Genetics Flashcards
Codominance
Both alleles participate in phenotype of heterozygote
Ex : blood groups, alpha1-antitrypsin deficiency
Variable expressivity
Same genotype, not same phenotype.
Ex : 2 NF1 patients not same symptoms/disease severity
Incomplete penetrance
Not all individuals with genotype have phenotype
Ex : BRCA1 not always ovarian or breast cancer (65% sein, 45% ovaire)
Pleiotropy
One gene contributes to multiple phenotypic effect (phenotype pas le reflet de l’effet seul du gène)
Ex: non-tx phenylketonuria manifests with light skin, intellectual disability, musty body odor
Anticipation
increased severity with generations
ex: huntington disease
Loss of heterozygosity
If patients inherits or develops mutation in tumor suppressor gene, complementary allele must be deleted/mutated before cancer develops
ex: Rb, Li-Fraumeni syndrome, Lynch syndrome
Dominant negative mutation
Exerts a dominant effect. Heterozygote produces nonfunctional altered protein that also prevents normal gene product.
ex: mutation of transcription factor in its allosteric site
Linkage desequilibrium
Tendency of 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 (2 or more genetically different sets of cells). Can be somatic or gonadal.
Locus heterogeneity
Mutation at different loci produce similar phenotype
ex: albinism
Allelic heterogeneity
Different mutations in the same locus produce same phenotype.
ex: beta-thalassemia
Heteroplasmy
Presence of both normal and mutated mtDNA resulting in variable expression in mitochondrially inherited disease.
Uniparental disomy
Kid receive 2 copies of chromosome from 1 parent and no copie from the other. If heterozygous meiosis I error. If homozygous meiosis II error. (when recessive disorder but 1 parent only is carrier)
McCune-Albright Syndrome
Mutation affecting G-protein signaling
Sx :
-unilateral café-au-lait spots with ragged (irrégulier) edges
-Polyostotic fibrous dysplasia
-At least 1 endocrinopathy
Prognosis : lethal if before fertilization, survivable if mosaism
Imprinting
At some loci, one allele is active and the other is inactive. If active allele mutated -> disease
Prader-Willi syndrome
Mutation/deletion on chromosome 15 (same locus as Angelman)
Maternal imprinting : maternal gene is silent, dad gene is mutated/deleted.
25% maternal uniparental disomy
Sx : hyperphagia + obesity, DI, hypogonadism, hypotonia
Angelman syndrome
Mutation/deletion on chromosome 15 (same locus as Prader-Willi)
Paternal imprinting : maternal gene is mutated/deleted, dad gene is silent.
5% paternal uniparental disomy
Sx: inappropriate laugher (happy puppet), seizures, ataxia, severe DI
Hypophosphatemic rickets
X-linked dominant
Rickets-like symptoms
MELAS syndrome
Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS)
Mitochondrial myopathy disease, rare
Pathogenesis: failure in oxidative phosphorylation
Dx: muscle biopsie -> ragged red fibers
Autosomal dominant diseases
Achondroplasia (nainisme) Autosomal dominant polycystic kidney disease (ADPKD) Familial adenomatous polyposis Familial hypercholesterolemia Hereditary hemorrhagic telangiectasia Hereditary spherocytosis Huntington disease Li-Fraumani syndrome Marfan syndrome Multiple endocrine neoplasias NF1 and NF2 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
X-linked recessive disorders
Ornithine transcarbamylase deficiency Fabry disease Wiskott-Aldrich syndrome Ocular albinism G6PD deficiency Hunter syndrome Bruton agammaglobulinemia Hemophilia A & B Lesch-Nyhan syndrome Duchenne (and Becker) muscular dystrophy
Cystic fibrosis
Autosomal recessive. Defect gene CFTR, chromosome 7.
Commonly deletion Phe508.
Most common lethal genetic disease in caucasian
Pathophysiology: CFTR encodes ATP-gated Cl- that secretes Cl- in lungs + GI and reabsorbs Cl- in sweat glands. Mutation -> protein not transported to cell membrane -> reduced Cl-/H2O secretion -> increased intracellular Cl- -> increased compensatory Na+ reabsorption -> increased H2O absorption -> thick mucus
Dx: Cl- > 60mEq/L in sweat. Raised immunoreactive trypsinogen (newborn screening). Can present with contraction alkalosis and hypokalemia.
CXR: reticulonodular pattern. Rx sinus: opacification
Complications: Recurrent pulmonary infections (S. aureus infancy -> P. aeruginosa adolescence), chronic bronchitis, bronchiectasis. Pancreactic insuffisency, malabsorption with steatorrhea, ADEK deficits, liver disease, biliary cirrhosis. Meconium ileus in newborns. Infertility in men (no vas deferens) and subfertility in women (thick cervical mucus). Clubbing. Nasal polyps.
Muscular dystrophy of Duchenne
X-linked recessive disorder (most frequent in male). Onset before 5 yo.
Frameshift or non-sense mutation = truncated or absent dystrophin protein -> progressive myofiber damage.
Sx:
- muscular weakness starting in pelvic girdle and progress superiorly. (Gower sign + lordosis)
- pseudohypertrophy of calf muscles (fibrofatty muscle replacement)
- Waddling (dandinant) gait
- dilated cardiomyopathy (main cause of death)
