Growth slows 7-8 years of age |
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Sotos syndrome
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Autosomal dominant
NSD1, histone-lysine N-methyltransferase Overgrowth in all parameters (vs BW internal organs out of proportion) 5q35 microdeletion including NSD1 (15%...70% Japanese) NSD1 sequencing (most non-Japanese) Macrocephaly Sparse frontotemporal hair High bossed forehead Long narrow face, small jaw, pointed chin Mild to severe learning disability Delayed motor skills Tall stature and increased body mass Low tumor risk |
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Diabetic mother
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Big baby
Hypoglycemia |
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Beckwith-Wiedeman and monozygotic twinning
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Increased chance of twins in BWS
Majority female Majority DISCORDANT (one has, one not) Mechanism: Maternal loss of methylation at DMR2 |
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Risks of Beckwith-Wiedeman
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20% infant mortality
Macroglossia and airway insufficiency Hypoglycemia can harm CNS |
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Beckwith-Wiedemann Inheritance
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85% no family history
10-15% familial AD with maternal transmission |
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Molecular testing for Beckwith-Wiedemann
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If familial:
1) High resolution karyotype 2) CDKN1C mutation scanning If sporadic: 1) High resolution karyotype (do first if MR) 2) Methylation studies (serves as UPD study too since both DMR1 and DMR2 will be abnormal if there is UPD) |
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Tumor risks for Beckwith-Wiedemann
(abdominal US every 3 months until age 8) |
Wilms tumor 43%
No risk with familial CDKN1C mutations Loss of methylation at DMR2 other tumor types Hemihyperplasia, nephromegaly means greater risk Highest with increased IGF2: 11p15 paternal UPD H19 hypermethylation Hepatoblastoma 20% Adrenocortical cardinoma 7% Rhabdomyosarcoma 6% |
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Conditions involving imprinted genes
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Prader-Willi/Angelman
Beckwith-Wiedemann/Russel-Silver Isolated Wilms tumor (IGH2/H19 locus) Transient neonatal diabetes Carotid body tumors |
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Truisms about imprinted genes
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CpG methylation
Tend to occur in clusters Antisense transcripts expressed on the other allele Long-range cis-acting mechanisms |
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What is the risk with IVF/ART?
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Loss of maternal imprinting
-DMR2 in Beckwith-Wiedemann -Angelman syndrome also loss of maternal imprinting center |
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Differential for Beckwith-Wiedemann
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Sotos syndrome
Simpson Golabi Behmel Perlman syndrome Costello syndrome Hemihyperplasia |
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Simpson Golabi Behmel
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X-linked recessive
Mutations in GPC3 Macrosomia Macroglossia Visceromegaly High rate cardiac defects Polydactyly Supernumerary nipples |
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Perlman Syndrome
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Autosomal recessive (unknown gene)
Macrosomia Nephroblastomatosis Risk of bilateral Wilms tumor Characteristic face |
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Costello syndrome
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Autosomal dominant
HRAS mutations Bladder cancer Rhabdomyosarcoma Neuroblastoma Overgrowth due to edema Macrocephaly Strabismus, nystagmus, myopia, astigmatism Bitemporal narrowing Cardiac defects Arrhythmias Failure to thrive "like trying to die" Motor and speech delay Later distinctive facies Skin looks like has a tan Doughy velvety skin with deep wrinkles Warty growths around anus, nose Retention hyperkeratosis Fine, sparse, curly hair Coarsening |
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Russell Silver Syndrome
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Undergrowth (1/75,000)
IUGR Assymmetry due to mosaicism Normal intelligence Short stature Normal head circumference and growth velocity Head LOOKS macrocephalic 5th finger clinodactyly Small triangular face, thin upper lip |
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Mechanism of Russell Silver Syndrome
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OPPOSITE of Beckwith-Wiedemann
Imprinting defect at DMR1 (H19, IGR2) 50% Paternal hypomethylation at DMR1 Decreased IGF2 expression (Missing paternal contribution) 10% Maternal UPD chromosome 7 (!!) If duplication of 11p, can alternate BWS and RSS depending on parent of origin. (Paternal duplication=BWS) |
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Normal hemoglobin in RBC
Fetal Newborn Adult |
Fetal: Hgb F (alpha2-gamma2)
Newborn: Hgb F (alpha2-gamma2) 60% lasts to 3 months Hgb A (alpha2-beta2) 40% Hgb A2 (alpha2-delta2) 1% Adult: Hgb A (alpha2-beta2) 98% Hgb A2 (alpha2-delta2) 1-3% |
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What is thalassemia?
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Diminished synthesis of one or more globin chains that combine to form hemoglobin
alpha2-beta2 2 beta genes (Chrom 11) 4 alpha genes (Chrom 16) |
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Alpha-thalassemia
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Most prevalent in:
Southeast Asian (into India) --/aa CIS American Blacks -a/-a TRANS Less common in Mediterranean |
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Alpha-thalassemia subtypes
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1 gene deleted (or Hbg constant spring)
alpha-thal trait (silent carrier: -a/aa) Blacks get, Asians not generally 2 genes deleted alpha-thal trait microcytosis, mild anemia 3 genes deleted Hemoglobin H disease Chronic hemolytic anemia Splenomegaly Asians get, not blacks 4 genes deleted alpha-thalassemia Barts Hgb Fetal hydrops (--/--) Asians get, not blacks |
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Why is it called Hgb H disease?
