Patterns of Inheritance: Lect 3-6 Flashcards
Recurrence risk
probability that the offspring of a couple will express the genetic disease.
-depends on mode of inheritance.
Autosomal Dominant:
define and name disorders.
-manifest in heterozygote state
-male-male transmission.
-50% recurrence risk to offspring regardless of child’s sex.
DISORDERS: NO HA2M2
-Familial hypercholesterolemia
-Huntington disease
-Myotonic dystrophy
-Marfan syndrome
-Osteogenesis imperfecta
-Achondroplasia
-Neurofibromatosis type I
-Acute intermittent porphyria
Mytonic dystrophy
- mutation in DMPK gene
- most pleitropic of all 3x repeat disorders.
- wasting of muscles, cataracts, heart conduction defects, endocrine changes and myotonia.
Achondroplasia
-FGFR3 mutations (differentiation of cartilage to bone)
Neurofibromatosis
- NF1 mutation; codes for a tumor suppressor protein.
- allelic hetrogeneity
- variable expressivity
Haplo-insufficiency:
- loss of function mutation; half nl levels of the gene product result in phenotypic effects
- FH, AIP, OI type I.
Dominant negative:
- mutant gene product interferes w/ the function of the nl gene product.
- OI type II, III, IV and Marfans.
Gain of function:
- increased levels of gene expression or development of new function.
- Huntington and Achondroplasia.
Autosomal recessive:
define and list disorders
- both parents are carriers; phenotypically nl.
- siblings commonly affected, horizontal inheritance, male:female equal.
- increased by consanguinity.
- recurrence risk = 25%; 2/3rd carrier risk among sibs.
DISORDERS: no 2/3rds to delayed onset
- Cystic fibrosis
- Sickle cell anemia
- Phenylketonuria
- Tay-Sachs disease
- Congenital deafness
- Hemochromatosis *delayed onset
- Alkaptonuria *delayed onset
- Homocytinuria
- Galactosemia
- SCID
Loss of function:
reduced activity (hypomorph) or complete loss of gene product (amorph). ex: enzyme deficiencies
Hemochromatosis:
- iron overload disorder
- C282Y mutation on HFE gene
- delayed age of onset
- allelic hetrogeneity
- variable expressivity
SCIDS:
-due to ADA deficiency = build up of dATP which is toxic to B and T cell development.
Psuedo-autosomal dominant
an AR condition in two or more generation, thereby appearing to follow a dominant inheritance pattern.
- vertical transmission
- due to Heterozygote adv: high carrier freq. (sickle cell in Africa)
- higher incidence of consanguinity (geographical, social/religious isolation)
- assortative mating
X-linked recessive disorders:
- more common in males *hemizygous.
- affected father = all daughters are carriers. w/ no male to male
DISORDERS:
- Dystrophin assoc. muscular dystrophy (Duchenne and Becker)
- G6PD
- Hemophilia A and B
- Lesch-Nyhan syndrome: HGPRT deficiency
- Red-green color blindness
- X-linked SCID (SCIDX1 gene)
Hemophilia A
deficiency of clotting factor VIII and involves inversions of an intron sequence.
-allelic heterogeneity
X-linked SCID
-defect in the gamma rcp for several different interleukins (IL2RG)
Manifesting heterozygote
due to assymeteric/skewed X-inactivation.
-mutant X is active in most of her cells.
X-linked dominant disorders
- male:female equal
- affected male transmits to all his daughters but none of sons.
DISORDERS:
- Rett syndrome
- Incontinentia pigmenti
- Vitamin D resistant Rickets
Rett syndrome
- affects females more
- males die in utero or after birth.
Incontinentia pigmenti
- males die in utero
- females less severely affected
- Marble cake appearance; hyperpigmentation, mental retardation and retinal detachment in some pts.
- variable expressivity.
Y-linked inheritance
- only males affected; usually causes sterility and aren’t passed on.
- mutations in the SRY gene
- H-Y histocompatibility antigen
- Hairy ears
Non-penetrance:
Fully penetrant:
- indiv has the disease genotype but doesn’t display the disease phenotype.
- if all carrying the mutation, express the manifestations of the disease
Incomplete penetrance
may be dependent of on age,
Waardenburg syndrome
- pleiotropic and variable expression
- white forelock, sensorineural hearing loss, heterochromia
Locus heterogeneity
mutations at diff loci that cause the same disease phenotype.
- OI
- Sensorineural hearing impairment
- Charcot Marie Tooth (AD, AR, XL)
- SCID (AR, XL)
- Breast cancer BRCA1/2
Allelic heterogeneity/Compound heterozygotes
diff mutations at the same locus cause the disease
- NF1
- Hemochromatosis
- Cystic fibrosis
- Hemophilia A
New Mutation
- transmitted from an unaffected parent to an affected offspring.
- no family hx of the disease
- increased age of father observed
- NF1, FGFR3, Duchenne, OI, Marfan
Germline mosaicism
-mutation present in a proportion of the germline cells; somatic cells will show no mutation.
Mitochondrial inheritance
- from mother
- all offspring of affected female are affected.
- heteroplasmy: variable expression in mitochondrial disorder.
DISORDERS:
- MELAS: Mitochondrial encephalomyopathy lactic acidosis and stroke-like episdoes
- Leber hereditary optic neuropathy: progressive blindness around 20-30yrs
- MERRF: Myoclonic epilepsy w/ ragged red muscle fibers.
Digenic disorder
- mutations in two genes
- Retinitis pigmentosa: mutation in two indep genetic loci ROM1 and peripherin.
Imprinting:
methylation of specific loci and silencing of the gene.
Prader Willi:
- microdeletion of paternal chrom 15 SNRPN 70%
- detected by FISH
- maternal uniparental disomy of chrom 15; w/ two active copies of UBE3A via trisomy rescue and no SNRPN 30%
- detected by methylation analysis; restriction enzyme does not cleave methylated DNA
- children are obese, w/ mental and development delay and underdeveloped genitalia, hypotonia and failure to thrive.
- Polymorphic marker analysis can be used to differentiate the cause of PW syndrome.
Angelman syndrome
- deletion of maternal UBE3A gene
- uniparental disomy of paternal chrom 15 (2 copies of active SNRPN)
- severe mental retardation, seizures, puppet like posture
Triple repeat disorders
- Fragile X: at the promoter/5’ region of the FMR1 gene; CGG. Anticipation observed in mother.
- Friedrich ataxia: in an intron, resulting in formation of heterochromatin GAA
- Huntington: in the coding region; polyglutamine expansion CAG. Anticipation observed in father w/ >40 repeats.
- Myotonic dystrophy: at the 3’ end CTG. Anticipation observed in mother.
Anticipation
-indiv in recent generation develops disease at an earlier age w/ greater severity.
Fragile X syndrome
-Increased methylation and silencing of the FMR1 gene.
- poor muscle tone, macro-orchidism, sunken in chest, elongated head, prominent ears, develop language skills at 4 or 5 yrs. Difficulty w/ eye contact, freq. hand slapping when excited.
- less severe in females
- diagnostic test: Southern blot analysis
- X chrom shows breakage in a folate deficient medium
