Repro Exam 1: Genetic Fact Sheets 1-7

Front 1

clinical features of DMD

Back 1

progressive muscle-wasting dz, confinement to wheelchair by 13yo, 1st sx: gross motor delays, gait abnormalities, gower maneuver, calf hypertrophy; cognitive impairment (decreased working memory, exec fcn)

Front 2

what is the difference between duchenne and becker muscular dystrophy?

Back 2

BMD has a slower progression, later onset, and longer lifespan

Front 3

cardiovascular features of DMD

Back 3

cardiomyopathy by 18yo --> mean age of death in mid-40s by CV or resp failure

Front 4

incidence of DMD

Back 4

1/3500 male births, female carriers ~1/1500. DMD is the MOST COMMON childhood muscular dystrophy.

Front 5

DMD inheritance basics

Back 5

x-linked. ~2/3 of mothers are carriers, ~1/3 from new mutations. DMD is genetic lethal --> affected males don't reproduce

Front 6

DMD mutations: hetero or homogeneous? what gene? what is the gene product?

Back 6

allelic heterogeneity. gene located on Xp21. gene codes for dystrophin. (interesting pearl: general rule is that mutations that alter reading frame result in DMD, those that don't result in BMD)

Front 7

lab testing for DMD

Back 7

DNA analysis by MLPA for deletions and duplications. If neg, mutation scanning/sequencing for other mutations. (microarray also option, but MLPA is preferred.) other testing: CK usually high, dystrophin on muscle bx can confirm dx in absence of mutation. prenatal dx/carrier testing available.

Front 8

management of DMD

Back 8

no proven effective treatment. PT assessment, eval for cardiomyopathy, developmental eval, bone health, pulm fcn, etc. may consider prednisone to improve strength

Front 9

counseling of DMD

Back 9

germline mosaicism estimated to occur in 15% --> risk for 2nd male affected is ~7%. identify other females at risk for being carriers. ~1/4 of carriers show mild symptoms --> should be tested for cardiac dz.

Front 10

clinical features of fragile X

Back 10

phenotype variable, becomes more pronounced w/age. mild-severe developmental delay, males usually more severely affected than females, hyperactivity, lack of eye contact, repetitive behaviors, autism

Front 11

physical features of fragile X

Back 11

prominent forehead, long thin face w/prominent jaw, large protuberant ears, post-pubertal macroorchidism (note: features more evident in late childhood/early adolescence)

Front 12

patients w/fragile X are at increased risk for ___

Back 12

seizures, ocular problems (strabismus, hyperopia, astigmatism), recurrent otitis media, orthopedic problems, mitral valve prolapse

Front 13

incidence of fragile X

Back 13

1/4000 males, 1/8000 females

Front 14

inheritance of fragile x

Back 14

x-linked w/anticipation due to trinucleotide repeat expansion. all affected individuals will have a parent w/an expanded allele

Front 15

mutation in fragile X

Back 15

expansion of CGG trinucleotide repeat in 1st exon of FMR1 gene on xq27. repeat sizes - 5-44: normal, 45-54: intermed, 55-200: premutation, 200+ and highly methylated: full mutation

Front 16

when do premutations in fragile x expand into full mutations?

Back 16

ONLY when inherited from a premutation carrier female. higher repeat size in premutation range --> higher chance for full expansion in next generation

Front 17

lab testing for fragile X

Back 17

southern blot for full and premutations, approx of repeat # and methylation status. PCR for normal and small premutation allele estimation. new PCR techniques may replace southern blotting. prenatal testing and carrier testing available

Front 18

what are some counseling issues for fragile x?

Back 18

carrier females may want to be tested in adolescence --> assoc w/premature ovarian failure. ~40% of premutation males >50yo develop fragile x-assotiated tremor/ataxia syndrome (FXTAS) and a small % of premutation females

Front 19

clinical features of huntington disease

Back 19

progressive d/o of cognition, motor, and psych disturbance. 2/3 affected individuals initially present w/neuro features, 1/3 present w/psych changes (depression, irritability). gait disturbance, progressive chorea, dysarthria, global decline in cognitive abilities, personality changes --> late stages: wt loss, total dependence, no speech, dysphagia

Front 20

onset of huntingtons

Back 20

mean age: 35-44, 25% w/late onset (>50), 10% have juvenile onset (<21, w/seizures + more rapid decline).

