Patterns of inheritance

Question 1

Prader Willi Syndrome

Answer 1

(opp of Angelman sydrome)
Caused by:
-microdeletion of paternal chrom 15 (70% of pts) - NO active copy of SNRPN (from father), so UBE3A (from mother) is active Detected by FISH
-Maternal uniparental disomy of chrom 15 - 2 active copies of UBE3A gene (bc 2 copies of maternal chrom 15), and NO active copy of SNRPN (absence of paternal chrom 15)
–use polymorphic marker analysis to differentiate which one of these 2 are the cause

Children are obese, have mental and developmental delay and underdeveloped genitalia. Hypotonia in infancy, failure to thrive

Question 2

Trisomy rescue

Answer 2

Hypothesis for uniparetal disomy, trisomy cell (2 from dad 1 from mom or vice versa) one from mom gets degraded or vice versa

Question 3

Methylation analysis

Answer 3

uses the differential methylation patterns of chrom 15
restriction enzyme only cleaves methylated paternal DNA at chrom 15, not maternal.
-Most useful when children are very young and have no yet developed classical phenotypes

Question 4

polymorphic marker analysis

Answer 4

used to differentiate caue of Prader-Willi syndrome (due to mirodeletion of paternal ch15 OR due to uniparental disomy of maternal ch15)

Question 5

Angelman syndrome

Answer 5

(opp of prader willi)
Caused by:
-deletion of MATERNAL ch15 (ABSENSE of active UBE3A gene)
-Uniparental disomy of paternal ch15 (2 copies of active SNRPN and absense of UBE3A)

Symptoms

• “Happy puppet syndrome”
• Happy disposition, laugh inappropriately
• Severe intellectual disability, seizures, puppet-like posture of limbs

Question 6

Anticipation

Answer 6

Indivs in newer generation develop disease at earlier age and with more severe symptoms
-The larger the repeat, the greater the chance for it to be UNSTABLE

Question 7

Huntington disease

Answer 7

• Autosomal dom
• trinucleotide repeat (CAG) in the coding region of a gene (exon) – results in a polyglutamine expansion protein
• Anticipation (bc triple repeat disorder)
• Has gain-of-function mutations

Question 8

Fragile X syndrome

Answer 8

-X-linked disorder
Triple repeat in promotor region of FMR1 gene (5’ end), result in reduced expression of gene (bc results in incr methylation which silences the gene)
-Females less severely affected
-Anticipation (bc triple repeat disorder)
-Diagnostic tests: southern blot, cytogenetic test (show if x chrom shows breakage in folate deficient medium–Fragile site only in ppl who show the mutation, and analysis of mothers x chrom

Question 9

Myotonic dystrophy

Answer 9

• Autosomal dom, mutation in DMPK gene
• Triple repeat in 3’ end of gene (3’UTR). Most PLEIOTROPIC phenotype of all unstable triple repeat disorders
• Anticipation (bc triple repeat disorder)
• Characterized by wasting of the muscles, cataracts, heart conduction defects, endocrine changes, and myotonia.

Question 10

General features of mitochondria inheritance

Answer 10

• all offspring (both male and femaleof affected female are affected (bc mito come from mother)
• Only females transmit the disease (affected father does not transmit disease to children)

Question 11

Heteroplasmy

Answer 11

-mom has mixture of normal and mutant mt DNA and gives unequal distribution to offspring – bc of this the severity of mt disorders vary in individs (variable expressivity)

Question 12

MELAS

Answer 12

= mitochondrial encephalopathy, lactic acidosis, and stroke like episodes
-type of mt disorder

Question 13

Leber hereditary optic neuropathy

Answer 13

• mt disorder

- manifests as progressive blindness around 20-30 years

Question 14

Myoclonic epilepsy with ragged red muscle fibers (MERRF)

Answer 14

Mt disorder

Question 15

When a female is affected with a severe mt disorder, one of the options offered is ________

Answer 15

artificial reproduction technology

Question 16

Digenic disorders

Answer 16

• mutations in 2 genes (A, B) are additive and necessary to produce the disorder
• ex- one form of retinitis pigmentosa

Question 17

Imprinting

Answer 17

• Some genes only active only when transmitted by mother or father
• involved methylation of specific loci (epigenetic change) and silencing the gene
• ex: normal imprinting pattern on ch15: SNRPN gene is silenced by methylation on maternal ch15, but UBE3A is active

Question 18

Familial hypercholesterolemia (LDL receptor deficiency

Answer 18

Autosomal dom

Question 19

Marfan syndrome

Answer 19

Autosome dom

-has dominant negative mutation

Question 20

Osteogenesis imperfecta

Answer 20

Autosomal dom

Question 21

Achondroplasia

Answer 21

Autosomal dom

• FGFR3 mutations.
• FGFR3 codes for TM receptor involved in differentiation of cartilage to bone. Has ‘mutation hot spots’ resulting in NEW MUTATIONS
• FGFR mutations result in severe stunting of growth
• ‘Gain of function’ mutation
• AA not compatible with life (homozygous for disease alleles is lethal)

Question 22

Neurofibromatosis type I (NF1)

