Diseases (Mutations, Phenotypes, etc.) Flashcards
Down Syndrome Mutation
Trisomy 21. 3-4% unbalanced 21 translocation. 1% mosaic trisomy. Associated with maternal age, Caused by abnormal non-disjunction (chiasmata too close or too far from centromere)
Down Syndrome Phenotype
Rate: 1/800 live births
Normal Size, Midface Hypoplasia, Upslanting Palpebral Features, Epicanthal folds, Small Ears, Large Tongue, Low Muscle Tone, Short Fingers, Increased Joint Mobility, Transverse Palmar Crease,
Down Syndrome Complications
Cardiac: 50%, atrioventricular canal common
GI: 10-15%, structural abnormalities (dudenal artresia) and feeding problems, GERD, constipation
Ophthalmic: blocked tear ducts, myopia, lazy eye, nystagmus, cataracts
Duchenne Muscular Dystrophy Clinical
Progressive Myopathy. Large calves, Gowers maneuver, abnormal gait, high creatine kinase levels (muscular damage)
Duchenne MD Inheritance/Prominence
X-linked recessive, 1 in 3,000 males
Onset at 2 years, Wheelchair bound at 13, death at 18
Duchenne MD Mechanism
Loss of function: deletion or frame shift mutation in Dystrophin gene (Xp21.2).
High new mutation rate. In-frame deletion or missense mutations lead to milder Becker’s MD
Duchenne MD Testing
Genetic Sequencing: can determine deletion and frame shift mutation.
Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) Clinical
Temporary neuropathy following pressure to nerves. Typically full recovery. Onset 20s-30s
HNPP: Inheritance/Prominence
Autosomal Dominant
HNPP Mechanism
Loss of function, Deletion of PMP22 gene (17p11.2) (glycoprotein in nerves).
HNPP Testing
Deletion: FISH, Microarray
Osteoenesis Imperfecta Type 1 Clinical
Brittle bones, increased fractures, blue sclerae, normal stature, adult progressive hearing loss
Osteogenesis Imperfecta 1 Inheritance/Prominence
Autsomal Dominant
Osteogenesis Imperfecta 1 Mechanism
Loss of function nonsense frame mutation in COL1A1 gene (early termination). Unstable mRNA that gets degraded, loss of collagen 1, decreases collagen strength
Osteogenesis Imperfecta 1 Testing
DNA sequencing for mutation in gene
Charcot-Marie-Tooth Type 1A Clinical
Demyelinating motor and sensory neuropathy, lower extremity weakness, muscle atrophy, and sensory loss.
CMT 1A Inheritance/Prominence
Autosomal Dominant
CMT 1A Mechanism
Gain of function duplication of PMP22 gene (17p11.2)
CMT 1A Testing
Duplication tested by FISH, Microarray, DNA sequencing
Osteogenesis Imperfecta II-IV Clinical
Brittle bones, increased fractures, blue sclerae
Ost Imperfecta II-IV Inheritance
Autosomal Dominant
Ost Imperfecta II-IV Mechanism
Novel Property Mutation: Collagen 1A2 has different folding due to mutation. Still forms trimers with Collagen 1.
Ost Imperfecta II-IV Testing
DNA sequencing?
Huntington Disease Clinical
Progressive neurodegeneration as adult, corea, death within 15 years of onset
Huntington Disease Inheritance
Autosomal Dominant, 1/10,000: presence with # of repeats
Genetic Anticipation: # of repeats likely to increase in subsequent generations 2’ to slippage. Maternal expansions more likely.
Huntington Disease Mechanism
Increase in # of CAG (glutamate) repeats in Huntington gene (4p16.3).
Ranges: 39 full penetrance; >60 juvenile onset
Huntington Disease Testing
Trinucleotide Repeat: Fish? DNA Sequencing gives specific number
Myotonic Dystrophy Clinical
Droopy eyes, intellectual difficulty, hypotonia
Myotonia Dystrophy Inheritance
Autosomal Dominant
Myotonia Dystrophy Mechanism
Increase of CTG repeats within 3’ UTR of DMPK gene
Myotonia Dystrophy Testing
Trinucleotide repeats: DNA sequencing
Phenylketouria Clinical
Early onset epilepsy, hyperactivity, intellectual delay
PKU Inheritance
Autosomal Recessive, High allelic heterogeneity w/ 400 mutant alleles
PKU Mechanism
Loss of function: Defect in phenylalanine hydroxylase enzyme which converts phenylalanine to tyrosine most common. Also possible to have BH4 deficiency (cofactor also used in dopamine and seratonin synthesis)
PKU Testing / Screening
Newborn screening post partum when mother’s enzymes gone, can change diet to prevent effects
Mass Spectrometry: fast detection of amount of enzyme in blood.
