Biochemistry- Genetics Flashcards
Codominance
Both alleles contribute to the phenotype of the
heterozygote (Blood groups A, B, AB; α1-antitrypsin
deficiency.)
Variable expressivity
Patients with the same genotype have varying
phenotypes. NF1
Incomplete
penetrance
Not all individuals with a mutant genotype
show the mutant phenotype. BRCA1
Pleiotropy
One gene contributes to multiple phenotypic
effects. Phenylketonuria
Anticipation
Increased severity or earlier onset of disease in
succeeding generations. Trinucleotide repeat diseases
Untreated phenylketonuria (PKU)
Manifests with light skin, intellectual disability, and musty body odor. gen PAH (phenylalanine hydroxylase)
Loss of heterozygosity
If a patient inherits or develops a mutation in a tumor suppressor gene, the complementary allele must be deleted/mutated before cancer develops.
Dominant negative
mutation
A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from
functioning.
Linkage
disequilibrium
Tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance.
Mosaicism
Presence of genetically distinct cell lines in the
same individual. McCune-Albright syndrome
- Somatic
- Gonadal
Locus heterogeneity
Mutations at different loci can produce a similar phenotype. Albinism
Allelic heterogeneity
Different mutations in the same locus produce the same phenotype. β-thalassemia.
Heteroplasmy
Presence of both normal and mutated mtDNA, resulting in variable expression in mitochondrially inherited disease
Uniparental disomy
Offspring receives 2 copies of a chromosome from
1 parent and no copies from the other parent.
Consider UPD in an individual manifesting a recessive disorder when only one parent is a carrier.
Hardy-Weinberg
equilibrium
p2 + 2pq + q2 = 1 and p + q = 1
p2 = frequency of homozygosity for allele A
q2 = frequency of homozygosity for allele a
2pq = frequency of heterozygosity (carrier
frequency, if an autosomal recessive disease)
frequency of an X-linked recessive disease
in males = q and in females = q2.
Hardy-Weinberg law assumptions include:
No mutation occurring at the locus
Natural selection is not occurring
Completely random mating
No net migration
Imprinting
At some loci, only one allele is active; the
other is inactive. With one allele inactivated,
deletion of the active allele = disease.
Prader-Willi syndrome (P paternal) Chromosome 15
Maternal imprinting: gene from mom is normally
silent and Paternal gene is deleted/mutated. 25% of cases due to maternal uniparental
disomy.
Results in hyperphagia, obesity, intellectual disability, hypogonadism, and hypotonia.
AngelMan syndrome (M maternal) Chromosome 15
Paternal imprinting: gene from dad is normally
silent and Maternal gene is deleted/mutated. 5% of cases due to paternal uniparental disomy
(“happy puppet”), seizures, ataxia, and severe
intellectual disability.
Autosomal dominant
Often due to defects in structural genes. Many
generations, both males and females are
affected.
Autosomal recessive
Often due to enzyme deficiencies. Usually seen
in only 1 generation.
X-linked recessive
Sons of heterozygous mothers have a 50% chance of being affected. No male-to-male transmission. Skips generations.
X-linked dominant
Transmitted through both parents. Mothers transmit to 50% of daughters and sons; fathers transmit to all daughters but no sons.
Hypophosphatemic rickets, fragile X syndrome, Alport
syndrome.
Hypophosphatemic rickets—formerly known as
vitamin D–resistant rickets.
Inherited disorder resulting in phosphate wasting at proximal tubule. Results in rickets-like presentation.
Mitochondrial
inheritance
Transmitted only through the mother. All offspring of affected females may show signs of disease. Mitochondrial myopathies
MELAS syndrome
(mitochondrial encephalopathy, lactic acidosis,
and stroke-like episodes).
2° to failure in oxidative phosphorylation. Muscle biopsy often shows “ragged red fibers”.
Autosomal dominant
diseases
Achondroplasia, autosomal dominant polycystic kidney disease, familial adenomatous polyposis,
familial hypercholesterolemia, hereditary hemorrhagic telangiectasia, hereditary spherocytosis,
Huntington disease, Li-Fraumeni syndrome, Marfan syndrome, multiple endocrine neoplasias,
neurofibromatosis type 1 (von Recklinghausen disease), neurofibromatosis type 2, tuberous
sclerosis, von Hippel-Lindau disease.