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3 alpha chains missing
Lots of extra beta 4 betas aggregate to form "Hgb H" Inclusions in the RBCs |
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Why is it called Bart's Hgb?
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4 alpha chains missing
Lots of extra gamma in fetal life 4 gammas aggregate to form "Hgb Bart's" Newborn screening looks for excess of this to diagnose Hgb H disease. |
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Why splenomegaly with alpha-thalassemia?
What other symptoms? |
Spleen is site of fetal RBC production. Ramps up now to sustain the patient.
Pale, jaundiced At risk for aplastic bone marrow crisis Extra billirubin forms gallstones (pain) |
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What do if baby tests positive on newborn screening for Hgb H disease?
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Genotype the parents
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What do you do if see a low MCV?
<80 |
Iron studies on patient
Test partner's MCV If is alpha-thalassemia, diagnosis of exclusion Normal transferrin Normal hemoglobin electrophoresis (deletions, not mutations) |
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Why is the anemia hemolytic?
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Hgb H (4 betas) aggregates
in old blood cells causes cell membrane injury and hemolysis |
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Why do fetuses with alpha-hydrops die in utero?
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Hgb H and Hgb Bart's can't carry oxygen as well
Die of hypoxia Heart overworked Cardiac failure Carrying a hydrops baby can HARM MOTHER'S HEALTH too |
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Beta-thalassemia trait
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Heterozygous for a beta mutation
Mild microcytic anemia Hypochromia, basophilic stippling Normal iron studies Increased Hgb A2 (delta compensates) Increased Hgb F (gamma compensates) |
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What are iron studies like in alpha- or beta-thalassemia?
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Normal
Serum iron Srum ferritin Saturation TIBC (total iron binding capacity) |
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Homozygous beta-thalassemia
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Increased Hgb A2 10% (delta compensates)
WAY Increased Hgb F 90% (gamma compensates) |
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What do excess alpha chains do in beta-thalassemia?
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Don't aggregate
Free in bone marrow Cause RBC membrane injury Hemolysis before get out of bone marrow Ineffective hematopoesis |
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Clinical features of beta-thalassemia
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Not notice until 6 months of age, since
Hgb A2 (alpha2-delta2) until 6 months Transfusion dependent (iron chelation) Irritable, fatigue, anorexia Heart murmur, cardiac dilation (overworked) Yellow sclera and skin jaundice Thalassemia facies Abdominal distention |
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Why thalassemia facies and abdominal distension?
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Extramedullary RBC production
Facies: frontal and parietal bossing Enlargement of maxilla Front teeth protrude, lip pushed up Nose bridge broadened Spleen and liver site of fetal RBC production Big belly Bone pain, risk of vertebral fractures or long bone fractures |
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What organs does iron overload affect?
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Heart (arrhythmia, hypertrophy, death)
Pancreas (diabetes) Liver (fibrosis, cirrhosis, death) Decreased pituitary and sex hormones Body doesn't excrete iron except through menstruation or blood letting |
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Velocardiofacial/DiGeorge deletion location
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22q11.2
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Prader-Willi/Angelman deletion location
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15q11.2
Infancy: Severe hypotonia Severe feeding difficulties Later: Excessive eating Morbid obesity Cognitive impairment Temper tantrums Manipulative behavior, OCD Hypogonadism Absence of paternal PWS/AS region Methylation testing |
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Smith-Magenis
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del(17)(p11.2)
De novo, recc risk <1% Self-injurious behavior Mild to moderate MR Sleep disturbance Impulsivity, Inattention, Hyperactivity Sterotyped behaviors: "self-hug" finger lick and page flipping ("lick and flip") Infant hypotonia, failure to thrive Must be woken for feedings, lethargic |
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Miller-Dieker
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17p13.3 deletion
80% de novo 20% parent has a translocation Deficient neuronal migration Lissencephaly "smooth brain" Absent gyri (agyria) or abnormally wide gyri (pachygyria) Characteristic facies Severe neurologic abnormalities |
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Cri du Chat
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5p- syndrome 5p15
Multiple congenital anomaly syndrome Microcephaly Cat-like cry Severe psychomotor and MR |
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Wolf-Hirschorn
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4p- deletion syndrome (4p16)
'Greek warrior helmet appearance' of the nose Short philtrum Microcephaly Hypertelorism Epicanthal folds Growth deficiency, hypotonia Variable MR Seizures Skeletal anomalies (60%-70%), Heart defects (~50%) Conductive hearing loss (>40%), Urinary tract malformations (25%), Structural brain abnormalities (33%) |
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Williams syndrome
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7q11.23 deletion syndrome
Includes ELN gene for elastin Most de novo; AD Connective tissue abnormalities Cardiovascular disease (Elastin arteriopathy, Supravalvular aortic stenosis, Hypertension) Distinctive facies Mild MR Hoarse voice Cocktail Party personality Growth/endocrine abnormalities Early puberty Hypotonia Hyperextensible joints Delayed motor milestones Sensorineural hearing loss |
