inheritance patterns

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    • Pedigree
      • Generations are assigned Roman numerals
      • individuals within each generation are indicated by Arabic numerals.
      • The arrow points at the proband, the person in whom the genetic disorder was first diagnosed.
    • Autosomal recessive inheritance
      • condition is expressed only in persons who have two copies of (ie, are homozygous for) the mutant allele
      • often observed with enzyme deficiencies (MCQ)
      • What is margin of safety effect.
        • heterozygotes express 50% of normal activity. (MCQ)
        • However, 50% of normal enzyme activity in these cases permits normal
        • physiologic function because expression of enzyme from the normal allele is sufficient to provide for the needs of the cell.
      • Both parents of an affected person must have one normal and one mutant allele, making them obligate carriers barring very rare new mutations.
      • The likelihood of a person being homozygous for an autosomal recessive trait increases in consanguineous matings because of the existence of a common ancestor. (MCQ)
      • Rare autosomal recessive diseases also occur with high frequency among genetically isolated populations due to inbreeding. (MCQ)
      • Pedigree charts show the following:
        • The disease phenotype is expressed by siblings but not by their parents or offspring. (MCQ)
        • Equal occurrence in males and females. (MCQ)
        • Recurrence risk for each sibling is 25%.(MCQ)
        • Possible consanguinity. (MCQ)

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Recessive inheritance is shown in pedigrees A and B.

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    • Autosomal dominant inheritance
      • this condition is expressed even if a single mutant allele is present, ie, in the heterozygous state
      • Following are four possible situations by which having one normal copy of a gene is insufficient to prevent disease, leading to a dominant
        • Situation 1 :
          • When the presence of 50% normal activity (ordinarily the margin of safety) is not generous enough to allow normal physiologic function, a condition called haploinsufficiency. (MCQ)
        • Situation 2 :
          • When the defective allele produces a malfunctioning protein product that binds to and interferes with function of the normal gene product—the dominant negative effect.
        • Situation 4 :
          • When the mutant protein has an enhanced function that overrides normal controls or is cytotoxic
        • Situation 5 :
          • When the phenotype appears as dominant inheritance even though the actual allele is recessive at the level of function in individual cells.
      • The homozygous mutant state usually produces a more severe clinical condition than the heterozygous condition in autosomal dominant diseases.
      • Pedigree charts for an autosomal dominant disorder
        • The disease phenotype appears in all generations, with each affected person having an affected parent. (MCQ)
        • There is an equal occurrence in males and females, except in cases when ex- pression of the trait is influenced by the person’s sex (ie, sex-limited). (MCQ)
        • Risk of transmission of the mutant allele is 50%, but because there usually are so few persons in a family, there may be deviations from this expectation. (MCQ)
        • Potential for some cases to be due to a new mutation, which is more likely for a dominant condition because disease symptoms would be expressed in heterozygotes. (MCQ)  

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Dominant inheritance is shown in pedigree, in which every affected person has an affected parent. 

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  • An autosomal dominant disorder exhibiting anticipation
  • In pedigree , the age of onset, indicated next to the symbols for affected individuals, becomes progressively earlier with each generation.  
    • X-linked recessive inheritance pattern
      • there can be no male-to-male transmission because the sex of male offspring is determined by contribution of a Y chromosome from the father. (MCQ)
      • Because they have only one X chromosome, the sons of heterozygous mothers have a 50% chance of being affected. (MCQ)
      • Pedigree charts
        • Incidence of disease is higher in males than in females. (MCQ)
        • Female heterozygotes are usually unaffected carriers. (MCQ)
        • Affected men transmit the gene to all daughters, but never to sons. (MCQ)
        • New mutations cause a significant number of isolated cases in males due to unopposed expression of the mutant allele. (MCQ)

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    • X-linked dominant diseases are relatively rare
      • Such genes may be transmitted either to sons or daughters by an affected mother but only to daughters by an affected father.
      • disorders with X linked dominant inheritance
        • Xg blood group
        • vitamin D–resistant rickets. (MCQ)
        • Rett syndrome
        • Most cases of Alport syndrome
        • Incontinentia pigmenti
        • Charcot–Marie–Tooth disease(MCQ)
      • Pedigree charts
        • All daughters of affected men are affected but never their sons, which may lead to prevalence of affected females over affected males. (MCQ)
        • Recurrence risk is 50% for both male and female offspring of an affected female. (MCQ)
        • Absence of affected males in several generations may suggest prenatal lethality for the hemizygous state. (MCQ)

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Pedigrees illustrating X-linked recessive (A) and dominant (B) inheri- tance patterns. Note the absence of male-to-male transmission in both pedigrees and the predominance of affected males over females in the X-linked recessive pedigree.  

  • Incompletely dominant disorders
    • occur in cases where the heterozygous genotype produces a different phenotype from that seen in the homozygous genotype.
    • The effect is often of intermediate severity between the unaffected and fully affected phenotypes.
    • For example, in sickle cell anemia, the normal allele is incompletely dominant in heterozygotes. (MCQ)
  • Mitochondrial disorders
    • The mitochondrial chromosome (mtDNA) is a 16.5 kb circular plasmid.
    • The mtDNA bears 37 genes encoding rRNAs, tRNAs, and some genes for
    • proteins involved in oxidative phosphorylation. (MCQ)
    • are maternally transmitted because the ovum provides all mitochondria to the fertilized embryo
    • What is heteroplasmy(MCQ)
      • In these disorders, affected cells usually have a mixture of mitochondria, some with mutant mtDNA and others with wild-type mtDNA, a condition called heteroplasmy.
    • Segregation of mitochondria during cell division is not as tightly controlled as for nuclear chromosomes, leading to random distribution of mitochondria carrying normal and mutant mtDNA to ova.
    • This contributes to variable expression and reduced penetrance of the phenotype among persons within kindreds with mitochondrial disorders.