Autosomal recessive
diseases
Albinism, autosomal recessive polycystic kidney disease (ARPKD), cystic fibrosis, glycogen
storage diseases, hemochromatosis, Kartagener syndrome, mucopolysaccharidoses (except
Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoses (except Fabry disease),
thalassemias, Wilson disease.
Cystic fibrosis
Autosomal recessive; defect in CFTR gene on chromosome 7; commonly a deletion of Phe508.
Cl− concentration (> 60 mEq/L) in sweat is diagnostic.
Recurrent pulmonary infections, Pancreatic insufficiency, Infertility in men, subfertility in women, biliary cirrhosis, liver disease. Meconium ileus in newborns.
X-linked recessive
disorders
Oblivious Female Will Often Give Her Boys
Her x-Linked Disorders
Ornithine transcarbamylase deficiency, Fabry
disease, Wiskott-Aldrich syndrome, Ocular
albinism, G6PD deficiency, Hunter syndrome,
Bruton agammaglobulinemia, Hemophilia
A and B, Lesch-Nyhan syndrome, Duchenne
Lyonization—
female carriers variably affected
depending on the pattern of inactivation of the
X chromosome
Duchenne
X-linked disorder typically due to frameshift
or nonsense mutations
Becker
X-linked disorder typically due to nonframeshift
deletions in dystrophin gene
Myotonic type 1
Autosomal dominant. CTG trinucleotide repeat
expansion in the DMPK gene (myotonin protein kinase)
CTG: Cataracts, Toupee (early balding in men),
Gonadal atrophy.
Gower sign—
patient uses upper extremities to
help stand up.
Fragile X syndrome
Trinucleotide repeat in FMR1 gene disorder (CGG)n.
Chin (protruding), Giant Gonads
Most common cause of inherited intellectual disability and autism and 2nd most common cause of genetically
associated mental deficiency.
Trinucleotide repeat expansion diseases
Try (trinucleotide) hunting for my fragile cage free
eggs (X).
Huntington disease, myotonic dystrophy,
fragile X syndrome, and Friedreich ataxia.
Huntington disease
Myotonic dystrophy
Fragile X syndrome
Friedreich ataxia
CAG: Caudate has lower ACh and GABA
CTG: Cataracts, Toupee (early balding in men), Gonadal atrophy
CGG: Chin (protruding), Giant Gonads
GAA: ataxic GAAit
Down syndrome
(trisomy 21) Mutation
- 95% of cases due to meiotic nondisjunction
- 4% of cases due to unbalanced Robertsonian translocation, between chromosomes 14 and 21.
- 1% of cases due to mosaicism
Down syndrome
(trisomy 21) Findings
intellectual disability, flat facies, prominent epicanthal folds, single palmar crease, gap between 1st 2 toes, duodenal atresia, Hirschsprung disease, congenital heart disease, Brushfield spots. Associated with early-onset Alzheimer disease (chromosome 21 codes for
amyloid precursor protein) and risk of ALL
and AML.
Down syndrome
(trisomy 21) epidemiology
Incidence 1:700.
Most common viable chromosomal disorder and
most common cause of genetic intellectual
disability.
Edwards syndrome
trisomy 18
PRINCE Edward—Prominent occiput, Rocker-bottom feet, Intellectual disability, Nondisjunction, Clenched fists
(with overlapping fingers), low-set Ears, micrognathia (small jaw), congenital heart disease.
Patau syndrome
trisomy 13
Findings: severe intellectual disability, rockerbottom
feet, microphthalmia, microcephaly, cleft liP/Palate, holoProsencephaly, Polydactyly, cutis aPlasia, congenital heart disease.
Robertsonian
translocation
Chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22.
One of the most common types of translocation (Down syndrome, Patau syndrome).
Cri-du-chat syndrome
Congenital microdeletion of short arm of chromosome 5 (46,XX or XY, 5p−).
Williams syndrome
Congenital microdeletion of long arm of chromosome 7.
“elfin” facies, intellectual disability, hypercalcemia ( sensitivity to vitamin D), well-developed verbal skills, extreme friendliness with strangers, cardiovascular problems.
Genetic disorders by
chromosome
Pagina 60 usmle
22q11 deletion
syndromes
CATCH-22
Cleft palate, Abnormal facies, Thymic aplasia, Cardiac defects, and Hypocalcemia 2° to parathyroid aplasia.
DiGeorge syndrome
Velocardiofacial syndrome
aberrant development of 3rd and 4th
branchial pouches.
