Patterns of inheritance Flashcards
Prader Willi Syndrome
(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
Trisomy rescue
Hypothesis for uniparetal disomy, trisomy cell (2 from dad 1 from mom or vice versa) one from mom gets degraded or vice versa
Methylation analysis
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
polymorphic marker analysis
used to differentiate caue of Prader-Willi syndrome (due to mirodeletion of paternal ch15 OR due to uniparental disomy of maternal ch15)
Angelman syndrome
(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
Anticipation
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
Huntington disease
- 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
Fragile X syndrome
-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
Myotonic dystrophy
- 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.
General features of mitochondria inheritance
- 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)
Heteroplasmy
-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)
MELAS
= mitochondrial encephalopathy, lactic acidosis, and stroke like episodes
-type of mt disorder
Leber hereditary optic neuropathy
- mt disorder
- manifests as progressive blindness around 20-30 years
Myoclonic epilepsy with ragged red muscle fibers (MERRF)
Mt disorder
When a female is affected with a severe mt disorder, one of the options offered is ________
artificial reproduction technology
Digenic disorders
- mutations in 2 genes (A, B) are additive and necessary to produce the disorder
- ex- one form of retinitis pigmentosa
Imprinting
- 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
Familial hypercholesterolemia (LDL receptor deficiency
Autosomal dom
Marfan syndrome
Autosome dom
-has dominant negative mutation
Osteogenesis imperfecta
Autosomal dom
Achondroplasia
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)
Neurofibromatosis type I (NF1)
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
Acute intermittent porphyria
Autosomal dom- exception bc most enzyme deficiency disorders are autosomal recessive
Which disease have mutation hot spots
Achondroplasia
NF1
Haplo-insufficiency
- 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
Dominant negative mutation
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.
Molecular explanations for auto dom mutations manifesting in heterozygous state
Haplo-insufficiency
Dominant negative mutation
Gain-of-function mutations
Function of the NF1 gene product (neurofibromin)
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
Autosome recessive general inheritance trends
- 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
Cystic fibrosis
Autosomal recessive
Sickle cell anemia
Autosomal recessive
Phenylketonuria
Autosomal recessive
Tay-Sachs disease (Hexosaminidase A deficiency)
Autosomal recessive
Congenital deafness
Autosomal recessive
Hemochromatosis
Autosomal recessive
- Delayed age of onset
- allelic heterogeniety
- C282Y is most common mutatino of the HFE gene
Alkaptonuria
Autosomal recessive
-Can be detected in infancy; but delayed age of onset
Homocystinuria
Autosomal recessive
Galactosemia
Autosomal recessive
Alpha1-antitrypsin deficiency
Autosomal recessive
SCID due to adenosine deaminase deficiency
Autosomal recessive
-If ADA is deficient, the build up of dATP is toxic to B-cell and T-cell development
Molecular basis for autosomal recessive disorders
Loss-of-function mutations
pseudo autosomal dominant
-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
Pseudoautosomal region
region of chromosomes that match. It is necessary to line up chromosomes correctly during meiotic recombination
General inheritance patterns of X-linked recessive disorders
- 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
Duchenne muscular dystrophy
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
Becker muscular dystrophy
X-linked recessive
- milder form
- due to mutations on the dystrophin gene
Glucose 6-phosphate dehydrogenase (G6PD) deficiency
X-linked recessive
-hemolytic anemia on ingestion of primaquine, sulfa drugs
Hemophilia A and B
X-linked recessive
-Result in bleeding tendencies
Lesch-Nyhan syndrome [Hypoxanthine Guanine Phosphoribosyl transferase (HGPRT) deficiency]
X-linked recessive
-Causes hyperuricemia, gout, & self mutilation
Red-green color blindness/deficiency
X-linked recessive
-non-lethal
X-linked SCID
X-linked recessive
-Defect in the SCIDX1 gene