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Langer-Giedion
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8q24 deletion syndrome
Includes EXT1 Multiple cartilage osteochondromas MR Large, laterally protruding ears Bulbous nose Sparse scalp hair Winged scapulae Digital anomalies Result from haploinsufficiency of TRPS1 |
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1p36 deletion syndrome (not strong phenotype)
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Most common terminal deletion syndrome
Facial features: Straight eyebrows Deep-set eyes, midface hypoplasia, Broad and flat nasal root/bridge Long philtrum, and pointed chin Microcephaly, brachycephaly Epicanthal folds Large late-closing anterior fontanel Posteriorly rotated, low-set, abnormally formed ears MR, hypotonia, seizures Structural brain abnormalities (88%) Congenital heart defects (71%), Eye/vision problems (52%) Hearing loss (47%) Abnormalities external genitalia (25%) Renal abnormalities (22%) Obesity |
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Angelman syndrome
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Loss of maternally imprinted genes
Testing: Methylation analysis UBE3A sequence analysis Severe developmental delay, MR No speech Gait ataxia, tremulous limbs Happy demeanor Frequent laughing, smiling, excitability Microcephaly Seizures are common |
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Ataxia Telangiectasia
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ATM gene
Autosomal recessive Sensitive to ionizing radiation Progressive cerebellar ataxia Begins ages 1-4 years Slurred speech Oculomotor apraxia (bumpy visual tracking) Choreoathetosis Telangiectasias of the conjunctivae Immunodeficiency Frequent infections Risk for malignancy Leukemia, lymphoma Premature aging, gray hair |
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Pallister-Hall syndrome
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GLI3 gene
Autosomal dominant Hypothalamic hamartoma, Central and postaxial polydactyly, Bifid epiglottis Imperforate anus Renal abnormalities Neonates may die from untreated pituitary insufficiency (producing cortisol/adrenal insufficiency) |
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Meier-Gorlin syndrome
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Autosomal recessive
Genes unknown Small, well-formed ears Absent patellae (kneecaps) Short stature Severe pre- and postnatal growth restriction Microcephaly Bilateral microtia Intellect usually normal |
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Smith-Lemli-Opitz syndrome
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DHCR7 gene
Autosomal recessive Abnormal cholesterol metabolism Deficiency of the enzyme 7-dehydrocholesterol (7-DHC) reductase Multiple anomaly syndrome: Characteristic facial features Microcephaly, MR Postaxial polydactyly 2-3 syndactyly of the toes Growth and mental retardation Cleft palate Hypospadias in males Cardiac defects |
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Kabuki syndrome
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MLL2 mutations
Autosomal dominant 1. Typical facial features Elongated palpebral fissures Eversion of lateral third of lower eyelid Arched and broad eyebrows Sparseness or notching at lateral third Short columella with depressed nasal tip Large, prominent, or cupped ears Cleft lip and/or palate Ear pits 2. Skeletal anomalies: Butterfly vertebrae Narrow intervertebral disc space Scoliosis Brachydactyly V Brachymesophalangy Fifth finger clinodactyly 3. Persistence of fetal fingertip pads 4. Mild to moderate intellectual disability 5. Postnatal growth deficiency Infections Seizures Hearing loss |
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Bardet-Biedl
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Autosomal recessive
At least 14 genes Night-blindness by 7-8 Legally blind ~ 15.5 years Cone-rod retinal dystrophy Truncal obesity (weight gain in first year) Postaxial polydactyly Learning difficulties Male hypogonadotrophic hypogonadism Female genitourinary malformations Renal dysfunction (mortality) |
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Conotruncal heart defects
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Cardiac outflow tract defects
Tetralogy of Fallot Pulmonary atresia Double-outlet right ventricle Truncus arteriosus communis Aortic arch anomalies 1/4 to 1/3 of isolated nonsyndromic congenital heart defects 22q11.2 found in 30% |
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Timothy Syndrome (LQT 8)
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Disorder of calcium channels
CACNA1C gene Gain of function Severe QT prolongation Age of death: 2.5 years Syndactyly of fingers (100%) 2-3 toe syndactyly Cardiac defects (60%) (patent ductus arteriosus, patent foramen ovale, ventricular septal defect, tetralogy of Fallot, hypertrophic cardiomyopathy) Dysmorphic faces Developmental delays Autistic symptoms (50%) |
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Andersen Tawil (LQT 7)
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KCNJ2 mutations
Autosomal dominant 50% de novo Periodic paralysis (episodic flaccid muscle weakness) Prolonged QT, ventricular arrhythmias Dysmorphic features: Low-set ears Ocular hypertelorism Small mandible Fifth-digit clinodactyly Syndactyly Short stature Scoliosis |
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Jervell and Lange-Nielsen syndrome
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KCNQ1 and KCNE1
(also cause Romano-Ward) Autosomal recessive RECESSIVE. DEAFNESS. Third most common type of autosomal recessive syndromic hearing loss Parents can have LQTS Profound bilateral sensorineural hearing loss QTc > 500 msec Deaf child Syncopal episodes during stress, exercise, or fright Untreated, half die by age 15 |
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Heritability of psych disorders
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autism > schizophrenia > bipolar > major depression
Heritability 90-100% for autism 70-90% for schizophrenia XX for bipolar 30-40% for major depression |
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If parent has Type 2 diabetes (only one in family) what is risk to child?
