Mendellian Inheritance Patterns

Inheritance patterns of single-gene disorders are based on traditional Mendelian laws of segregation and independent assortment. The following assumptions are made as a result of these laws: (1) An offspring inherits one autosomal chromosome from each parent and, thus, one of any given allele from each parent; (2) both alleles, regardless of inheritance, are equally expressed and heterozygotes can transmit either allele to their offspring with equal frequency; and (3) the phenotypic pattern of inheritance is dependent on whether the allele in question is located on an autosome or sex chromosome and whether the genetic disorder is dominant or recessive.

Dominant disorders are those in which a single mutant allele results in disease. Both heterozygotes and homozygotes of an autosomal dominant disorder express the disease phenotype, however, individuals homozygous for a dominant disorder are relatively rare. Recessive disorders, on the other hand, are those in which two copies of the mutant allele must be present for the disease phenotype; heterozygotes are indistinguishable from normal homozygotes. It is important to note that in recessive disorders, heterozygotes might have subtle phenotypic differences at the biochemical level that often go unnoticed. Individuals carrying one normal allele and one mutant allele are called carriers. If two individuals are carriers of alleles that cause the same recessive disorder, their offspring have a 25% chance of being affected and a 50% chance of being carriers.

The result of a mutant allele, dominant or recessive, is the result of the effect of the mutation on the role of a gene product associated with any given biological system. Disease phe-notypes can be the result of the total loss or gain of protein function as a result of a single-base mutation. In some cases, a total or partial loss of protein function is observed, whereas in others, the protein functions abnormally or there is excessive normal activity. Most mutant alleles resulting in a loss of protein function exhibit recessive phenotypes. A dominant allele typically confers a gain of function, either abnormal or normal. Dominant negative phenotypes have been described, which refer to a mutant protein interfering with the normal function of the protein produced by the normal allele in heterozygotes.

The typical patterns of autosomal dominant and recessive inheritance are depicted in the following pedigrees. Autosomal dominant disorders are characterized by vertical transmission of the disease from generation to generation, equal expressivity in males and females, an affected individual having a 50% chance of offspring being affected, lack of affected children from unaffected parents, and most affected individuals having an affected parent, except in the case of a new mutation (Fig. 5). In contrast, autosomal recessive disorders are characterized by horizontal penetrance, affected homozygous individuals having unaffected heterozygous parents, and heterozygous parents having a 25% chance of offspring being affected (Fig. 6).

Several exceptions to these classic Mendelian rules of inheritance have been recognized and include recently described

Marfan Syndrome Inheritance Pattern

Fig. 5. Family pedigree showing autosomal dominant inheritance pattern of a genetic disease. Examples include Huntington's disease, neurofibromatosis, myotonic dystrophy, familial hypercholesterolemia, Marfan syndrome, adult polycystic kidney disease, and multiple endocrine neoplasia (MEN). Circle, female; square, male; open, unaffected; solid, affected.

Fig. 5. Family pedigree showing autosomal dominant inheritance pattern of a genetic disease. Examples include Huntington's disease, neurofibromatosis, myotonic dystrophy, familial hypercholesterolemia, Marfan syndrome, adult polycystic kidney disease, and multiple endocrine neoplasia (MEN). Circle, female; square, male; open, unaffected; solid, affected.

Pedigree Analysis Cystic Fibrosis

Fig. 6. Family pedigree showing autosomal recessive inheritance pattern of a genetic disease. Examples include cystic fibrosis, Tay-Sachs disease, phenylketonuria, alpha-1-antitrypsin deficiency, and sickle cell anemia. Circle, female; square, male; open, unaffected; solid, affected; half-shaded, carrier.

Fig. 6. Family pedigree showing autosomal recessive inheritance pattern of a genetic disease. Examples include cystic fibrosis, Tay-Sachs disease, phenylketonuria, alpha-1-antitrypsin deficiency, and sickle cell anemia. Circle, female; square, male; open, unaffected; solid, affected; half-shaded, carrier.

