Genetics: Diseases

Question 1

Cystic Fibrosis

Answer 1

Most common Mendelian inherited disease. Autosomal recessive. Caused by compound heterozygosity - 2 different mutations (deltaF508 + R1066C). Affects 1/2500, carriers 1/25. LOF disease.

Question 2

Deafness

Answer 2

Common in double heterozygosity

Question 3

Patau Syndrome

Answer 3

Caused by Trisomy 13, may survive to term

Question 4

Edwards Syndrome

Answer 4

Caused by Trisomy 18, may survive to term

Question 5

Down Syndrome

Answer 5

Caused by Trisomy 21, only aneuploidy that allows survival to adulthood (age 40 or more): 47XX+21. 47XXX, 47XXY, 47XYY have minor problems and normal lifespan. Also commonly caused by 46XXder(14;21)(q10;q10)+21.

Question 6

Williams Syndrome

Answer 6

Caused by deletions at chromosome 7. Delayed speech, later strong language, developmental delay, mild//moderate MR, feeding issues, cocktail/extroverted personality, unique faces (elfish features)

Question 7

Achondroplasia

Answer 7

One of most common dwarfism syndromes; bones spaced out in hands. Associated with spontaneous mutations in fathers of advanced age (> 35). Autosomal dominant, GOF. 98% of cases caused by c.11138G->A (p. Gly380Arg) in FGFR3 gene - causes ligand-independent stabilization of FGFR3 dimers that activate downstream signaling, shuts off long bone growth (regardless of ligand present). Defective differentiation of chondrocytes leads to growth retardation of longitudinal bones.

Homozygous state is lethal - need some bone growth.

80-90% de novo mutations exclusively in paternal germline. But normal dominant transmission (reproductive fitness) once the mutation occurs.

Question 8

Duchene Muscular Dystrophy

Answer 8

LOF disease caused by mutations in DMD gene (dystrophin on X) in early childhood (X-linked recessive). Most common X-linked disorder in man. 55-75% deletions, 25-35% small mutations (point mutations, insertions, duplications). Delayed milestones (sitting, walking), progressive skeletal muscular atrophy, wheelchair bound at age 12, mild, variable mental retardation, few survive beyond 30s. Will die from cardiac or respiratory failure (can be helped with antibiotics). Can test for with MLPA. If reading frame is maintained and can still produce protein, will be a milder form. 1/3500 live male births. 1/10,500 gametes/generation (highest known spontaneous mutation rate). 1/3 = new mutations.

Question 9

Spinal Muscular Atrophy

Answer 9

LOF disease, autosomal recessive

Question 10

Osteogenesis Imperfecta

Answer 10

LOF disease, clinically heterogeneous group of disorders characterized by brittle bones. Autosomal dominant phenotype (because collagen is lost) that results from haploinsufficiency. Almost always from new mutations, germline mosaicism (mutant allele in some of parent’s cells).

Type I: Frequent fractures of long bones of arms, legs, ribs, small bones of hands and feet. Fractures heal normally and usually without deformity. Patients only have half of normal amount of proalpha1(I) chains of Type I collagen.

Type II: Innumerable fractures present at birth and generally fatal in the first few weeks or months of life. Mutant collagen peptide is incorporated into nascent procollagen triple-helical molecule; 3/4 of procollagen is abnormal rather than half.

Question 11

Sickle Cell Disease

Answer 11

GOF disease. Autosomal recessive - GOF (sickle cells) leads to LOF (anemia).

Question 12

Triple repeat expansion diseases

Answer 12

SBMA, SCA, HD, FMR1 and FMR2, myotonic dystrophy, Friedreich’s Ataxia

Question 13

Myotonic Dystrophy

Answer 13

Triple repeat expansion disease (in 3’-UTR) where expanded repeats sequester mRNA so needed proteins cannot be produced. Severe disease - open, triangular shaped mouth, minimal movement.

Question 14

Huntington’s Disease

Answer 14

Expanded polyglutamine tract (10-30 CAG repeats is normal, 36-121 CAG repeats in HD) in coding region, triplet repeat expansion disease. Autosomal dominant, affects 1/20,000. Avg age of onset is 37 yrs, penetrance is high (100% by age 80). Death follows 10-20 yrs after onset (up to 30). Symptoms: personality changes, memory loss, series of motor problems including chorea (involuntary movement of arms and legs).

Huntington (htt) protein is expressed in a wide range of cell types, especially neurons.

Question 15

HD initial symptoms

Answer 15

Muscle coordination is slightly impaired, forgetfulness, cognitive disorganization, personality changes.

Question 16

HD middle stages

Answer 16

Both involuntary and voluntary movements become uncontrolled with jerking and writhing, speech is slurred, though processes diminish, and severe psychiatric conditions appear, including depression, paranoid delusions, and uncontrolled rage.

Question 17

HD later stages

Answer 17

Patients are mute, cognitively nonfunctional, and immobilized in contorted positions as a result of rigid joints and severe contractions.

Question 18

Hemoglobinopathies

Answer 18

Thalassemias, SCD

Question 19

Thalassemias

Answer 19

LOF diseases

Question 20

Spinal Muscular Atrophy

Answer 20

Autosomal recessive; LOF of survival motor neuron 1 (SMN) protein. Motor neuron degenerative disease that results in muscle atrophy.

Mutation in SMN1 + more copies of SMN2 = reduced severity of disease because SMN2 will produce some normal protein. 95% of SMA cases are deletions of SMN1 or gene conversion replacing SMN1 with SMN2. 5% are mutations that affect protein function or exon 7 splicing.

Question 21

Type I SMA

Answer 21

Werdnig-Hoffman disease: born with very little muscle tone, weak muscles, and feeding and breathing problems. Life expectancy of < 2 yrs.

Question 22

Type II SMA

Answer 22

Intermediate disease: sits, but never stands; diagnosis by 2 yrs, childhood lethal.

Question 23

Type III/IV SMA

Answer 23

Milder disease: stands and walks, adult survival. Later becomes wheelchair bound but almost normal life expectancy.

Question 24

DMD development

Answer 24

Starts with delayed motor development (late walking), proximal muscle weakness, calf enlargement to compensate. Classic microscopic myopathic changes and electromyographic changes; cycles of myofiber degeneration and regeneration (eventually runs out), necrotic fibers, accompanied by gradual replacement of fibers with adipose and connective/scar tissue (fibrosis). Regenerated muscle fibers display a large variation in diameter and have centrally located nuclei.

Question 25

95% of DMD patients develop what later in the course of the disease?

Answer 25

Dilated cardiomyopathy.

Question 26

Becker Muscular Dystrophy

Answer 26

Also caused by mutations in dystrophin gene, but milder and later onset. Lower levels of normal protein or truncated proteins that are mildly functional.

Question 27

(T/F) Mutations anywhere in DGC complex lead to diseases similar to DMD.

Answer 27

True.

Question 28

Leber hereditary optic neuropathy

Answer 28

Common disorder of mitochondrial inheritance; blurring and loss of central vision.