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~10%
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If child has ASD but met language milestones they have
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Asperger syndrome
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Features of muscular dystrophy
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A group of more than 30 inherited diseases
Muscle weakness Loss of muscle tissue Apparent lack of coordination Joint fixations (contractures) Progressive Usually symmetrical Voluntary muscles are most affected |
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Prevalence of muscular dystrophies
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Facioscapulohumeral muscular dystrophy
= 1/14,286 Duchenne and Becker Muscular dystrophy = 1/20,000 Steinert myotonic dystrophy = 1/22,222 |
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Dystrophinopathies
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Duchenne MD
Becker MD X-linked inheritance DMD is on Xp21.2 Caused by a defect in protein dystrophin Involves the DMD gene Mostly boys affected |
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Duchenne Muscular Dystrophy
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X-linked
Complete lack of dystrophin in muscles DILATED CARDIOMYOPATHY CONGESTIVE HEART FAILURE (Female carriers at risk) Most severe form Onset in early childhood (< age 5) Rapidly progressive Wheelchair bound by age 12 Dilated cardiomyopathy by age 18 Death by 20s or early 30s (respiratory or cardiac failure) Signs and symptoms Delayed sitting, standing, walking Waddling gait Large calf muscles Difficulty getting up from lying or sitting Gower’s maneuver Mild mental retardation, sometimes |
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Becker Muscular Dystrophy
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Milder form
Abnormal quality or quantity of dystrophin 85% deletions (MORE THAN DMD) 10% duplications 10% small mutations Symptoms similar to Duchenne Onset later: around age 11 Sometimes not until mid-20s or even later Progresses more slowly Usually able to walk through teens, into 20s Most frequent cause of death: heart failure Result of dilated cardiomyopathy Mean age of death in mid-40s |
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Spinal Muscular Atrophy
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Autosomal recessive
Mutations in SMN (SMN2 compensates) Poor muscle tone Symmetric muscle weakness Spares the face and ocular muscles Fasciculations of the tongue Absence of deep tendon reflexes |
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DMD gene
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2.4 Mb of DNA
79 exons. At least four promoters Largest known human gene Deletions, duplications Smaller point mutations |
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Steinert Myotonic Dystrophy
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Autosomal dominant
“CTG” repeat expansion in DMPK gene (19q13) Multisystem disorder Skeletal and smooth muscle Onset in adulthood Slow progression Begins with distal muscles Hands, feet, lower legs Cataracts Breathing affected along with Heart Rhythm Swallowing Diabetes |
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Steinert Myotonic Dystrophy Signs
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Myotonic Grip
Muscle weakness, pain, stiffness Inability to relax muscles at will Common causes of death Pneumonia Respiratory failure Heart arrhythmia |
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Mechanism of Myotonic Dystrophy?
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CTG trinucleotide repeat
non-coding region of DMPK Dystrophia myotonica protein kinase Produces embryonic forms of protein through RNA splicing "Toxic mRNA" 5-34 normal 45-49 premutation >49 disease The more CTG repeats, more severe >1000-2000 repeats causes congenital form: Maternal (sometimes paternal) expansion Hypotonia Myopathic facies Respiratory deficiency Mental retardation |
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Facioscapularhumoral Muscular Distrophy (FSHD)
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Most common form of muscular dystrophy
Last major type to have its genetic cause identified Facial muscles Scapular stabilizer muscles Upper arm muscles Can also affect: Abdomen Hips Lower leg Causes wasting of muscles in upper body Scapular winging Side-to-side asymmetry Onset in teens or twenties Slowly progressive Disability often minor, 20% will need a wheelchair Lifespan not affected |
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Unusual mechanism of FSHD
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Autosomal dominant
Contraction of repeats! Toxic gain of function from more DUX4 protein 1/3 de novo Subtelomeric deletion on 4q Deletion involves D4Z4 macrosatellite repeats Located on 4q35 Each repeat 3.3kb long Normal: 11 to 100 repeats Pathogenic contraction: 1 to 10 repeats NEEDS PERMISSIVE CHROMOSOME BACKGROUND Poly-A stable RNA More full-length, embryonic-type Dux4 protein |
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Ehlers-Danlos Syndrome
Classic type |
Classic type
(EDS type I and EDS type II) Autosomal dominant 50% de novo 50% have mutations in Type V Collagen COL5A1 or COL5A2 Connective tissue disorder Skin hyperextensibility Abnormal wound healing Joint hypermobility Hyperelastic, extensible skin Velvety and smooth to touch Fragile skin Prone to splitting over knees, shins, etc Wound healing delayed Hypertrophic scars Joint hypermobility Dislocations Hypotonia Easy bruising Hernia Mitral and tricuspid valve prolapse Aortic root dilatation Spontaneous rupture of large arteries |
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EDS Hypermobility type (EDS type III)
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Autosomal dominant
Gene unknown (TenascinX, TNXB, in some) Joint hypermobility is the primary manifestation Skin soft, velvety, may be mildly hyperextensible Dislocations are common Degenerative joint disease Chronic pain Easy bruising NO TISSUE FRAGILITY Atrophic scarring makes you think more of CLASSIC EDS Entirely a clinical diagnosis An autosomal recessive form has TNXB (tenascin X) deficiency |
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EDS Vascular type (EDS type IV)
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The one people fear
COL3A1 mutations Thin, translucent skin Easy bruising Characteristic facial appearance Aged-looking hands Fragility of: Arteries Intestines and/or uterus Pneumothorax Affected individuals are at risk for Arterial rupture and/or dissection Aneurysm Gastrointestinal perforation or rupture Uterine rupture during pregnancy 25% have a significant medical problem by age 20 80% by age 40 years Median age of death is 48 The diagnosis of EDS, vascular type is based on clinical findings and confirmed by biochemical and/or molecular genetic testing. Biochemical studies in affected individuals demonstrate abnormal electrophoretic mobility and abnormal efficiency of secretion of type III procollagen by cultured dermal fibroblasts. Molecular genetic testing is used to identify mutations in COL3A1. Inheritance is autosomal dominant. |
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Loeys-Dietz Syndrome
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Autosomal dominant
75% de novo TGFBR1, TGFBR2 Vascular findings Cerebral, thoracic, abdominal Arterial aneurysms and/or dissections Skeletal manifestations: Pectus excavatum or carinatum Scoliosis Joint laxity Arachnodactyly Talipes equinovarus (club foot) Approximately 75% have LDS type I with craniofacial manifestations: Ocular hypertelorism Bifid uvula/cleft palate Craniosynostosis (saggital) 25% have LDS type II with cutaneous manifestations: Velvety and translucent skin Easy bruising Atrophic scars Aggressive arterial aneurysms Mean age at death 26 Pregnancy-related complications: Death and uterine rupture |
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De novo in connective tissue disorders?
