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59 Cards in this Set
- Front
- Back
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HARDY-WEINBERG EQUILIBRIUM
ASSUMES? |
① No MUTATION at locus
② No SELECTION for mutant locus ③ No MIGRATION ④ RANDOM mating (completely) |
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If in HARDY-WEINBERG EQUILIBRIUM
DISEASE PREVALENCE |
p² + 2pq + q² = 1
p & q are separate alleles |
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If in HARDY-WEINBERG EQUILIBRIUM
ALLELE PREVALENCE |
p + q = 1
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If in HARDY-WEINBERG EQUILIBRIUM
HETEROZYGOTE PREVALENCE |
2pq
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If in HARDY-WEINBERG EQUILIBRIUM
PREVALENCE of X-LINKED RECESSIVE DISEASE |
q in ♂
q² in ♀ |
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IMPRINTING
DEFECT SYNDROMES |
At a single locus, only 1 allele is ACTIVE
- the other is INACTIVE = IMPRINTED / INACTIVATED by methylation. - DELETION of ACTIVE ALLELE → DISEASE IMPRINTING Syndromes - d/t inactivation / deletion of genes on chr 15 or UNIPARENTAL DISOMY: (1.) PRADER-WILLI (2.) ANGELMAN'S |
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PRADER-WILLI Syndrome
DEFECT CLINICAL PRESENTATION |
DELETION of normally active PATERNAL allele on Chr 15 (or uniparental disomy)
& Imprinted maternal genes Clinical: - Mental retardation - AGGRESSIVE behaviour - HypO-TONIA - HypO-GONADISM - HypER-PHAGIA + OBESITY |
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ANGELMAN'S Syndrome
DEFECT CLINICAL PRESENTATION |
DELETION of normally active MATERNAL allele on Chr 15 (or uniparental disomy)
& Imprinted paternal genes Clinical: "HAPPY PUPPET" - Mental retardation - SEIZURES - ATAXIA - INAPPROPRIATE LAUGHTER |
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MODES of INHERITANCE
AUTOSOMAL DOMINANT |
- Many generations, both sexes, affected
- FHx crucial to Dx Often - PLEIOTROPIC - d/t defects in STRUCTURAL GENES - Present AFTER PUBERTY |
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MODES of INHERITANCE
AUTOSOMAL RECESSIVE |
- 25% of offspring from 2 CARRIER parents affected
- seen in only 1 generation Often - d/t ENZYME DEFICIENCIES - more SEVERE vs dominant disorders - Present in CHILDHOOD |
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★ AUTOSOMAL RECESSIVE DISEASES ★
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[MATCH the GAPSS]
MUCOPOLYSACCHARIDOSES (except Hunter's) ARPKD THALASSEMIAS CYSTIC FIBROSIS HEMOCHROMATOSIS GLYCOGEN STORAGE Dzs ALBINISM PHENYLKETONURIA SICKLE CELL ANAEMIAS SPHINGOLIPIDOSES (except Fabry's) |
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MODES of INHERITANCE
X-LINKED RECESSIVE |
- 50% of SONS from HETEROz MOTHERS
- NO ♂-to-♂ transmission - Often more SEVERE in ♂ - HETEROz ♀ rarely affected d/t RANDOM INACTIVATION of an X Chr in each cell |
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★ X-LINKED RECESSIVE DISORDERS ★
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[Be Wise, Fools GOLD Heeds silly Hope]
BRUTONS AGAMMAGLOBULINEMIA WISKOTT-ALDRICH Syndrome FABRY'S Dz G6PD Deficiency OCULAR ALBINISM LESCH-NYHAN Syndrome DUCHENNE'S / BECKER'S HUNTER'S Syndrome HAEMOPHILIA A/B |
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MODES of INHERITANCE
X-LINKED DOMINANT |
- Transmitted thru BOTH PARENTS
- ♂/♀ offspring from affected MOTHER may be affected - ALL ♀ offspring of affected FATHER are diseased Eg. HYPO-PHOSPHATEMIC RICKETS = Inherited d/o → ↑ PO₄ WASTING at PROXIMAL TUBULE → RICKETS-like presentation |
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MODES of INHERITANCE
MITOCHONDRIAL INHERITANCE |
- Transmitted ONLY thru MOTHER
- ALL offspring of affected mother may show signs of dz - Variable expression in population d/t HETEROPLASMY Eg. Mitochondrial Inheritance Diseases: ① Mitochondrial myopathies ② Leber's Hereditary Optic Neuropathy |
