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Flashcards in genetics diseases premidterm Deck (50):

Familial hypercholesterolemia (LDL rec deficiency)

Autosomal dominant. Haplo-insufficiency


Huntington disease

Autosomal dominant. Gain of function mutation. Triplet repeat expansion in father - CAG (codes for glutamine) in exon 1 of Huntington gene = polyglutamine expansion in protein. Late onset - manifests at approx 40 yrs of age. Progressive dementia, loss of motor control. Degeneration of neurons in cerebral cortex, chorea caused by degeneration of basal ganglia, cognitive and language design. Dx via RFLP for probe G8, closely linked to dz


Myotonic dystrophy

Autosomal dominant. Triplet repeat expansion in mother - CTG at 3' end of DMPK gene. Most pleiotropic phenotype of all unstable repeat disorders. Wasting of mm, cataracts, heart conduction defects, endocrine changes, developmental delay, and myotonia. DM1 worse than DM2 (DM2 = muscle pain, stiffness, fatigue, wkness in extremities)


Marfan syndrome

Autosomal dominant. Dominant-negative mutation in fibrillin gene. Skeletal abnormalities (long limbs, pectus excavatum, arachnodactyly), hypermobile joints, ocular abnormalities (myopia, lens dislocation), cardiovascular disease (mitral valve prolapse, aortic aneurysm)


Osteogenesis imperfecta

Autosomal dominant. Dominant negative model - mutation in one allele of collagen alpha 1 gene. Association of triple helical molecules w/at least one mutant alpha 1 results in the degradation of collagen (75% of the collagen is degraded, only have 25% normal collagen). Easily fractured bones, blue sclerae



Autosomal dominant. Gain of function mutation in gene for FGFR3 (fibroblast growth factor rec) involved in differentiation of chondrocytes into osteoblasts, differentiation of cartilage to bone. Severe stunting of growth w/normal mental development


Neurofibromatosis (NF1) type I

Autosomal dominant. Mutation in neurofibromin 1 (NF1) gene that codes for tumor suppressor protein. Caused by different mutations in NF-1 gene (allelic heterogeneity). High penetrance (generally all patients express at least some signs of disorder) but variable expression. Cafe au lait spots, Lisch nodules on iris, neurofibromas on skin, bone deformities, learning disabilities


Acute intermittent porphyria

Autosomal dominant


Cystic fibrosis

Autosomal recessive. Mutant CFTR channels


Sickle cell anemia

Autosomal recessive. Allelic heterogeneity.



Autosomal recessive


Tay-Sachs disease (hexosaminidase A)

Autosomal recessive


Congenital deafness

Autosomal recessive. Don't have to be homozygous recessive for two alleles -> homozygous recessive for one allele is enough to be deaf



Autosomal recessive. More severe in males. C282Y mutation (most common mutation of HFE gene). Also exhibits allelic heterogeneity (other known mutations of HFE gene are H63D and S65C). Delayed age of onset of sx's


Xeroderma pigmentosum

Autosomal recessive. More severe in individuals exposed more frequently to UV radiation


Duchenne muscular dystrophy

X-linked recessive. Due to mutation on dystrophin gene. Very little to no production of normal dystrophin. SEVERE - lethal before the age of 30, low reproductive fitness. Muscle wasting


Becker muscular dystrophy

X-linked recessive. Due to mutation on dystrophin gene


Glucose 6 phosphate dehydrogenase (G6PD) deficiency

X-linked recessive. Hemolytic anemia when taking drugs such as primaquine, sulfa drugs


Hemophilia A and B

X-linked recessive. Most of severe mutations due to inversion of intron sequence, but there's also allelic heterogeneity. Deficiency of clotting factor VII -> increased tendency to bleed on minor trauma.


Lesch-Nyhan syndrome (hypoxanthine guanine phosphoribosyl transferase (HGPRT))

X-linked recessive. Hyperuricemia and self-mutation


Red-green color blindness

X-linked recessive


Rett syndrome

X-linked. Due to mutation in x-linked gene MeCP2. Affects females more often than males. Males with mutant X gene usually die in utero or soon after birth UNLESS they have Klinefelter (XXY). Females may have skewed X chromosome inactivation that causes varying degrees of dzallows survival (normal cells rescues mutant cells), or may be due to germline mutation in mother.

Sx's - develop normally until 6 to 18 months. Regression phases include loss of speech and acquired hand skills. Most get seizures, repetitive hand movements, irreg breathing, and motor control problems.


Vitamin D-resistance Rickets (hypophosohatemic Rickets)

X-linked dominant disorder


Incontinentia pigmenti

X-linked dominant. Due to mutation in IKBKG gene. Males with disorder die in utero. Females less severely affected bc of protection from other X - have skewed X-inactivation in favor of normal IKBKG gene. Rashes and blisters in early life. Later, patches of hyperpigmentation, "marble cake appearance" of skin - darker pigmentation where normal X has been inactivated (mutant X is active). Areas of normal pigmentation = normal X is active. Mental retardation and/or retinal detachment in some patients.