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25% Marfan
50% EDS 75% Loeys-Dietz |
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Alport syndrome
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Collagen IV-related
Component of basement membranes Nephropathy leading to end-stage disease Hearing loss, sensorineural Postlingual >10 years old, progressive Most commongly X-linked 85% X-linked COL4A5 15% Recessive COL4A3, COL4A4 rare-Dominant COL4A3 (ALL 3 INHERITANCES) |
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Ring chromosomes
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Subtelomeric deletions in ring formation can cause MR
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Nonsyndromic MT deafness
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Caused by mutations in MT DNA
One gene (of the 2) makes sensitive to aminoglycoside antibiotics Maternal inheritance Start with targeted mutation analysis Mutation in MT-RNR1 (encoding mitochondrial 12S ribosomal RNA) Aminoglycoside ototoxicity and/or Late-onset sensorineural hearing loss. or MT-TS1 (encoding MT tRNA serine 1) Childhood onset of sensorineural hearing loss Gentamycin, tobramycin, amikacin, kanamycin, or streptomycin |
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Incidence of Fragile X
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1/4000 boys
1/6000 girls |
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Mechanism of Fragile X premutation
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RNA toxicity
(is no hypermethylation with premutation) Can also get learning difficulties Anxiety Depression Executive function deficits OCD Prominent ears, flexible joints |
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Which RASopathy is not associated with increased cancer risk?
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TKTK
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Osteogenesis Imperfecta
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COL1A1 or COL1A2
7 types, 60-100% de novo (the more severe, more likely de novo) MOSTLY Autosomal dominant 1 Autosomal recessive (type VII) 1 Unknown Brittle bone disease Fractures with minimal or absent trauma Blue sclera Hearing loss after puberty Dentinogenesis imperfecta (DI) Short stature Biochemical testing preferred (i.e., analysis of structure and quantity of type I collagen synthesized in vitro by cultured dermal fibroblasts) Can be done on CVS OI Type II is prenatal lethal, hips in "frog leg" position |
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Prelingual hearing loss
vs Postlingual hearing loss |
Prelingual:
50-60% have a genetic origin 70% isolated, 30% syndromic Recessive inheritance most common Postlingual: Dominant inheritance most common |
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Environmental causes of hearing loss in children
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Prenatal exposures:
CMV - first infection during pregnancy Rubella Postnatal exposures: H. flu (otitis media, meningitis) Ototoxic drugs like gentamycin with MT-RNR1 gene mutation |
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Phenocopy for congenital CMV infection
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Aicardi-Goutieres
Autosomal recessive (rare dominant) TREX1 A subgroup of infants with AGS present at birth with abnormal neurologic findings (calcification of basal ganglia, cerebral atrophy) hepatosplenomegaly elevated liver enzymes thrombocytopenia highly reminiscent of congenital infection |
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What can ventriculomegaly in the fetus indicate?
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CMV infection
or abnormal brain development |
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What causes syndromic congental hearing loss most often?
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Conductive or mixed
Problems with the way the ears are formed |
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Syndromic hearing loss
When to consider chromosome abnormality |
Hearing loss
Global developmental delay/MR Major malformations Multiple minor anomalies Growth retardation |
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Deletion 18q
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Conductive hearing loss
Narrow or atretic ear canals Global developmental delay/MR |
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Waardenburg syndrome
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Most common AD syndromic hearing loss
Multiple genes (multiple types) PAX3, paired box protein, HOX TF involved in melanocyte development Sensorineural hearing loss in 70-85% Pigmentary abnormalities of hair, iris, skin White forelock/early graying Monobrow, widow's peak Heterochromia of the irides Tubular nose, deficient nostrils Inner canthi laterally displaced Type IV has Hirschsprung disease (and has an AR form) Neural crest migration problems May have neural tube defect FOLIC ACID SUPPLEMENTATION if pregnant |
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Most common forms of AD syndromic hearing loss?
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1) Waardenburg syndrome
2) Branchio-oto-renal syndrome |
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Branchio-oto-renal syndrome
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Second most common form of AD syndromic hearing loss
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Usher syndrome
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Autosomal recessive
Multiple genes (~11) Majority due to MYO7A, USH2A: myosin VIIa, usherin Most common AR syndromic hearing loss Congenital profound sensorineural hearing loss Retinitis pigmentosa (constricts visual field) Fundoscopic findings AFTER first decade Abnormal ERG between 2-4 years Type I: Vestibular dysfunction, balance problems Type II: Normal vestibular Type III: Variable vestibular Ask about sitting, walking, motor skill aquisition Balance test |
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What are the most common AR syndromic forms of hearing loss?