Front 21

huntingtons survival

Back 21

median: 15-18 yr.s after age onset. avg. age of death is 55yo. SUICIDE RATE is up to 12%

Front 22

incidence of huntingtons

Back 22

3-7/100,000 in those of w. european descent. less in asia and africa

Front 23

huntingtons inheritance

Back 23

autosomal dominant. new mutations are rare (most have affected parent). anticipation characteristic.

Front 24

huntingtons mutation

Back 24

expansion of CAG triplet repeat w/in HD gene on chromosome 4p. inverse correlation b/w # of repeats and age of onset

Front 25

describe anticipation in HD

Back 25

normal <26 CAG repeats, adult onset is 40-59 repeats, juvenile onset >60 repeats. expansions more likely to occur during paternal gametogenesis --> juvenile onset HD ~exclusively inherited through affected fathers

Front 26

lab testing for huntington disease

Back 26

PCR detects repeat #

Front 27

counseling of HD

Back 27

genetic testing of asymptomatic individuals is predictive, not diagnostic. cannot test asymptomatic children --> risks stigmatization w/in and outside family, no clear benefit. there are very specific protocols for giving this dx to minimize long-term psych. damage.

Front 28

incidence of down syndrome (if you are going to learn 1 disease's incidence, let it be this one!)

Back 28

1/800 newborns

Front 29

clinical features of down syndrome

Back 29

variable, but include: dysmorphic features, microcephaly/brachycephaly, intellecutal disability (mostly moderate, IQ ~50%), hypotonia, short stature, congenital heart defects (50%), hearing problems (75%), vision problems (60%), sleep apnea (50-75%), GI atresias, hypothyroidism, seizures, hematologic problems, celiac dz, alzheimer dz in middle age...

Front 30

describe the dysmorphic features associated w/down syndrome

Back 30

upslanting palpebral fissures, epicanthal folds, brushfield spots (eyes), flat nasal bridge, small dysplastic ears, large tongue/small mouth, excess nuchal skin, short fingers, 5th finger clinodactyly, wide space b/w 1st and 2nd toes, single transverse palmar creases

Front 31

inheritance pattern of down syndrome

Back 31

chromosomal

Front 32

mutations in down syndrome (name all 3 options - give the %s)

Back 32

95% have TRISOMY 21, most caused by maternal meiotic nondisjunction. 3-4% due to TRANSLOCATION (14;21 most common), ~3/4 of translocations are de novo and 1/4 from balanced translocation carrier. 1-2% MOSAIC w/normal cell line.

Front 33

lab tests for down

Back 33

karyotyping. peripheral blood karyotype detects almost all cases. prenatal dx available w/cells obtained w/CVS or amniocentesis

Front 34

down syndrome management

Back 34

there's a ton. important things include down syndrome growth chart, heart, vision, cerv. spine x-rays, developmental intervention

Front 35

counseling for down syndrome

Back 35

if trisomy 21, review recurrence risk (women <30 have 8x age-related risk/~1%, women >30 have 2x age-related risk). prenatal dx available. if translocation, may want to karyotype parents and notify relatives as appropriate. refer to national and local support groups

Front 36

prenatal features of turner syndrome

Back 36

45,X karyotype assoc. w/cystic hygroma, severe lymphedema, hydrops fetalis, high risk of fetal demise

Front 37

clinical features of turner syndrome

Back 37

webbed neck, congen heart defects (coarctation of aorta common), short stature, scoliosis, delayed puberty and epiphyseal fusion, infertility/anovulation, increased risk for cognitive deficits (but not MR), assoc. w/renal structural abnormalities

Front 38

incidence of turner syndrome

Back 38

1/2500 female live births. 1-2% of all conceptions, 6-7% of all SABs

Front 39

inheritance of turner syndrome

Back 39

chromosomal

Front 40

mutations in turner syndrome

Back 40

~50% have 45,X karyotype, most caused by paternal meiotic non-disjunction. various mosaics possible (46,XX, 46,XY, 47,XXX)

Front 41

counseling for turner

Back 41

recurrence risk <1% for future pregnancy. most girls w/turner syndrome are infertile. consider growth/sex hormone replacement (often not needed).