Waardenburg syndrome

Autosomal dominant. Mutation in PAX3 gene. Sensorineural hearing loss, white forelock, heterochromia


Fragile X syndrome/Martin Bell syndrome

X-linked dominant. Triplet repeat expansion in mother - CGG in promoter at 5' end of FMR1 gene -> increased methylation of this region and silencing of FMR1 gene. Dx w/southern blot analysis of triplet repeats, or X chromosomes show breakage in folate-deficient medium (cytogenetic test) in pts with full mutation. Average age of dx is 8 years of age. Poor muscle tone, sunken chest, elongated head, difficulty learning, macroorchidism. Females less severely affected than makes. Mother's X chromosome may have have germline mutation (???) 50-200 repeats represent the full mutation, 200 is full mutation


Mitochondrial encephalopathy, lactic acidosis, stroke-like episodes (MELAS)

Mitochondrial inheritance


Leber hereditary optic neuropathy

Mitochondrial inheritance. Manifests as progressive blindness around 20-30 yrs


Myoclonic epilepsy with ragged red muscle fibers (MERRF)

Mitochondrial inheritance


Angelman syndrome

Imprinting. Deletion of maternal 15q11-13 (absence of UBE3A), a region not normally methylated in mom's chromosome or uniparental disomy via nondisjunction I and trisomy rescue of 15. Have 2 copies of SNRPN. Dx by FISH using specific probes against the region, methylation analysis (unmethylated DNA cleaved by enzyme). Happy puppet syndrome, severe metal retardation, seizures


Turner's syndrome

Phenotype X,O. Due to chromosomal non-disjunction after meiosis II ???


Klinefelter's syndrome

Genotype XXY. Due to chromosomal nondisjunction after meiosis I


Trisomy 21

Due to chromosomal non-disjunction. Risk for disease increases if mother is over the age of 35


Prader-Willi syndrome

Imprinting. Deletion of paternal 15q11-13 (absence of SNRPN), a region not normally methylated in dad's chromosome or uniparental disomy via nondisjunction I and trisomy rescue of 15. Have 2 copies of UBE3A. Dx by FISH using specific probes against the region, methylation analysis (unmethylated DNA cleaved by enzyme). Obese bc of increased ghrelin, OCD behavior, mental and developmental delay, underdeveloped genitalia, hypotonia in infancy, failure to thrive


Various mutations in SRY genes

Y-linked inheritance


H-Y histocompatibility antigen

Y-linked inheritance


Charcot Marie Tooth disease

Autosomal dominant or X-linked recessive. Neuropathy, little myelination of peripheral nerves


Retinitis pigmentosa

Digenic disorder, result of mutation in two independent genetic loci (ROM1 and peripherin). Progressive visual disorder


Friedrich ataxia

Autosomal recessive. Triplet repeat expansion disorder, possibly paternal anticipation - GAA in intron 1 of frataxin gene -> altered chromatin structure , formation of triplex DNA, and DNA methylation of bases and histone methylation -> transcrip repression of frataxin gene. Progressive neuro-degenerative disease. Ataxia and muscle weakness, vision and hearing impairment, scoliosis, diabetes, heart disorders. Typical onset between 5-15 years of age, sometimes between 20-35 years. First sx's are difficulty walking and loss of LE DTRs


New mutation diseases

OI, Marfan syndrome, achondroplasia, Duchenne muscular dystrophy, hemophilia


Immunodeficiency-centromeric instability-facial anomalies syndrome (ICF)

Autosomal recessive. Due to mutation of Dnmt3b gene. Sx's - facial dysmorphism, mental retardation, recurrent an prolonged infections, and variable immune deficiency with a constant decrease of IgA. Immunodeficiency associated w/centromere instability of chrmsms 1, 9, and 16


Beckwith-Wiedemann syndrome (BWS)

Due to maternal chromosomal rearrangements of 11p15 (imprinted region). Paternal uniparental disomy. Abnormal methylation at 11p15. Children of IVF have 4-9 fold higher chance of BWS bc IVF causes abnormal methylation of 11p15

Sx's - macroglossia, high birth weight and length, abdominal wall defects like umbilical hernia, ear creases/pits, neonatal hypoglycemia, increased risk of cancer


Number of repeats in Huntington disease

- >40 repeats - you will develop HD, children have 50% chance of HD
- 36-39 repeats - you may develop HD
- <35 repeats - you will not develop HD
- 29-39 repeats - children may or may not develop HD
- <29 repeats - children will not develop HD


Proposed mechs for Huntington disease

1. Increase in polyglutamine tract length causes Huntington protein to aggregate, form inclusion bodies, and behave as a toxin
2. Abnormal Huntington protein interacts with different transcription factor proteins casing dysregulation of gene expression


Spinocerebellar ataxia

Autosomal dominant, autosomal recessive, or X-linked. CAG repeat expansion in exons of at least 29 different genes, polyglutamine disorder (see mechs for Huntington dz). Progressive, degenerative disease. Sx's - lack of muscle coordination and lack of coordination of hands, eyes, and speech.

Spinocerebellar ataxia 8 is unique bc it's caused by CTG repeat expansion in 3' terminal exon of non-protein coding RNA from SCA8 gene causing altered protein binding to the RNA



Mutation in SHH or Six3 (regulator of SHH)


Smith-Lemli-Opitz syndrome

Mutation in 7-dehydrocholesterol reductase. Microcephaly, mental retardation, malformation of mesodermal origin, syndactyly, and polydactyly


Gorlin syndrome (Nevoid basal cell carcinoma)

Mutation in Ptc. Early basal cell carcinoma (<20 years). Rib defects


Pallister-Hall syndrome

Mutation in Gli genes. Brain tumors, polydactyy


Rubinstein-Taybi syndrome

Mutation in CREBBP. Broad thumbs and toes, mental disability, short stature, small head, facial features