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  • Genetic terms
    • Codominance
      • Both alleles contribute to the phenotype of the heterozygote.
      • Blood groups A, B, AB; α1-antitrypsin deficiency; HLA groups.
    • Variable expressivity
      • Patients with the same genotype have varying phenotypes.
      • 2 patients with neurofibromatosis type 1 (NF1) may have varying disease severity.
    • Incomplete penetrance
      • Not all individuals with a mutant genotype show the mutant phenotype.
      • % penetrance × probability of inheriting genotype = risk of expressing phenotype.
      • BRCA1 gene mutations do not always result in breast or ovarian cancer.
    • Pleiotropy
      • One gene contributes to multiple phenotypic effects.
      • Untreated phenylketonuria (PKU) manifests with light skin, intellectual disability, and musty body odor.
    • Anticipation
      • Increased severity or earlier onset of disease in succeeding generations.
      • Trinucleotide repeat diseases (eg, Huntington disease).
    • 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. This is not true of oncogenes.
      • Retinoblastoma and the “two-hit hypothesis, Lynch syndrome (HNPCC), Li-Fraumeni syndrome
    • Dominant-negative mutation
      • Exerts a dominant effect. A heterozygote produces a nonfunctional altered protein that also prevents the normal gene product from functioning.
      • Mutation of a transcription factor in its allosteric site. Nonfunctioning mutant can still bind DNA, preventing wild-type transcription factor from binding.
    • Linkage disequilibrium
      • Tendency for certain alleles at 2 linked loci to occur together more or less often than expected by chance. Measured in a population, not in a family, and often varies in different populations.
    •  Mosaicism
      • Presence of genetically distinct cell lines in the same individual. Can result from chromosomal nondisjunction and mutations during the first stages of embryonic development
      • Somatic mosaicism—mutation arises from mitotic errors after fertilization and propagates through multiple tissues or organs. May have milder forms of the disease or symptomatic, depending on ratio of abnormal to normal cells.
      • Gonadal mosaicism—mutation only in egg or sperm cells (gametes), allowing the affected genes to pass to the offspring. The chance of the child being affected depends on the proportion of gametes that carry the mutation. When mosaicism is limited to the germline, the affected parents do not develop clinical manifestations.
    • McCune-Albright syndrome—due to mutation affecting G-protein signaling. Presents with unilateral café-au-lait spots (A) with ragged edges, polyostotic fibrous dysplasia (bone is replaced by collagen and fibroblasts), and at least one endocrinopathy (eg, precocious puberty). Lethal if mutation occurs before fertilization (affecting all cells), but survivable in patients with mosaicism. MAS results from a mosaic somatic mutation during embryogenesis in the GNAS gene encoding the stimulatory α subunit of G protein.  This mutation causes constitutive activation of the G protein/cAMP/adenylate cyclase signaling cascade, which leads to a gain of function of the affected cells.  Persistent G-protein stimulatory activity in melanocytes results in prominent café-au-lait macules (CALMs).  CALMs, usually the first manifestation of MAS, are often large and unilateral with an irregular, “coast of Maine” border. In addition, autonomous endocrine function most commonly results in precocious puberty (onset of secondary sexual development before age 8 in girls).  The mutation also results in increased proliferation of fibroblast-like cells, increased secretion of IL-6, and activation of osteoclasts (fibrous dysplasia).  The term polyostotic refers to the presence of lesions in many bones, although they are typically unilateral.
    • 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.
      • mtDNA passed from mother to all children.
    • Uniparental disomy
      • Offspring receives 2 copies of a chromosome from 1 parent and no copies from the other parent.
        • HeterodIsomy (heterozygous) indicates a meiosis I error.
        • IsodIsomy (homozygous) indicates a meiosis II error or postzygotic chromosomal duplication of one of a pair of chromosomes, and loss of the other of the original pair.
      • Uniparental is euploid (correct number of chromosomes). Most occurrences of uniparental disomy (UPD) → normal phenotype. Consider UPD in an individual manifesting a recessive disorder when only one parent is a carrier. Examples: Prader-Willi and Angelman syndromes.
    • Hardy-Weinberg population genetics
      • If a population is in Hardy-Weinberg equilibrium and if p and q are the frequencies of separate alleles, then:
        • The total gene pool is given by (p + q) = 1.  By convention, p = normal allele (A) frequency and q = mutant allele (a) frequency in the population of interest.
        • Phenotypic frequency: p2 + 2pq + q2 = 1
        • p2 = frequency of homozygosity for normal allele A
        • q = mutant allele frequency
        • q2 = frequency of homozygosity for mutant allele (aa) = disease prevalence in autosomal recessive diseases
        • Carriers have only 1 mutant allele that may be inherited in 2 different ways (ie, Aa or aA); consequently, the probability of being a carrier = 2pq.  For rare autosomal recessive disorders, p ≈ 1; therefore, the probability approximates to 2 times the frequency of the mutant allele, or 2q.
        • The 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