Answer 22

Autosomal dom

• Mutations in NF-1 gene that codes for neurofibromin protein (tumor suppressor)
• Caused by diff mutations in the NF-1 gene (ALLELIC HETEROGENIETY)
• NF1 gene has ‘MUTATION HOT SPOTS’ –> NEW MUTATION
• can cause “cafe au lait spots, neurofibromas (swellings on skin), Lisch nodules in iris,
• VARIABLE EXPRESSIVITY but HIGH PENETRANCE

Question 23

Acute intermittent porphyria

Answer 23

Autosomal dom- exception bc most enzyme deficiency disorders are autosomal recessive

Question 24

Which disease have mutation hot spots

Answer 24

Achondroplasia

NF1

Question 25

Haplo-insufficiency

Answer 25

- Loss-of-function mutations in which half normal levels (50%) of the gene product result in phenotypic effects. Reduced protein levels (50%) are not sufficient to carry out normal functions of the protein) - Molecular explanation for auto dom mutations manifesting in heterozygous state

Question 26

Dominant negative mutation

Answer 26

A mutant gene product interfered with the function of the normal gene product. In some cases, the assembly of the MULTIMERIC PROTEIN is affected (hindered) by the presence of the mutant protin.

Question 27

Molecular explanations for auto dom mutations manifesting in heterozygous state

Answer 27

Haplo-insufficiency Dominant negative mutation Gain-of-function mutations

Question 28

Function of the NF1 gene product (neurofibromin)

Answer 28

Works as tumor suppressor bc removes GTP from actica ras (sig for growth) and adds GDP to ras making it inactive and thus halting growth

Question 29

Autosome recessive general inheritance trends

Answer 29

- usually both parents are carriers - only seen in one generation (horizontal inheritance). Siblings more commonly affected - males and females are affected equally - Consanguinity might be a finding

Question 30

Cystic fibrosis

Answer 30

Autosomal recessive

Question 31

Sickle cell anemia

Answer 31

Autosomal recessive

Question 32

Phenylketonuria

Answer 32

Autosomal recessive

Question 33

Tay-Sachs disease (Hexosaminidase A deficiency)

Answer 33

Autosomal recessive

Question 34

Congenital deafness

Answer 34

Autosomal recessive

Question 35

Hemochromatosis

Answer 35

Autosomal recessive - Delayed age of onset - allelic heterogeniety - C282Y is most common mutatino of the HFE gene

Question 36

Alkaptonuria

Answer 36

Autosomal recessive | -Can be detected in infancy; but delayed age of onset

Question 37

Homocystinuria

Answer 37

Autosomal recessive

Question 38

Galactosemia

Answer 38

Autosomal recessive

Question 39

Alpha1-antitrypsin deficiency

Answer 39

Autosomal recessive

Question 40

SCID due to adenosine deaminase deficiency

Answer 40

Autosomal recessive | -If ADA is deficient, the build up of dATP is toxic to B-cell and T-cell development

Question 41

Molecular basis for autosomal recessive disorders

Answer 41

Loss-of-function mutations

Question 42

pseudo autosomal dominant

Answer 42

-An autosomal recessive conditional present in individs in 2 or more generations of a family, thereby appearing to have a dominant inheritance pattern. This is when heterozygote and homozygote for auto rec have affected children Common explanations: -High carrier freq -- sickle cell anemia in Africa -Higher incidence of consanguinity -Assortative mating-- ppl associate and marry with "like" Genetic isolation

Question 43

Pseudoautosomal region

Answer 43

region of chromosomes that match. It is necessary to line up chromosomes correctly during meiotic recombination

Question 44

General inheritance patterns of X-linked recessive disorders

Answer 44

- Males require only one copy of the mutation (hemizygous) to express the disease. - More common in males than females - Skipped generations - Affected father transmits the mutation to all his daughters who are NOT affected and are carriers. The daughters transmit it to their sons. - Male to male transmission is not seen - When child is affected, look for the disorder in maternal relatives

Question 45

Duchenne muscular dystrophy

Answer 45

X-linked recessive - severe, usually lethal before age 30. SO very low reproductive (genetic fitness) - due to mutations on the dystrophin gene - enlarged calves (pseudohypertrophy of calves), and wasting of the thigh muscles

Question 46

Becker muscular dystrophy

Answer 46

X-linked recessive - milder form - due to mutations on the dystrophin gene

Question 47

Glucose 6-phosphate dehydrogenase (G6PD) deficiency

Answer 47

X-linked recessive | -hemolytic anemia on ingestion of primaquine, sulfa drugs

Question 48

Hemophilia A and B

Answer 48

X-linked recessive | -Result in bleeding tendencies

Question 49

Lesch-Nyhan syndrome [Hypoxanthine Guanine Phosphoribosyl transferase (HGPRT) deficiency]

Answer 49

X-linked recessive | -Causes hyperuricemia, gout, & self mutilation

Question 50

Red-green color blindness/deficiency

Answer 50

X-linked recessive | -non-lethal

Question 51

X-linked SCID

Answer 51

X-linked recessive | -Defect in the SCIDX1 gene