Table 2

Human Genes Exhibiting Differential Parental Expression

Table 2

Human Genes Exhibiting Differential Parental Expression

Gene

Expressed allele

WT-1 (Wilm's tumor suppressor)

Maternal

INS (insulin)

Paternal

IGF2 (insulinlike growth factor)

Paternal

SNRPN (small nuclear riboprotein particle)

Paternal

IGF2R (insulinlike growth factor receptor)

Maternal

unstable mutations, uniparental disomy, and genetic imprinting (5,6,13,14). Unstable mutations refer to the trinucleotide repeat expansions responsible for disorders such as Fragile X syndrome, myotonic dystrophy, and Huntington's disease. The identification of this type of mutation at the molecular level helped to define the phenomenon of anticipation, whereby there is an increase in the severity of a disease phentoype from one generation to the next. Premutations, a slight increase in the trinucleotide repeat number, exist without phenotypic expression. However, these premutations are prone to further expansion, which can result in a full mutation and the disease phenotype in subsequent generations. Uniparental disomy and genetic imprinting contradict assumptions that each individual inherits one copy of a single chromosome from each parent. Uniparental disomy refers to the inheritance of two copies of a chromosome from one parent and none from the other parent. This can result from differential expression of genes in one or the other parent, whereby only the expressed genes are inherited (imprinting). Parental dependency, however, can also result from the normal distribution of genetic material in male and female gametes (i.e., X vs Y chromosomes, mitochondrial genes). More commonly, parental dependent traits are the result of genetic imprinting, whereby male and female alleles are present but not equally expressed. Several human genes exhibit parental-dependent expression or imprinting, which is thought to be the result of differences in methylation patterns of specific alleles (Table 2) (14).

Other patterns of inheritance include those for X-linked disorders and mitochondrial disorders. Genes responsible for X-linked disorders are located on the X chromosome. Because females have two X chromosomes and males have only one X chromosome, the severity and risk for developing these disorders is different for the two sexes. Females can be heterozygous or homozygous for a mutant X-linked gene, so that the

Pedigree For Unaffected Male Symbol
Fig. 7. Family pedigree showing X-linked recessive inheritance pattern of a genetic disease. Examples include muscular dystrophy and retinitis pigmentosa. Circle, female; square, male; open, unaffected; solid, affected; circle with dot, carrier female.
Pedigree For Unaffected Male Symbol
Fig. 8. Family pedigree showing X-linked dominant inheritance pattern of a genetic disease. Examples include several mental retardation syndromes. Circle, female; square, male; open, unaffected; solid, affected.
Pedigree For Unaffected Male Symbol
Fig. 9. Family pedigree showing mitochondrial DNA inheritance pattern of a genetic disease. Examples include Leber's hereditary optic neuropathy and Kearn-Sayre syndrome. Circle, female; square, male; open, unaffected; solid, affected.

associated trait can be either dominant or recessive. Males, on the other hand, express the mutant gene whenever they inherit it. As seen in the pedigree for X-linked disorders, there is absence of male-to-male transmission and all daughters of an affected male inherit the mutant gene. If the disorder is X-linked recessive, then affected individuals are primarily male (Fig. 7). In X-linked dominant disorders, all daughters of affected males are affected, an affected female has a 50% chance of having an affected offspring, and affected individuals have an affected parent (Fig. 8). X-inactivation, or lyonization, refers to the expression of X-linked genes in females. One X chromosome is irreversibly inactivated in females early in embryonic development and, thus, genes on only one X chromosome are expressed. Expression of a mutant allele is therefore dependent on its location on either an active or inactive X chromosome. Unlike X-linked disorders, inheritance of mitochondrial associated disorders is strictly maternal (Fig. 9). Thus, females transmit these traits to all of their offspring.

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Responses

  • tomi
    How is cystic fibrosis inherited?
    6 years ago

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