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1) Usher syndrome
2) Pendred syndrome 3) Jervell and Lange-Nielsen syndrome |
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Pendred syndrome
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Autosomal recessive
SLC26A4 mutations Chloride/Iodide exchanger in inner ear and thyroid in 50% familial, 20% simplex cases Second most common AR syndromic hearing loss Severe to profound SNHL Vestibular abnormalities: Mondini dysplasia Abnormal bony labyrinth Enlarged vestibular aqueduct Normal thyroid function, but Goiter 75% If Connexin testing fails, reflex to Pendred |
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When will a temporal CT scan help the diagnosis?
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CHARGE syndrome
(Mondini dysplasia, absent vestibular) Pendred syndrome (Mondini dysplasia) |
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Peroxisomal disorders
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Autosomal recessive
Severe progressive hearing loss Retinitis pigmentosa Seizure disorder Elevanted very long chain fatty acids |
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Nonsyndromic hearing loss
Modes of inheritance |
75-85% Autosomal recessive
15-25% Autosomal dominant 1-2% X-linked <1% Mitochondrial |
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In recessive nonsyndromic hearing loss, what percentage have mutations involving DFNB1 locus?
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50-60%
DFNB1 is first-line testing GJB2 (connexin 26) GJB6 (connexin 30) Gap junction proteins |
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GJB2
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Connexin 26
Autosomal recessive In 40% of sporadic cases of deafness Carrier frequency: 4% Ashkenazi Jews (167delT) 2-3% Caucasians (35delG) 1% Japanese (235delC) Are some dominant mutations With ectodermal dysplasia symptoms Ichthyosis Palmoplantar keratoderma Normal nails |
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Evaluating a child with nonsyndromic severe-profound SNHL
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Family history
Evaluate vestibular function If delayed, consider ERG (Usher) Connexin 26/30 mutations CMV testing in neonatal period Optho exam for CMV scarring Can't look for retinitis pigmentosa till age 10 CT scan of temporal bone if progressive (CHARGE, Pendred) EKG for Jervell Lange-Nielsen |
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Thanatophoric dysplasia
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De novo FGFR3 mutations
Autosomal dominant Short-limbed dwarfism Micromelia Type I: bowed femurs Cloverleaf skull deformity Short ribs, narrow thorax Macrocephaly Distinctive facial features Brachydactyly Hypotonia Redundant skin folds on limbs Death by respiratory insufficiency shortly after birth |
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Hemophilia A
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Factor VIII deficiency
The more common one (80% of cases) Inversion of exon 22 affects 50% of severe, 20% all Small gene defects 75% all No promoter mutations 1/5000 males Big gene product (2332 amino acids) |
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Hemophilia B
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Factor IX deficiency
Small gene defects Only 2% deletions 1/20,000 males Smaller gene product: 415 amino acids |
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von Willebrand disease
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AUTOSOMAL DOMINANT
1% of the population This is a carrier for factor VIII Causes platelets to adhere to e/o and to damaged endothelium 1/100 F=Male since autosomal A total lack of von Willebrand factor looks like Hemophilia A |
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Features of hemophilias
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X-linked recessive
30% of cases are new mutations Expressed in males Carried by females Severity CONSISTENT between family members Less than 50% of factor level causes disease Severe when <1% enzyme activity |
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Treatment of hemophilias
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Replace missing clotting protein
Intravenously Antifibrinolytic agents to make clots stable More deletions in hemophilia A (factor VIII) so get antibodies formed to infused clotting factors in 20-30% patients |
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How are hemophilias and vWD different?
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Hemophilia A and B: X-linked recessive
von Willebrand: Autosomal Dominant |
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Factor V Leiden Thrombophilia
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Increased clotting
Makes Factor V resistant to Protein C degradation Deep venous thrombosis Can be heterozygote Or homozygote (higher risks) Heterozygosity risks 2-3x: Pregnancy loss Perhaps: Preeclampsia Fetal growth retardation Placental abruption |
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General rule about sporadic X-linked disorders
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2/3 of time mom is a carrier
--mutation occurred in HER FATHER 1/3 of time new mutation --mutation occurred in MOM |
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Conditions with thoracic aortic aneurysm and mitral valve prolapse
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Marfan
Ehlers-Danlos Loeys-Dietz |
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Most common cause of inherited intellectual disability?
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Fragile X
1/4000 males 1/6000 females |
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Where is the Fragile X repeat location?
