Williams Manual of Pregnancy Complications, 23 ed.

CHAPTER 7. Nonmendelian Disorders

In addition to autosomal dominant, autosomal recessive, and X- and Y-linked inheritance, several patterns of inheritance have been characterized which do not conform to Mendel’s laws and are termed nonmendelian. These include mitochondrial inheritance, trinucleotide repeat expansion, uniparental disomy, imprinting, and multifactorial and polygenic inheritance.

MITOCHONDRIAL INHERITANCE

Mitochondria are derived exclusively from the mother and replicate autonomously. Each mitochondrion has multiple copies of a circular DNA molecule that contains 37 unique genes. Mitochondrial inheritance allows the transmission of genes from mother to offspring without the possibility of recombination. Mitochondrial diseases have a characteristic transmission pattern—individuals of both sexes can be affected, but transmission is only through females. As of May 2012, 28 mitochondrial diseases or conditions with known molecular basis were described in the Online Mendelian Inheritance in Man Web site. Examples include myoclonic epilepsy with ragged red fibers (MERRF), Leber optic atrophy, Kearns-Sayre syndrome, Leigh syndrome, and susceptibility to both amino-glycoside-induced deafness and chloramphenicol toxicity.

TRINUCLEOTIDE REPEAT EXPANSION—ANTICIPATION

Certain genes are unstable, and their size and function may be altered as they are transmitted from parent to child. This is manifested clinically by anticipation, a phenomenon in which disease symptoms seem to be more severe and appear at an earlier age in each successive generation. Trinucleotide repeat expansion, also called DNA-triplet repeat expansion, may lead to the disorders listed in Table 7-1. In each, the mutation is a region of unstable DNA that is characterized by repeated sequences of the same trinucleotide. For example, in fragile X syndrome there is an unstable DNA region on the X chromosome consisting of a series of CGG (cytosine-guanine-guanine) repeats. The number of repeats influences gene methylation, which in turn determines whether an individual is affected by mental retardation from fragile X syndrome. Males who have the full mutation typically have methylation of the FMR1 gene and full expression of the syndrome. In females, expression is variable, due to X-inactivation of the affected X chromosome. The risk of expansion of the trinucleotide repeats is also affected by which parent carries the premutation. In fragile X syndrome, the gene is much more unstable when transmitted by the mother, but in Huntington disease, the gene is more unstable when transmitted by the father.

TABLE 7-1. Some Disorders Caused by DNA Triplet Repeat Expansion

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UNIPARENTAL DISOMY

Uniparental disomy describes the situation in which both members of one pair of chromosomes are inherited from the same parent, instead of one member being inherited from each parent. Particularly when this involves chromosomes 6, 7, 11, 14, or 15, offspring may be at increased risk for an abnormality that results from parent-of-origin differences in gene expression. Isodisomy is the unique situation in which an individual receives two identical copies of one chromosome in a pair from one parent. This mechanism explains some cases of cystic fibrosis, in which only one parent was a carrier but the fetus inherited two copies of the same abnormal chromosome. It has also been implicated in abnormal growth related to placental mosaicism.

IMPRINTING

Imprinting describes the process by which certain genes are inherited in an inactivated or transcriptionally silent state. This type of gene inactivation is determined by the gender of the transmitting parent and may be reversed in the next generation. When a gene is inherited in an imprinted state, gene function is directed entirely by the cogene inherited from the other parent.

Selected diseases that can involve imprinting are shown in Table 7-2. One interesting example concerns chromosomal deletion at 15q11-13, which causes two very different diseases. If the maternally derived chromosome 15 region is missing, the result is Angelman syndrome (severe mental retardation with absent speech, paroxysms of inappropriate laughter, ataxia, and seizures), and if the paternally derived chromosome 15 region is missing, the result is Prader Willi syndrome (hyperphagia with obesity, small hands and feet and genitalia, and mild retardation). There are a number of other examples of imprinting important to obstetricians. Complete hydatidiform mole, which has a paternally derived diploid chromosome complement, is characterized by the abundant growth of placental tissue, but no fetal structures. Conversely, ovarian teratoma, which has a maternally derived diploid chromosome complement, is characterized by the growth of various fetal tissues but no placental structures. It thus appears that paternal genes are vital for placental development and maternal genes are essential for fetal development, but both must be present in every cell in order for normal fetal growth and development.

TABLE 7-2. Some Disorders That Can Involve Imprinting

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MULTIFACTORIAL AND POLYGENIC INHERITANCE

Most inherited traits are multifactorial or polygenic. Polygenic traits are determined by the combined effects of more than one gene, and multifactorial traits are determined by multiple genes and environmental factors. Birth defects caused by such inheritance are recognized by their tendency to recur in families, and characteristics of the inheritance pattern are shown in Table 7-3. The empirical recurrence risk for first-degree relatives is usually quoted as 2 to 3 percent.

TABLE 7-3. Characteristics of Multifactorial Diseases

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Multifactorial traits may be categorized as continuously variable traits, threshold traits, and complex disorders of adult life. Continuously variable traits, such as height or head size, have a normal distribution in the general population and are believed to result from the individually small effects of many genes combined with environmental factors. Because of regression to the mean, these traits tend to be less extreme among offspring. Threshold traitsbecome manifest when individuals exceed a threshold number of abnormal genes or environmental influences. Each of these influences or factors is assumed to be normally distributed, but in individuals from high-risk families, the liability for the phenotype is close to the threshold. The abnormality occurs in an all-or-none fashion, and examples include cleft lip and pyloric stenosisComplex disorders of adult life are those in which many genes determine the susceptibility to environmental factors, with disease resulting from the most unfavorable combination of both. Examples include heart disease and hypertension.


For further reading in Williams Obstetrics, 23rd ed.,

see Chapter 12, “Genetics.”