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LEBER'S HEREDITARY OPTIC NEUROPATHY
MODE of INHERITANCE PATHOGENESIS |
MITOCHONDRIAL INHERITANCE
- Degeneration of RETINAL GANGLION cells + AXONS → ACUTE CENTRAL VISION LOSS & WPW Syndrome |
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ACHONDROPLASIA
MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT
CELL-SIGNALLING defect of FGFr3 (fibroblast growth factor receptor 3). Clinical: - DWARFISM (short limbs) - normal head & trunk size - a/w PATERNAL AGE |
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ADPKD
MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DZ
- 90% d/t defective APKD1 Chr 16 [16 letters in "polycystic kidney"] Clinical: - BILATERAL kidney enlargement d/t multiple large cysts - FLANK PAIN - HTN - HEMATURIA - RENAL FAILURE |
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ADPKD
ASSOCIATED CONDITIONS |
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DZ
Associated w/: - BERRY ANEURYSMS - MITRAL VALVE PROLAPSE - POLYCYSTIC LIVER DZ |
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FAMILIAL ADENOMATOUS POLYPOSIS
(FAP) MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT
Chr 5 deletion of APC gene → → Error in DNA repair. [5 letters in "polyp"] Clinical: - Adenomatous polyps cover colon after puberty → COLON Ca unless resected. |
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FAMILIAL HYPERCHOLESTEROLEMIA
MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
Absent / ⇊ LDL RECEPTORS (AD)
→ → ⇈LDL Clinical: "Hypercholesterolemia" - elevated bld cholesterol ⁂ Heteroz: chol ~300 mg/dL ⁂ HOMOz: chol ~700. -- ACRUC - corneal -- Achilles / eyelid XANTHOMAS -- Accelerated ATHEROSCLEROSIS, AMI early |
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HEREDITARY HEMORRHAGIC TELANGECTASIA
(OSLER-WEBER-RENDU Syndrome) MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT
- Disorder of BLOOD VESSELS. Clinical: [STAR] - Skin discolouration - TELANGIECTASIA - AVMs - Recurrent EPISTAXIS |
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HEREDITARY SPHEROCYTOSIS
MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT
- SPECTRIN / ANKRIN defect → → SPHEROID RBCs Clinical: - HAEMOLYTIC ANAEMIA - ↑MCHC - SPLENECTOMY = curative |
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HUNTINGTON'S DISEASE
MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT
- Chr 4 (CAG)x trinucleotide repeat disorder → ↓GABA & ↓ACh in brain → CAUDATE ATROPHY Clinical: - Onset 20 - 50 yo - CHORIEFORM movement - DEPRESSION - Progressive DEMENTIA |
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MARFAN'S SYNDROME
MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT
- FIBRILLIN gene mutation. Clinical: (+ pectus EXCAVATUM) [MARFAN'S] -- MITRAL VALVE Prolapse -- Ao Incompetence + ANEURYSMS d/t cystic medial Ao necrosis -- Retinal detachment -- FIBRILLIN gene mutation -- ARACHNODACTYLY (= tapering fingers + toes) -- Neg Nitroprusside test (vs homocystinuria) -- SUBLUX LENS |
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NEUROFIBROMATOSIS Type 1
(von Recklinghausen's disease) MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT
- LONG ARM of Chr 17 Clinical: - CAFE-AU-LAIT spots - LISCH nodules (pigmented iris hamartomas) - OPTIC pathway GLIOMAS - NEURAL TUMOURS - SCOLIOSIS (skeletal d/o) |
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NEUROFIBROMATOSIS Type 2
MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT
- NF2 gene on Chr 22. [Type 2 = 22] Clinical: - Bilateral ACOUSTIC SCHWANNOMAS - JUVENILE CATARACTS |
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TUBEROUS SCLEROSIS
MODE of INHERITANCE CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT
- INCOMPLETE penetrance - VARIABLE presentation Clinical: - ADENOMA SEBACEUM (facial lesions) - 'ASH LEAF SPOTS' (hypopigmented skin) - Renal ANGIOMYOLIPOMAS + CYSTS - ↑ASTROCYTOMAS incidence - CORTICAL + RETINAL HAMARTOMAS - Cardiac RHABDOMYOMAS (= hamartoma) - SEIZURES |