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In the promotor region
CpG shuts down gene activity |
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Cystic fibrosis symptoms
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Pulmonary
Pancreatic Gastrointestinal Biliary Reproductive system Cough, wheezing Failure to thrive Loose fatty stools Abdominal main Male infertility due to Congenital absence of vas deferens Only 15% are pancreatic sufficient Have a milder course 1300 mutations identified 23 mutation panel detects 94% in AJ 88% other Caucasian |
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Spinal muscular atrophy (SMA)
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LEADING GENETIC CAUSE OF INFANT DEATH
Autosomal recessive SMN1 gene deletion (95%), conversion, mutation "Survival motor neuron gene" Accurate phenotype prediction not possible SMN2 mRNA missing exon7 10% SMN2 normally spliced Rescues 0 copies, Lethal 2 Copies, Type I 4 copies, Type II 4-8 copies, Type III 1/10,000 incidence 1/50 carrier frequency Tongue fasciculation Weakness, poor suck and swallow Aspiration pneumonia Death: Respiratory failure Range of severity Type I-III Type II most common, onset by age 2, sit not walk, die adolescence 3-4% of pop has 2 copies of SMN1 on one chromosome Not ID as carriers ACMG, NOT ACOG, recc offer to all ACOG: Family history, or request it |
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Diastrophic dysplasia
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Autosomal RECESSIVE
SLC26A2 sulfate transporter Cystic ears Hitchhiker thumbs Limb shortening Normal-sized skull Slight trunk shortening Hitchhiker thumbs Small chest Protuberant abdomen Contractures of large joints Dislocation of the radius Cleft palate (in approximately one-third of individuals) Cystic ear swelling in the neonatal period (in approximately two-thirds of infants with classic findings) Other usual findings: ulnar deviation of the fingers, gap between the first and second toes, clubfoot, and flat hemangiomas of the forehead |
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Diseases in which male gametes are more often mutated than female gametes
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Hemophilia A (Factor VIII)
Lesh-Nyhan syndrome |
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Lesch-Nyhan syndrome
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NOT a deletion syndrome
HPRT enzyme X-linked recessive Persistent self-injurious behavior (biting the fingers, hands, lips, and cheeks; banging the head or limbs) Motor dysfunction Resembles cerebral palsy Cognitive and behavioral disturbances Hyperuricemia Hypotonia and developmental delay Most never walk Dystonia Choreoathetosis Pyramidal involvement (e.g., spasticity, hyperreflexia, extensor plantar reflexes) become evident Hyperuricemia with kidney stones Renal failure |
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Huntington's
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HTT gene
1/20,000 people CAG repeats (exon 1) Polyglutamine Toxic HTT protein, apoptosis Forms inclusion bodies in brains Basal ganglia and limbic system Dysarthria - difficulty talking, slurring speech Dysphagia - difficulty swallowing Anticipation through the father Chorea, movement disorder, tics, grimaces Cognitive deficits, loss executive function Psychiatric/emotional disturbances Depression, disinhibition 35-45 years at onset |
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What are the repeat diseases?
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Huntington's CAG (in coding region, polyglutamine)
TOXIC PROTEIN, apoptosis Fragile X CGG (5' untranslated region) Myotonic Dystrophy CTG (3' downstream untranslated, gene silencing, toxic RNA) Friedreich Ataxia GAA (intronic, terminates transcription) Polyglutamine: Huntington Kennedy disease Spinocerebellar Ataxia (except type 8) Spinobulbar muscular atrophy |
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Huntington's repeat sizes
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10-26 Normal
27-35 Pre-mutation 36-39 Reduced penetrance 40 Mutation 60 Juvenile onset PCR can detect up to 100 repeats Southern blot for larger |
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Frontotemporal dementia
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10% of cases AD
5% have MAPT (tau) mutation --missense, toxic gain of function 5% have GRN mutation --haploinsufficiency of progranulin ubiquitin inclusions Most common dementia <60 Younger than Alzheimer's Atrophy of frontal lobes Progressive decline in Memory Language Executive function (judgment, planning) Visuospatial Disinhibition Later apathy |
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Tuberous Sclerosis
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TSC1 and TSC2 sequencing
(Hamartin and Tuberin) Autosomal dominant 2/3 de novo Angiofibroma Shagreen patch Subependymal glial nodules Cortical tubers Astrocytoma Seizures Angiomyolipomas Cardiac rhabdomyoma TSC2/PCKD contiguous gene deletion with features of TS, PKD |
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Leopard syndrome
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PTPN11 (SHP2 protein, loss of function)
OPPOSITE of Noonan mutations Autosomal dominant Lentigenes Electrocardiographic conduction anomalies Ocular hypertelorism Pulmonary stenosis Abnormal genitalia Retardation of growth Deafness, sensorineural |
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Noonan syndrome
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PTPN11 GAIN of function
Activating mutations Ras/MAPK pathway (opposite of Leopard) SOS1 KRAS CRAF1 Autosomal dominant 1/1000-1/2500 Increased risk leukemia Rhabdomyosarcoma Neuroblastoma "Male Turner Syndrome" Learning disabilities (25%), delayed speech Short stature Pulmonary valve stenosis (50%) Hypertrophic cardiomyopathy (30%) Cryptorchidism Renal malformation Lymphedema Scoliosis Bleeding disorders Tall forehead Hypertelorism Down slanting palpebral fissures Low-set posteriorly rotated ears Deep philtrum Short neck |
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EDS Type VI
Kyphoscoliotic type |
PLOD1
Deficiency in enzyme crosslinks collagen Autosomal RECESSIVE Marfanoid habitus Rupture of medium-sized arteries Aortic root dilation Scleral fragility EYE GLOBE RUPTURE Joint laxity Hyperextensible, friable skin Widened, atrophic scars Easy bruising Scoliosis |
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FGFR-related craniosynostosis
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FGFR1, 2, 3
Increased mutations with paternal age Autosomal dominant inheritance Bicoronal craniosynostosis or Cloverleaf skull Variable hand and foot anomalies Developmental delay Hearing loss Visual impairment--cranial nerve compression Otitis media MR (greatest risk in Alpert) Hypertelorism Proptosis Downslanting palpebral fissures Midface hypoplasia Choanal atresia Prognathism Small beaked nose High arched palate Cleft palate or bifid uvula |
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FGFR1
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5% Pfeiffer 1
Pro252Arg |
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FGFR2
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Crouzon-shallow orbits, significant proptosis
Normal intellect Normal hands and feet Acanthosis nigricans if FGFR3 mutation Apert "Mitten hands, feet" syndactyly bone and soft tissue Thumbs broad, radially deviated Rhizomelic shortening Midline calvarial defect 50% have MR Pfeiffer 1 (95%), 2 and 3 Variable brachydactyly Broad, medially deviated thumbs and big toes Type 2 has cloverleaf skull Hydrocephalus, seizures, MR common Jackson-Weiss FGFR2-related acanthosis nigricans |
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FGFR3
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Muenke
Screen all patients with nonsyndromic coronal synostosis Does not have distinctive facial features Pro250Arg activating mutation May be carpal or tarsal fusion Thumbs normal Big toes may be broad |
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Achondroplasia
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Activating FGFR3 mutations
Paternal origin (age) 99% have G380R mutation Most common disease-causing mutation in human genome 80% de novo Inhibits chondrocyte proliferation Thanatophoric dysplasia mutations More strongly activating |
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Most common form of craniosynostosis
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60% of nonsyndromic
is isolated saggital 1/5000 births Males 3:1 |
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Second most common form of craniosynostosis
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Isolated coronal
20-30% of all nonsyndromic 1/10,000 births Females predominate |
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What are the FGFR proteins?
