One key use of the carefully collected and verified pedigree is determination of the most likely mode of inheritance of a condition in a family. This will have relevance to assessing recurrence risks, approaches to testing, and in some cases, even prognosis. The concept of patterns of inheritance extends from the work of Gregor Mendel, who in the 17th century described transmission of traits associated with single genetic loci.10 Transmission of human genetic conditions and traits has proven to be more complex, involving not only the single gene patterns first described by Mendel but also chromosomal inheritance, mitochon-drial inheritance, and numerous atypical patterns of inheritance, including contiguous gene disorders, imprinting, uniparental disomy, trinucleotide repeat expansion, multi-factorial inheritance, mosaicism, epigenetic influences, and synergistic heterozygosity. Undoubtedly, more atypical patterns of transmission will be elucidated as our understanding of the human genome expands. As of June 14, 2006, Victor McKusick's classic reference Mendelian Inheritance in Man (12th ed., 1998; http://www.ncbi.nlm.nih.gov/ OMIM)11 lists 16,850 defined gene loci, 2290 of which have been associated with specific clinical entities. There are, however, more than 7500 human traits and/or conditions that have defined classic patterns of inheritance.10 These primarily fall into three categories, autosomal, X-linked, and
Y-linked; however, a number of mitochondrial conditions also have been confirmed.
In classic autosomal dominant inheritance, an affected individual has one non-functional or mutant allele at a particular locus. Each affected individual in a pedigree has a 50% chance of passing the disease-associated mutation to each of his or her offspring. Many factors, however, influence the occurrence of these conditions in families. These will be described as a group following review of the classic modes of inheritance. A key feature of autosomal dominant inheritance is male-to-male transmission of the condition or trait, a pattern not seen in X-linked dominant inheritance, which can be confused with autosomal dominant inheritance on first analysis. Table 4-2 lists additional features of autosomal dominant inheritance, and an example pedigree is shown in Figure 4-6. Codominant inheritance describes equal expression of both alleles of a pair, that is, with equal, coexisting phenotypic effect. An example of this is the ABO blood group.
In autosomal recessive inheritance, an affected individual has two nonfunctional or mutant alleles at a particular locus. One of these is inherited from each of the parents, who are called carriers and who are unaffected by the condition. There is a 1 in 4 (25%) chance of having an affected offspring with each pregnancy of a known carrier couple, and a 2 in 4 (50%) chance that an offspring will be a carrier like the parents. After birth, if a child of a carrier couple is not affected by the condition in question, he or she has a 2 in 3 chance of being a carrier. Risk to future offspring of a known carrier depends on the likelihood that his or her partner is also a carrier. This is influenced by the frequency of the disease gene in the population, which may vary among different populations. Features of autosomal recessive inheritance are listed in Table 4-2, and a pedigree is shown in Figure 4-6.
In X-linked dominant inheritance, an affected individual has one non-functional or mutant allele at a locus on an X-chromosome. X-linked dominant conditions can occur in either males or females. Risk for offspring of an affected female is 50%, regardless of the gender of the offspring. Risk to offspring of affected males is gender dependent, with all daughters but no sons inheriting the gene. Many of these conditions, however, are lethal in males, so pedigrees may show overrepresentation of females or increased frequency of miscarriages, presumably of affected male fetuses (see Table 4-2 and Figure 4-6).
Table 4-2. Features of Mendelian Patterns of Inheritance
Autosomal Dominant Inheritance
Male-to-male transmission occurs;both genders can transmit to offspring
Condition occurs in multiple generations
Males and females affected, typically to comparable extent
Variability of clinical findings
Later/adult onset in some disorders
Vertical transmission; affected descendants of affected individuals, unaffected descendants of unaffected individuals (in general)
Homozygotes may be more severely affected than heterozygotes Homozygosity may be lethal Occurrence of new mutations Nonpenetrance;apparent "skipping" of generations Gender-limited occurrence of conditions (transmission through the unaffected gender) Germline mosaicism reported
Autosomal Recessive Inheritance
Affected family members are usually in one generation;
"horizontal" inheritance Parental consanguinity or small mating pool may influence disease occurrence Male and female are affected
Usually consistent in degree of severity among affected family members
Early onset of symptoms more typical New mutations rare
May see higher frequency of disease in certain ethnic groups
X-linked Dominant Inheritance
No male-to-male transmission
Affected females usually have milder symptoms than affected males
Affected males have no affected sons, but all daughters will be affected
May mimic autosomal dominant inheritance May be lethal in affected males; paucity of males or overrepresentation of females in the pedigree Increased occurrence of miscarriage
X-linked Recessive Inheritance
No male-to-male transmission Males more frequently affected
Carrier females usually unaffected but may have mild symptoms Affected males in a family are related through females Occurrence of new mutations, often from maternal grandfather
Male-to-male transmission only
Association with increased infertility rates in families
Discrepancy between chromosomal and phenotypic gender
Traditional X-linked recessive inheritance is characterized by occurrence of the condition in males with a non-functional or mutant allele on the X-chromosome who are related through females. (See the pedigree in Figure 4-6, and Table 4-2 for additional features.) Typically, carrier females are unaffected; however, due to lyonization (random inactivation of one X chromosome in each cell in a female), carrier females may have mild symptoms. This occurs when, by chance, more of the X chromosomes with the nonfunctional allele remain active in the cells. The likelihood of symptoms in carrier females varies considerably among disorders. Risk to offspring of carrier females is 25% overall, or 50% for affected status if the fetus/offspring is male. Offspring of affected males will not be classically affected, but all daughters will be carriers.
In rare cases, one of a limited number of genes on the Y chromosome can be mutated. This can result in disparity between chromosomal and phenotypic gender if the SRY region is involved, or can be associated with genetic/ hereditary forms of infertility. This may be identified more frequently as reproductive technologies such as intracytoplasmic sperm injection (ICSI) are used to aid in achieving pregnancies for previously infertile males, due to Y-chromosome deletions, for example (see Table 4-2 and Figure 4-6).
Autosomal recessive er
Figure 4-6. Example pedigrees for Mendelian patterns of inheritance.
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