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von HIPPEL-LINDAU DISEASE
MODE of INHERITANCE DEFECT CLINICAL PRESENTATION |
AUTOSOMAL DOMINANT
- Deletion of VHL gene on Chr 3 (= tumour suppressor) → constitutive expression of HIF (= TF) & → ANGIOGENIC GF activation. Clinical: - HEMANGIOBLASTOMA of RETINA / CEREBELLUM / MEDULLA - BILATERAL RCC (50%) |
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CYSTIC FIBROSIS
MODE of INHERITANCE DEFECT |
AUTOSOMAL RECESSIVE
⁂ Most common lethal genetic dz in Caucasians CFTR channel actively - SECRETES Cl⁻ in LUNGS + GIT - REABSORBS Cl⁻ from SWEAT DEFECT: - Deletion of Phe at position 508 in CFTR gene on Chr 7. → Abn PROTEIN FOLDING → CFTR Cl⁻ channel DEGRADED ā reaching plasma membrane → Defective Cl⁻ channel → secrete abnormally THICK MUCUS |
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CYSTIC FIBROSIS
DIAGNOSIS & TREATMENT |
Diagnosis =
PCR of the Chr 7 mutation &/OR ↑↑[Cl⁻] ions in SWEAT TEST Treatment = N-ACETYL-CYSTEINE (cleaves DISULFIDE bond in mucous GLYCOPROTEINS) |
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CYSTIC FIBROSIS
CLINICAL PRESENTATION |
① Recurrent PULMONARY infx (S. aureus, Pseudomonas)
→ Chronic BRONCHITIS & BRONCHIECTASIS ② PANCREATIC INSUFFICIENCY → (MALABSORPTION + STEATORRHEA) → Fat soluble VIT (A,D,E,K) deficiency ③ ♂ INFERTILITY -- d/t BILATERAL absence of VAS DEFERENS ④ MECONIUM ILEUS (newborns) |
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DUCHENNE'S MUSCULAR DYSTROPHY
DEFECT Mode of INHERITANCE |
DYSTROPHIN helps ANCHOR SKELETAL + CARDIAC mm fibers
DEFECT: (X-linked RECESSIVE) X-linked FRAME SHIFT mutation → DYSTROPHIN (DMD) gene DELETION → ACCELERATED MM BREAKDOWN DYSTROPHIN gene = LONGEST known human gene → ⇈susceptible to mutation |
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DUCHENNE'S MUSCULAR DYSTROPHY
CLINICAL PRESENTATION & DIAGNOSIS |
- PELVIC GIRDLE wkness (progresses SUPERIORLY)
- CALF PSEUDO-HYPERTROPHY - CARDIAC myopathy - GOWER'S maneuver use characteristic - ONSET before 5 yo Diagnosis = ⇈CPK & MUSCLE BIOPSY |
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BECKER'S MUSCULAR DYSTROPHY
DEFECT Mode of INHERITANCE |
DEFECT: (X-linked RECESSIVE)
X-linked DYSTROPHIN (DMD) gene MUTATION - less severe than not having gene at all (= Duchenne's) - ONSET = ADOLESCENCE / EARLY ADULT |
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FRAGILE X SYNDROME
Mode of INHERITANCE DEFECT CLINICAL PRESENTATION |
X-linked RECESSIVE defect affecting
FMR1 gene METHYLATION - a/w Chr breakage - (CGG)x repeats Clinical: [MALE] - MACRO-ORCHIDISM - MITRAL PROLAPSE - AUTISM - LONG FACE, LARGE JAW - EVERTED EARS |
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What are the
★ TRINUCLEOTIDE EXPANSION DISEASES ★ |
[Hunting for My Fried X]
HUNTINGton's dz = (CAG)x MYo[t]onic dystrophy = (CTG)x FRIEDrich's [a]taxi[a] = (GAA)x fra[g]ile X syndrome = (CGG)x |
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Which condition has (CAG)x repeats?
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(CAG)x repeats = HUNTINGTON'S DZ
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Which condition has (CTG)x repeats?
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(CTG)x repeats = MYO[T]ONIC DYSTROPHY
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Which condition has (CGG)x repeats?
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(CGG)x repeats = FRA[G]ILE X Syndome
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Which condition has (GAA)x repeats?
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(GAA)x repeats = FRIEDRICH'S ATAXIA
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What is the INCIDENCE of trisomy 21?
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Trisomy 21 = DOWN Syndrome
1 : 700 |
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What is the INCIDENCE of trisomy 18?
