Single Gene Disorders and Complex Inheritance Flashcards
Mendelian Single Gene Disorders
How are they classified?
How to track?
`Classified by location of defect, and mode of transmission
Most are familial, track with pedigree
What is a mutation?
any permanent change to DNA
Framshift mutations?
Point Mutations?
insertion or deletion of 1 or 2 codons that leads to a shift in the reading frame
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Autosomal Dominant Disorders
Mutation of ?
Describe inheritance patterns:
Sex?
Parents?
Transmission?
Offspring?
Hetero mating?
Mutation of dominant gene on autosome
Patterns:
Male/female equal
affected usually have
affectde parent
Unaffected dont transmit
Offspring of affected-50%
75% mating
Autosomal Dominant Disorder Examples (2)
Marfans
Huntington
Marfans Syndrome
What chromo
disorder of CT
tall slender, long appendages
arachnodactyly
skeletal/joint deformities
CV lesions
Fibrillin 1 gene on chromo 15
Huntington Disease
Chromo affected
Neurologial dysfunction
mental deterioration: invol appendage movement
Late acting lethal dominant
chromo 4 has abnormal CAG repeats
Autosomal Recessive Disorders
Mutation of? Inheritance pattern: sex? parents? unaffected transmission? Hetero mating?
Mutation of recessive gene on autosomes
Male/female equal
disease not apparent in parents of affected
unaffected may transmit
hetero mating- 25% afflicted, 75% not
Autosomal Recessive Disorder Examples (3)
Albinism
Phenylketonuria
CF
Albinism
Lack of skin, hair, eye pigment
six forms:some have organ effects
one form: lack of tyrosinase
converts tyrosine to
melanin
risk sunburn, skin cancer, impaired vision, photosensitivity
Phenylketonuria
inability to metabolzie phemylalanine
inborn error of metabolsim
buildup of dietary phenylalanine in body- affects NS
Irritability, tremorousm slow developing retardation
excess phenylalanine excreted in urine-musty odor
manage with low phenylalanine diet
Cystic Fibrosis
Most common single gene disorder in caucasian
defective chloride in membrane transporter
productions of abnnormally thick secretions in lungs and pancreas
gene on chromo 7 many diff mutations
Sex Linked disorders
Aka
most are dom or recessive?
Females may?
Males may?
aka X linked disorders
most are x linked recessive
females may express, carry or not carry
males may express or not express
Sex Linked patterns of inheritance
dependent on?
Affected sex more is?
Affected fathers?
Unaffeted males are?
carrier female has __ chance of affected son.
__ chance of carrier daughter
females affected by
Dependent on sex
Affected are usually male
affected fathers transmit to daughters
unaffected male, are unable to carry
carrier female has 50% chance of affected son, 50% chance of carrier daughter
Females affected by: affected or carrier mother to affected father
Sex linked disorders
Examples:
Duchenne MD, Hemphilias A & B, chronic granulomatous disease, agammaglobulinemia, others lol
Hemophilia A
Bleeding disorder- lack of factor VIII
bleed easily and profusely
transmitted b/w royal families of europe
queen victoria-first carrier
NON MENDELIAN SINGLE GENE DISORDERS:
Fragile X
Triple repeat mutations-Fragile X syndrome
LOng repeating sequences of three nucleotides
Fragile X - mental retardation
Constriction on long arm of X contains CGG
Normal: 29 cGG
Fragile x: 230-4k repeats
Premutation: 52-230 repreats
AMPLIFIED DURING OOGENISIES
Non Mendelian
Mitochondiral Gene Mutations
Passed during cell division
Code for oxidative resp enzymes
dysfunction in tissues with High ATP needs
Tricky inheritance pattern
Non mendelian single gene:
Genomic Imprinting?
Prader willi syndrome:
Angelman Syndrome
maternal and parental chromosomes are different
Deletion on Paternal 15
mental retardation, short stature, obesity, poor muscle tone, hypogonadisn
Deleteion on MATERNAL 15
mental retardation, ataxia, laugh inappropriately
Polygenic Disorders
What are they?
Two or more mutant genes act together
Influenced by environment
No clear models of inheritance
range of expression = range of severity
geneticits nightmare
very common
High blood pressure, cancer, DM, cleft lip, heart defects
Digenic Retinitis Pigmentosa
Simple example of multigenic trait
Causes retinal degen by retinitis pigmentosa
2 rare mutations in 2 diff unlinked genes which are part of the photoreceptor
1 Mutation causes missense the other is null allele
Hetero for either = NO disease
Hetero for BOTH = disease
two mtations cause enough damage to kill photoreceptor cells
Venous Thrombosis
Idiopathic cerebral vein thrombosis
Gene/gene interaction with enviro influence
Idiopathic cerebral vein thrombosis
young adults- high
mortality
Three factors, 2 genetic/1 enviro
Venous Thrombosis
type of genetic error
Variation in 3' UTR of prothrombin gene heterozygotes 3-6x risk Oral conreceptive use 14-22x risk Combined all 3 30-150x risk
Missense mutation in clotting factor V
Factor V Leiden-FVL
Heterozygotes-7X risk
Homo-80x Risk
Hirschsprung Disease (HSCR)
Abnormality of parasympthetic innervation of gut…causes?
Usually isolated to one segment but can be more
Very complex genetics, high risk ratio for siblings
NO PERISTALISIS
HSCR
Occurs through multiple generations and multiple siblings
what does this suggest
Genes assoc
Suggests autosomal dom or recessive
BUT
Males have 2x higher risk = sex linked?
RET gene
EDNRB or EDN3
TYPE 1 DIABETES
Onset?
Patho?
Major genetic factor?
CTLA4, PTPN22 also seen
GENETIC FACTORS ALONE DO NOT CAUSE TYPE ! DIABETES
In childhood or adolescence
Autoimmune destruction of beta cells in pancreatic islands = no insulin production
MHC locus is MAJOR GENETIC FACTOR
HLA-DR3, HLA-DR4, HLA Class II locus
Alzheimer Disease
Fatal Neurodegen disease
Only definitive dx?
Most common cause of dementia in elderly
CHrinic progressive loss of memory and other intellicutal functions
Only definitive dx after death—-AMYLOID PLAQUES
What are B amyloid plauges
B amyloid plaques and neurofibrillary tangles destroy cortical tissue
plaques contain AB peptibe
derived from clevage or normal protien
Alzheimers Disease
GENE and GENE LOCATION
What genotype was found 2-3x more in AD patients?
What genotype had earlier onset?
APOE Locus- apolopoprotein E
Part of LDL particles
Part of Amyloid plaques
APOE gene maps to CHROMOSOME 19
Genotype with one e4 allele found 2-3x more often in AD patients
HOMOZYGOUS genotype for e4 had earlier onset
Mental Illness
affect?
Most severe?
4% of humans
Schizo/BPD
Schizo
affects ? humans
1%
Genetic info supported by twin and family studies
Little certainty as to what genes and alleles predisopse
One exception HIGH PREVELANCE IN CARRIERS OF 22Q11 DELETION WHO HAVE DIGEORGE SYNDROME
CAD
some genetic components
FAMILIAL HYPERCHOLESTEOLEMIA
Autosomal dom defect of LDL receptor
Multifactorial inheritance