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Receptor tyrosine kinases
Dimerize when bind FGF Gain of function mutations Enhance dimerization Enhance FGF binding Make less specific for FGF |
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What is TWIST1?
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Basic helix-loop-helix (bHLH)
transcription factor Mesoderm differentiation Causes Saethre-Chotzen syndrome Autosomal dominant TWIST happloinsufficiency Coronal craniosynostosis |
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RasGap protein we know in a different disease?
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NF1
50% de novo Neurofibromin haploinsufficiency Once Ras is activated, RasGaps turn it off Regulates cell cycle progression Transcription Differentiation Survival Motility Mitogen-activated protein pathway Puts the breaks on |
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NF1
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1/3500
Cancers: 10% Malignant peripheral nerve sheath tumors Pheochromocytoma, etc... 6 or more CAL >5mm prepubertal (>15mm postpubertal) Axial and inguinal freckling Two or more neurofibromas of any type (85%) Or one plexiform neurofibroma (15%) Two or more Lisch nodules Optic glioma Tibial pseudarthrosis Learning disabilities 50-75% May have Noonan-like CV defects |
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Cardiovascular anomalies with Ras/MAPK pathway
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Pulmonic stenosis
Aortic coarctation ASD VSD Tetralogy of Fallot Conotruncal defects Mitral valve prolapse EKG abnormalities LV hypertrophy |
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CFC
Cardio-facio-cutaneous syndrome |
BRAF-moles
MEK1 MEK2 KRAS Characteristic facial features Ptosis Earlobe creases Deep philtrum, cupid's bow lip Sparse, curly, fine hair or Thick, WOOLY, brittle ABSENT eyebrows and eyelashes Heart defects Skin hemangiomas, keratosis Pigmented moles Hypotonia Motor and speech delay Learning disability in 100% Ptosis, strabismus, nystagmus Seizures Ventriculomegaly, hydrocephalus |
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Legius
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NF1-like syndrome
SPRED1 haploinsufficiency A negative regulator of Ras-Raf Autosomal dominant Cafe au lait macules Axillary freckling Macrocephaly NS-like facies NO LISCH NODULES NO NEUROFIBROMAS NO CNS TUMORS |
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Syndromes associated with neural tube defects
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Meckel-Gruber
Most common syndromic cause RECESSIVE Renal cysts, hepatic duct dysplasia Polydactyly Walker-Warburg Syndrome RECESSIVE Congenital muscular dystrophy Spine rigidity Ocular abnormalities Waardenburg Syndrome DOMINANT SOME RECESSIVE |
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Heritability
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Autism >90%
Schizophrenia 90% Bipolar disorder 90% ADHD 80% OCD 50% Major depressive disorder 40% Depression 10% pop 20% if sib with it |
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Autism causes
1/1000 1/160 for ASD Males predominate 90% idiopathic 10% can find a genetic cause 2-8% recurrence risk for sibs When idiopathic Very high heritability |
Start with aCGH
Fragile X Metabolic studies MECP2, PTEN, TSC1/2, CACNA1C, NF1 Panels for X-linked intellectual disability Neurexin (autosomal), Neurolignin (x-linked) Multifactorial Fragile X (1-3% all autistic kids) 22q11.2 (20% have autism) Tuberous sclerosis MECP2 Rett syndrome Smith-Lemli-Opitz PKU Maternal 15q DUPLICATION PW/Angelman critical region (most common chromosomal reason) 1-3% of children with autism Trisomy 21 PTEN with macrocephaly Sotos syndrome Timothy syndrome NF1 16p11.2 deletions |
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Neonatal Marfan
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FBN1
Aged appearance Arachnodactyly Contractures Valvular disease, severe progressive: Mitral, tricuspid Emphysema Diaphragmatic hernia |
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Mitral valve disease
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Ehlers-Danlos
Loeys-Dietz Marfan |
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Polyvalvular disease
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Neonatal Marfan
Trisomy 18 |
