Cystic fibrosis: how was the gene isolated?
Primarily positional cloning: Using linked marker genes which surround the CFTR gene. Also able to identify which genes were expressed in sweat glands, which were preserved/not preserved in other species, etc. Also, haplotype maps.
Autosomal recessive. Allelic heterogeneity, locus heterogeneity. Sx: fair-skinned, mousy odor, mental retardation. Dx: by presence of [blood] in a pterin screen.
Autosomal recessive. Inability to degrade GM2 ganglioside in lysosomes, leading to neuronal death. Infantile, juvenile and adult onset versions. Sx: cherry red retina spot, no HEXA. More common in Ashkenazi Jews, oi vey! (Bonus: why isn't this disease screened for?)
LHON (Leber hereditary optic neuropathy)
homoplasmic mitochondrial inheritance. Results from NADH dehydrogenase mutation; 1 of 4 genes. Sx: painless vision loss, blurred central vision. onset in 20s or later. may develop cardiomyopathy. 95% of cases have 1 of 3 mutations, listed by increasing severity: T14484L, G3460A, G11778A. Often worsens with age.
MERRF (myoclonic epilepsy with ragged red fibers)
heteroplasmic mitochondrial inheritance. Results from tRNALys gene, 90% have 1 of 3 mutations, listed in order from most common to least common: 8344G->A, 8356T->C, 8363G->A. Reduces charge of tRNALys by 50%. Sx: myoclonic epilepsy, myopathy with ragged red fibers, hearing loss, ataxia, renal dysfunction, diabetes, cardiomyopathy, dementia.
Trisomy 21 (Down Syndrome)
1/800 live births. 90% are errors in maternal meiosis I, 10% are errors in paternal meiosis II. Sx: hypotonia, flat face, brachycephaly, upslanting palpebral fissures, Congenital HD, duodenal and tracheoesophageal atresia, 15 times greater risk of leukemia. Sources: 95% translocation, 4% robertsonian translocation (14;21). Recurrence risk is only 1% if you've already had one affected kid.
Trisomy 18 (Edward Syndrome)
Sx: mental retardation, failure to thrive, poor feeding, heart malformations. Fist clench with 2nd and 5th digits over 3rd and 4th. Usually dead by age 1. Results from maternal meiotic II nondisjunction, or translocation. Mosaicism decreases severity.
Trisomy 13 (Patau Syndrome)
Sx: severe mental retardation, thrive fail, poor feeding, heart malformation. Fist clench with 2nd and 5th digits over 3rd and 4th. Polydactyly common. Results from maternal meiosis I nondisjunction or translocation.
Sx: Tall, thin males, hypogonadism, infertile, learning disorders, psychosocial deficits. Most cases result from meiotic nondisjunction, 50% paternal meisosis 1, 50% maternal.
47, XYY Syndrome
This disorder can only result from nondisjunction in male meiosis II- think about it! Mild symptoms.
1/1000 female births- mild symptoms which worsen depending on the number of extra chromosomes. Increased height, decreased IQ. Most result from maternal meiosis I errors, some from maternal meiosis II.
Turner Syndrome (45, X-)
One in four thousand female births. Short stature, gonadal dysgenesis, webbed neck. In seventy percent of cases, X chromosome is from the mother. It may appear as a ring chromosome. Only viable human monosomy.
Sx: mental retardation, growth retardation, hypertelorism, cleft lip, heart defects, seizures. Deletion of part of chromosome 4. Most cases result from a sporadic deletion, but can also result from an unbalanced viable translocation.
Most cases are a result of sporadic deletion, however an unbalanced viable translcation involving chromosome 5 can also result in this disorder. Sx: Sharp, shrill cries, failure to thrive, heart defects; adults who live beyond infancy have IQ <20.
Sx: mental retardation, microcephaly, hypertelorism, etc. Results from a ring chromosome where breakage of both ends of this chromosome allows it to bind together forming a ring.
tetrasomy 18p syndrome
Sx: developmental delay, mild to severe mental retardation, microcephaly, high-arched palate. Results from isochromosome formation of one chromosome.
Sx: hypotonic, broad forehead, agyria on MRI, abormal EEG, lissencephaly, facial features; results from deletion of several genes due to inherited translocation chromosome 17 from parent. Missing a bit of 17, duplicated a bit of 12.
XLAG (X-linked lissencephaly with ambiguous genitalia)
gene which produces lissencephaly, genital defects. mutation in aristaless-related homeobox gene on X
deletions or point mutations, produces posterior lissencephaly. Transcribes the non-catalytic subunit of platelet activating factor acetylhydrolase (PAFAH) which interface with dynein and is important for migration.
heritable pro-oncogene. Multiple endocrine adenomatosis type 2. Auto dominant mutation of a receptor YK.
Follicular B-cell lymphoma
18;14 BCL2 constituitively activates anti-apoptotic gene BCL2 in b cells.
40% heritable; 75% are new mutations. Familial version is earlier age of onset, and degree of severity (bilateral tumors) Autosomal dominant, but cellular recessive. Mutation in 1 copy of a tumor suppressor gene increases risk once LOH occurs. 2 or more primary cancers in the same individual = familial cancer.
FAPC (familial adenomatous polyposis coli)
Auto. dom. mutation of APC gene which dysregulates proliferation of B-catenin (increases). After LOH of second APC, polyps become malignant.
Auto. dom. mutation in one copy of a DNA mismatch repair gene. Once both are lost, rate of cellular mutations greatly increases. Men are at a higher risk for malignancy than women even with the same mutation.
Auto. dom. 20-40% of family breast cancer. increased risk for ovarian and other cancers. associated with BRIP1, CHK2, and ATM.
mutation in both copies of p53 most likely; mutation in RB1 or of one copy of BRCA1/BRCA2 in half of sporadic breast ca.
X dom. MECP2. 99% due to spontaneous mutation; 70% in paternal germline. If couple has affected child but no MECp2 mutation, recurrence risk is low. Deceleration of head growth, hand and arm flapping, impaired language development. Sx stabilize and progress without further degradation. male lethal (unless mosaic or klinefelter XXY)
FGFR3 auto. dom mutation, complete penetrance. constituitively active GOF mutation of membrane receptor responsible for inhibiting chondrocyte proliferation. G380R