Guthrie test: too much PA let bacteria grow
PKU Treatment
Low phenylalanine diet. Maintained during pregnancy to prevent complications
BH3 replacement PO
Alpha 1 Trypsin Deficiency Clinical
Adult onset, increased risk of emphysema and liver cirrhosis/cancer
ATD Inheritance
Autosomal Recessive. 1/2500. 1/25 carriers.
ATD Mechanism
Loss of SERPINA1 protein is inhibitor of elastase. Elastase released in lungs by neutrophils, if not degraded it destroys lung elastin. Process accelerated by smoking b/c more neutrophils recruited to lungs.
ATD Allelic Heterogeneity
M allele normal, most common Z allele (Glu342Lys) misfolded protein that accumulates in ER of liver cells. S allele (Glu264Val) unstable, less effective protein Z/S intermediate between Z/Z and S/S
ATD Testing
Sequencing for point mutations, FISH probes for each allele, Enzyme function tests
ATD Treatment
Enzyme infusion and aerosol treatment
Tay-Sachs Disease Clinical
Progressive CNS neurodegeneration, onset 3-6 months. Muscle weakness, decreased attentiveness, startling at sound. Then seizures, vision/hearing loss, reduced mental function, paralysis. “Cherry red spot in eye”. Death at 3-4 years
Tay-Sachs Inheritance
Autsomal Recessive. 1/360,000 general; 1/3,600 Aschkenazi Jewish
T-S Mechanism
LSD, defect in HexA subunit of GM2 degrading complex. GM2 cannot be degraded, aggregates in lysosomes of CNS neurons.
Allelic heterogeneity: 4 bp insertion frame shift mutation most common
T-S Screening/Testing
Screen potential carriers for enzyme function, test for 3 main mutant alleles in parents and child
Sandhoff Disease
Similar to T-S but mutation in HexB subunit
AB-Variant of T-S
Severe form of T-S where HexA and HexB are fine but mutation in GM2AP prevent normal funciton.
Cystic Fibrosis Clinical
Salty skin, poor growth and weight gain, mucus accumulation, chest infections, coughing and SOB
Cystic Fibrosis Inheritance
Autosomal Recessive
Cystic Fibrosis Mechanism
Loss of function mutation of CFTR gene
Achondroplasia Clinical
Short Stature, Rhizomelic limb shortening, large head, megalencephaly, trident hand, spinal cord compression 2’ to small foramina. Brain stem compression = 3-7% early death
Achondroplasia Inheritance
Autosomal Dominant. 1/40,000. Homozygous is lethal!
Achondroplaisa Mechanism
Gain of function mutation Gly380Arg in FGFR3 gene. Tyrosine kinase constitutively on, inhibits bone growth. Mutations in father’s germline.
Neurofibromatosis Clinical
Cafe au lait spots, axillary and inguinal freckling, multiple neurofibromas, Lish nodules on eyes. 100% penetrant.
Neurofibromatosis Inheritance
Autosomal Dominant
Neurofibromatosis Mechanism
Mutation of NF1 gene on chromosome 17
Marfan Syndrome Clinical
Connective tissue disorder with ocular, skeletal, and cardiac manifestation. Tall and skinny. Hypermobile joint, pectus excatum. Risk of Aortic Aneurysm
Marfan Syndrome Inheritance
Autosomal Dominant 1/5,000
Marfan Syndrome Mechanism
Mutation in FBN1 gene (fibrillin)
Familial Hypercholesteremia
High cholesterol levels from mutations in LDL receptor so it can’t clear LDL from bloodstream
Fragile X Clinical
Childhood onset mental deficiency, dysmorphic facies, enlarged testicles, speech delay, autism-like, large ears and prominent jaws
Fragile X Inheritance
X-linked dominant
Fragile X Mechanism
Trinucleotide expansion in 5’ UTR of fragile X region leading to hypermethylation. Haplotype effect.
Ranges: Grey zone 6-45; Premutation 59-200; penetrance 200+
Maternal genetic anticipation.
Fragile X Premutations
FTAXS (59-200 repeats): adult onset tremor, ataxia, Parkinsonian features, memory loss. Women also premature ovarian failure.
From increased RNA production, sites not hypermethylated yet
Hemophilia A Clinical
Reduced clotting
Hemophilia A Inheritance
X-linked Recessive
Hemophilia A Mechanism and Treatment
Factor VIII deficiency, fixed with Factor VIII supplementation
Turner Syndrome Clinical
Gonadal Dysgenesis, short stature, heart defects, fused kidneys, webbed neck, brown nevi, wide nipple placement, infertility, social difficulties, difficulty with math
Turner Syndrome Inheritance and Mechanism
45 X0; 1/2,000-5,000 live births; Meiotic non-disjunction
Klinefelter Syndrome Clinical
Gonadal dysgenesis/hypogonadism, infertility, tall stature, gynecomastia, likely sterile, language trouble
Klinefelter Inheritance and Mechanism
47, XXY; Meiotic Nondisjuction