Front 42

management issues for turner syndrome

Back 42

all the usual (cardiac, thyroid, scoliosis...). also if karyotype includes Y chromosome, increased risk for gonadoblastoma. may want to consider sex/growth hormone replacement - refer to peds endocrinologist

Front 43

clinical features of 22q11.2 deletion syndrome

Back 43

variable phenotype (inter- and intrafamilial variability). features include congenital heart disease (commonly conotruncal malformation e.g., tetraology of fallot), palatal abnormalities, feeding difficulties/dysphagia, hypocalcemia (can lead to seizures), immune deficiency, facial features, cognitive disabilities (nl-moderate, can see autism), and others

Front 44

incidence of digeorge

Back 44

1/4000

Front 45

inheritance pattern of digeorge syndrome/velocardiofacial syndrome

Back 45

chromosomal (microdeletion). ~7% inherited from a parent

Front 46

mutation in digeorge

Back 46

deletion w/in 22q11.2. ~85% have a 3mB deletion, ~10% have smaller nested deletions. <1% have chromosome rearrangements. ? some people may have point mutations

Front 47

lab testing for digeorge

Back 47

FISH for 22q11.2 deletion. deletions may be detected by microarray if phenotype is non-specific. prenatal dx available using cells obtained by CVS or amniocentesis

Front 48

management issues for digeorge

Back 48

calcium, PTH, TSH, CBC, immune work-up, ophtho, audiology, renal US, baseline cardiac exam, scoliosis, developmental issues

Front 49

counseling for digeorge

Back 49

recurrence risk <1% if deletion is de novo, 50% if parent carries deletion. may want to refer to 22q and you, etc.

Front 50

facial features assoc. w/22q11.2 deletion

Back 50

prominent nose w/squared nasal root, sml eyes, sml ears w/overfolded helices, malar flatness

Front 51

clinical features of cystic fibrosis

Back 51

chronic lung dz and recurrent infections, pancreatic insufficiency, 15-20% have meconium ileus at birth, male infertility secondary to altered vas deferens, diabetes in 40%, liver dz in 6-10%. mean age of survival ~34yo, usually 2ary to pulm complications

Front 52

how is CF usually diagnosed?

Back 52

newborn screening (immunoreactive trypsinogen assays). can see milder symptoms --> later diagnoses (altough usually by 2yo). dx confirmed w/genetic and sweat testing.

Front 53

incidence of CF

Back 53

1/2500-1/3200 of n. european and ashkenazi jews. much lower in other populations. carrier frequency ranges from 1/25-1/150.

Front 54

mutations in CF

Back 54

allelic heterogeneity w/>1400 mutations in CFTR gene at 7q31.2. delta F508 most common (3 basepair mutation, ~70% CF mutations)

Front 55

inheritance of CF

Back 55

autosomal recessive

Front 56

lab tests for CF

Back 56

gold standard: sweat chloride testing (can be normal w/mild dz). DNA testing usually done w/sweat chloride testing --> standard panel of 23 mutations. detection rate highest in n. european and ashkenazi jewish ethinicity (can detect <90% of carriers). prenatal testing available, best when family mutations are known.

Front 57

management of CF

Back 57

chest physiotherapy, antibiotics, bronchodilators, enzyme and vit replacement, ?lung transplantation

Front 58

counseling of CF

Back 58

review recurrence risks, availability of prenatal dx. carrier testing to other relatives. (false neg common in general population)