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inheritance of a mitochondrial disorder . note the similarity to the X-linked dominant inheritance pattern but incomplete penetrance as exemplified by individuals II-4 and III-4.

  • Major Concepts in Human Genetics
    • When similar phenotypes or disease conditions can be caused by different geno- types, this may produce heterogeneity.
    • Allelic heterogeneity (MCQ)
      • occurs when different alleles of the same gene produce clinically similar conditions.
      • Allelic heterogeneity may account for phenotypic variability in some families with genetic disease.
    • Locus heterogeneity (MCQ)
      • refers to the condition when mutations of more than one gene or locus can produce similar disease states.
      • This genotypic variability is responsible for different inheritance patterns of some disorders.
      • For example, Ehlers-Danlos syndrome may be caused by mutations at more than 10 known loci, producing inheritance patterns ranging from autosomal recessive or dominant to X-linked. (MCQ)
    • Variable expression
      • arises when the nature and severity of the phenotype for a genetic condition varies from one person to another.
    • Pleiotropy
      • refers to a condition in which a mutant allele may have different phenotypic effects in various organ systems in an affected person.
    • Genomic imprinting
      • expression of an allele differs depending on whether it is inherited from the mother or the father.
      • A gene that is shut off when inherited from the mother is maternally imprinted. (MCQ)
      • A gene that is silenced when inherited from the father is paternally imprinted. (MCQ)
      • Imprinting involves an epigenetic mechanism, ie, an alteration in phenotype that does not result from a change in the genotype. (MCQ)
      • Expression of the imprinted genes is silenced or shut off by methylation of certain chromatin regions after DNA replication during gametogenesis.
      • The imprint is reversible upon passage through gametogenesis in the nextgeneration.
    • Genetic Anticipation
      • Certain inherited disorders exhibit increased severity of phenotype or decreased age of onset as the disease gene is passed from one generation to the next, an effect known as anticipation
      • Examples of genetic diseases that show anticipation are Huntington disease, Fragile X syndrome(MCQ)
      • disorders that arise from trinucleotide repeat expansion show Genetic anticipation(MCQ)
      • Disease symptoms occur only when the length of the trinucleotide repeat region exceeds a threshold.
    • Mosaicism
      • It is defined as the presence of cells in the body that are genetically different.
      • Somatic mosaicism
        • mutation of a gene occurs in a non-germline (somatic) cell at some point during early development of the person, and all cells descendent from that progenitor are genetically distinct.
      • Germline mosaicism
        • a mutation that occurred in the parent’s gonadal make-up is transmitted through some gametes, but not all.
        • All females are technically mosaic for the genes of their X chromosomes due to inactivation of one or the other X chromosomes early in development, a phenomenon termed the Lyon hypothesis or lyonization. (MCQ)
        • Because X inactivation is random, this phenomenon accounts for variable expression of some X-linked disorders, depending on whether the diseaseallele or wild-type allele was inactivated. (MCQ)
        • Distribution of cells from the early embryo to the tissues may be imbalanced, so that expression of the disease phenotype is not uniform among the organs.
        • Up to 25% of patients with Turner syndrome exhibit a mosaic karyotype, in which only some cells have the 45,X karyotype classically associated with the condition. (MCQ)
    • Uniparental disomy
      • refers to a condition in which one or more cells of the body have two identical chromosomes derived from a single parent, which increases the likelihood of expression of recessive alleles inherited from that parent. (MCQ)
        • Applied Aspects :
        • Variable expression in neurofibromatosis type
          • The biochemical defect involves loss-of-function mutations of the NF1 tumor suppressor gene.(MCQ)
          • variability of expression in kindreds makes genetic counseling very difficult.
        • Disorders that exhibit imprinting
          • Two clinically distinguishable conditions arise from deletion of the same region of chromosome 15 (15q11–q13) .(MCQ)
          • Prader-Willi syndrome
            • Arises when deleted chromosome 15 is paternally inherited. .(MCQ)
            • exhibit .(MCQ)
              • failure to thrive and short stature initially
              • converts to a tendency toward excessive eating, obesity
              • mild-to-moderate mental retardation, hypogonadism
              • characteristic facial dysmorphology.
          • Angelman syndrome
            • occurs when chromosome 15 with the deletion is maternally inherited. .(MCQ)
            • involve paternal imprinting of UBE3A, encoding a ubiquitin-protein ligase so that this gene product must be produced from the maternal chromosome. .(MCQ)
            • it is a devastating neurologic disorder featuring
              • severe mental retardation
              • a “happy puppet” demeanor
              • seizures, ataxic gait, and aphasia.
        • Uniparental disomy in Beckwith-wiedemann syndrome
          • They show an .(MCQ)
            • overgrowth condition from birth
            • macroglossia (enlarged tongue).
            • severe hypoglycemia that may become life-threatening
            • en hanced tendency to develop cancers of the liver, kidney, and adrenal glands.
          • The mapped to chromosome 11 (11p15), a region encompassing the gene for insulin-like growth factor II (IGF2), which is maternally imprinted and thus is expressed only when paternally inherited. .(MCQ)
          • Uniparental disomy may contribute to BWS in that excess paternal or decreased maternal contributions of chromosome 11 have been observed in some patients.


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