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Trisomy 18 = EDWARDS' Syndrome
1 : 8,000 |
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What is the INCIDENCE of trisomy 13?
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Trisomy 13 = PATAU'S Syndrome
1 : 15,000 |
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TRISOMY 21
CLINICAL PRESENTATION |
[DEAD FACTS]
Dumb - Mental retardation EPICANTHAL FOLDS ALZHEIMER'S Dz - early DUODENAL ATRESIA FLAT facies ALL - ↑ risk (acute lymphoblastic leukemia) Congenital heart dz (usu SEPTUM PRIMUM-type ASD) TOE GAP 1st-2nd SIMIAN CREASE |
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TRISOMY 21
CAUSES |
95% = NON-DISJUNCTION of homologous chr (trisomy 21)
-- a/w ↑MATERNAL AGE 4% = ROBERTSONIAN TRANSLOCATION 1% = DOWN MOSAICISM -- NO maternal assoc |
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How is Trisomy 21 reflected in the quad screen?
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↓ AFP
↓ ESTRIOL ↑ β-hCG ↑ INHIBIN A |
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What is the clinical presentation of trisomy 18?
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[EDWARDS']
Eighteen = trisomy 18 Digit overlapping flexion = ★ CLENCHED HANDS Wide head = prominent occiput Absent intellect - severe MR Rocker-bottom feet Diseased heart = Congenital heart dz Small jaw = ★ MICROGNATHIA DEATH by 1 yo |
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What is the clinical presentation of trisomy 13?
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★ CLEFT LIP / PALATE
★ HOLO-PROSENCEPHALY ★ POLYDACTYLY Micropthalmia Microcephaly Mental retardation - severe Rocker-bottom feet Congenital heart disease DEATH by 1 yo |
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If NONDISJUNCTION of Chr 21 occurs at ANAPHASE I,
what are the chances of OFFSPRING being affected? |
100 %
50% = n+1 50% = n-1 |
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If NONDISJUNCTION of Chr 21 occurs at ANAPHASE II,
what are the chances of OFFSPRING being affected? |
50%
25% = n-1 25% = n+1 |
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What is a ROBERTSONIAN TRANSLOCATION?
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LONG ARMS of 2 ACROCENTRIC Chr FUSE at the CENTROMERE
→ SHORT ARMS are lost (= NON-RECIPROCAL Chr translocation) ACROCENTRIC Chr = Chr w/ centromeres near their ends - BALANCED translocations → normal phenotype - UNBALANCED translocations → miscarriage, stillbirth, Trisomy syndromes |
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Which Chr are MOST OFTEN involved in ROBERTSONIAN TRANSLOCATIONS?
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13, 14, 15
21, 22 |
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What is a possible result in chromosomal inversions?
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↓FERTILITY
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CRI-DU-CHAT Syndrome
DEFECT CLINICAL PRESENTATION |
Congenital microdeletion of SHORT ARM of chr 5
(46,XX or XY,5p--) CLINICAL: HIGH PITCHED CRYING / mewing ("cry of the cat") EPICANTHAL folds MICROCEPHALY Mental retard-mod-severe Cardiac abnormalities |
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WILLIAMS Syndrome
DEFECT CLINICAL PRESENTATION |
Microdeletion of LONG ARM of chr 7
(includes ELASTIN gene) CLINICAL: [CDEFGH] Cardiac abnormalities Dumb - mental retardation "ELFIN" facies FRIENDLY - extremely GLIB - well developed VERBAL SKILLS HYPERCALCEMIA d/t ↑ Vit D sensitivity |
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22q11 DELETION Syndromes
DEFECT CLINICAL PRESENTATION |
Microdeletion at Chr 22q11 →
ABN development of 3rd + 4th BRACHIAL POUCHES CLINICAL: [CATCH-22] CLEFT PALATE ABN FACIES THYMIC APLASIA → T-cell deficiency CARDIAC defects HypO-CALCEMIA 2° to PARATHYROID APLASIA |
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DiGEORGE Syndrome
DEFECT CLINICAL PRESENTATION |
22q11 deletion.
[CATCH-22] THYMIC APLASIA → T-cell deficiency HypO-CALCEMIA 2° to PARATHYROID APLASIA CARDIAC defects |
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VELOCARDIOFACIAL Syndrome
DEFECT CLINICAL PRESENTATION |
22q11 deletion.
CLEFT PALATE ABN FACIES CARDIAC defects |