    • Modes of inheritance
      • Autosomal dominant
        • Often due to defects in structural genes. Many generations, both males and females are affected.
        • Often pleiotropic (multiple apparently unrelated effects) and variably expressive (different between individuals).
        • Family history crucial to diagnosis. With one affected (heterozygous) parent, on average, 1/2 of children affected.
        • Achondroplasia, autosomal dominant polycystic kidney disease, familial adenomatous polyposis, familial hypercholesterolemia, hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome), hereditary spherocytosis, Huntington disease, Li-Fraumeni syndrome, Marfan syndrome, multiple endocrine neoplasias, myotonic muscular dystrophy, neurofibromatosis type 1 (von Recklinghausen disease), neurofibromatosis type 2, tuberous sclerosis, von Hippel-Lindau disease.
      • Autosomal recessive
        • Often due to enzyme deficiencies. Usually seen in only 1 generation.
        • Commonly more severe than dominant disorders; patients often present in childhood.
        • ↑ risk in consanguineous families.
        • With 2 carrier (heterozygous) parents, on average:
          • ¼ of children will be affected (homozygous)
          • ½ of children will be carriers
          • ¼ of children will be neither affected nor carriers.
        • Unaffected individual with affected sibling has 2/3 probability of being a carrier.
        • Albinism, autosomal recessive polycystic kidney disease (ARPKD), cystic fibrosis, Friedreich ataxia, glycogen storage diseases, hemochromatosis, Kartagener syndrome, mucopolysaccharidoses (except Hunter syndrome), phenylketonuria, sickle cell anemia, sphingolipidoses (except Fabry disease), thalassemias, Wilson disease.
      • X-linked recessive
        • Sons of heterozygous mothers have a 50% chance of being affected. No male-to-male transmission. Skips generations.
        • Commonly more severe in males. Females usually must be homozygous to be affected.
        • Ornithine transcarbamylase deficiency, Fabry disease, Wiskott-Aldrich syndrome, Ocular albinism, G6PD deficiency, Hunter syndrome, Bruton agammaglobulinemia, Hemophilia A and B, Lesch-Nyhan syndrome, Duchenne (and Becker) muscular dystrophy. Oblivious Female Will Often Give Her Boys Her x-Linked Disorders
      • X-inactivation (lyonization)—female carriers variably affected depending on the pattern of inactivation of the X chromosome carrying the mutant vs normal gene. Females with Turner syndrome (45,XO) are more likely to have an X-linked recessive disorder.
      • 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—formerly known as vitamin D–resistant rickets. Inherited disorder resulting in ↑ phosphate wasting at proximal tubule. Results in rickets-like presentation.
        • Other examples: fragile X syndrome, Alport syndrome.
      • Mitochondrial inheritance
        • Transmitted only through the mother. All offspring of affected females may show signs of disease.
        • Variable expression in a population or even within a family due to heteroplasmy.
        • Mitochondrial myopathies—rare disorders; often present with myopathy, lactic acidosis, and CNS disease. 2° to failure in oxidative phosphorylation. Muscle biopsy often shows “ragged red fibers” (due to accumulation of diseased mitochondria). Blotchy red muscle fibers on Gomori trichome stain. Abnormal irregular mitochondria accumulate under the sarcollema of muscle fibers. Mutations, deletions or duplications of mtDNA.
          • MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes).
          • MERFF (myoclonic epilepsy with ragged red fibers)
          • Leber optic neuropathy (blindness)—cell death in optic nerve neurons → subacute bilateral vision loss in teens/young adults, 90% males. Usually permanent.
          • Kearns-Sayre syndrome (KSS) – progressive external ophthalmoplegia (PEO), pigmentary retinitis and an onset before the age of 20 years. Additional features include deafness, cerebellar ataxia and heart block.
      • Polygenic inheritance
        • Androgenetic alopecia – hormonal and genetic
          • Short am of chromosome 20, X and Y chromosomes
          • Some may be X-linked recessive (gene variations in androgen receptor), others may be autosomal dominant
        • Epilepsy
        • Glaucoma
        • Hypertension
        • Ischemic heart disease
        • Schizophrenia
        • Type II diabetes mellitus
      • Trinucleotide repeat expansion diseases
        • Huntington disease, myotonic dystrophy, fragile X syndrome, and Friedreich ataxia.
        • May show genetic anticipation (disease severity → and age of onset ↓ in successive generations).
        • Try (trinucleotide) hunting for my fragile cage-free eggs (X).
Disease Trinucleotide repeat Mode of inheritance Mnemonic
Huntington disease (CAG)n AD  Caudate has ↓ACh and GABA
Myotonic dystrophy (CTG)n AD Cataracts, Toupee (early balding in men),

Gonadal atrophy

 Fragile X syndrome (CGG)n XD  Chin (protruding), Giant Gonads
Friedreich ataxia (GAA)n AR Ataxic GAAit
  • Genetic disorders by chromosome
3 von Hippel-Lindau disease, renal cell carcinoma
4 ADPKD (PKD2), achondroplasia, Huntington disease
5 Cri-du-chat syndrome, familial adenomatous polyposis
6 Hemochromatosis (HFE)
7 Williams syndrome, cystic fibrosis
9 Friedreich ataxia, tuberous sclerosis (TSC1)
11 Wilms tumor, β-globin gene defects (eg, sickle cell disease, β-thalassemia), MEN1
13 Patau syndrome, Wilson disease, retinoblastoma (RB1), BRCA2
15 Prader-Willi syndrome, Angelman syndrome, Marfan syndrome
16  ADPKD (PKD1), α-globin gene defects (eg, α-thalassemia), tuberous sclerosis (TSC2)
17 Neurofibromatosis type 1, BRCA1, p53
18 Edwards syndrome
21 Down syndrome
22 Neurofibromatosis type 2, DiGeorge syndrome (22q11)
X Fragile X syndrome, X-linked agammaglobulinemia, Klinefelter syndrome (XXY)
      • Robertsonian translocation
        • Chromosomal translocation that commonly involves chromosome pairs 13, 14, 15, 21, and 22.
        • One of the most common types of translocation. Occurs when the long arms of 2 acrocentric chromosomes (chromosomes with centromeres near their ends) fuse at the centromere and the 2 short arms are lost.
        • Balanced translocations normally do not cause any abnormal phenotype. Unbalanced translocations can result in miscarriage, stillbirth, and chromosomal imbalance (eg, Down syndrome, Patau syndrome).

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