Mendelian disorders result from a mutation at a single genetic locus. A locus may be present on an autosome or on a sex chromosomes, and it may manifest in a dominant or a recessive mode. There are over 10,000 traits believed to be inherited in a mendelian fashion, but only a few of the more common disorders of interest to the obstetrician-gynecologist have been highlighted in this chapter to illustrate patterns of inheritance.

The patterns of inheritance for the various mendelian traits are illustrated by the idealized pedigrees in Figure 3-1. An autosomal recessive trait (disease) is expressed only when the mutant gene is present in a double dose (homozygous state). Both parents are heterozygous and possess one copy of the mutant gene and one copy of the normal or functional gene. Autosomal recessive traits are characterized as follows:

1. 
   

   There is rarely a positive family history outside the affected sibship.

   
   
2. 
   

   Males and females are equally likely to be affected.

   
   
3. 
   

   Heterozygous parents are usually unaffected and have a 25% chance of producing an offspring affected with the disease.

Autosomal dominant traits manifest in the heterozygous state (single-gene dose) and are characterized by the following:

1. 
   

   They can be transmitted from generation to generation.

   
   
2. 
   

   The probability that a person carrying the gene will pass it on to his or her offspring is 50%.

   
   
3. 
   

   Males and females are equally likely to be affected.

Males (XY) and females (XX) differ in the number of X chromosomes they possess. As a result, the inheritance pattern of mutations carried on the X-chromosome will differ from the inheritance pattern of mutations on autosomes. A recessive trait controlled by a gene on the X chromosome will be expressed in all males carrying the allele. Affected males are said to be hemizygous. Females will be affected if they are homozygous or if they inactivate most of the X chromosomes carrying the normal allele. The following are characteristics of X-linked inheritance:

1. 
   

   There is no male-to-male transmission.

   
   
2. 
   

   All daughters of an affected male receive the mutant gene and are therefore carriers.

   
   
3. 
   

   One-half of the sons, and one-half of the daughters of a heterozygous female receive the mutant gene.

The distinction between X-linked dominant and X-linked recessive is unclear, but in general, X-linked recessive refers to a trait that is not clinically expressed in the heterozygous female, and X-linked dominant to a trait that is expressed in the heterozygous female.

Neurologic Diseases.

The onset of many of the autosomal dominant neurologic diseases occurs in adulthood, and these diseases are generally more familiar to the neurologist than to the obstetrician-gynecologist. However, two of these disorders—myotonic dystrophy and Huntington disease—will be discussed to illustrate the necessity of having a basic knowledge of the mechanisms of inheritance and the clinical implications of these disorders.

Myotonic dystrophy (MD) is a condition characterized by myotonia, cataracts, and other variable features, such as male-pattern baldness.¹ The onset of symptoms usually occurs in the third or fourth decade of life. In addition to the adult form, there is neonatal form of the disorder, known as congenital myotonic dystrophy. This disorder is characterized by severe hypotonia, respiratory compromise, and often death in the newborn period. Those infants who do survive commonly have severe developmental delay.

The MD gene is characterized by a repeated sequence of cytosine-thymidine-guanine (CTG), which in normal persons is repeated between 5 and 34 times. This “trinucleotide repeat” is expanded to greater than 100 repeats in persons affected with adult-onset MD. Neonates with congenital MD may have more than 2000 copies of the repeat. Figure 3-2 presents a pedigree of a family that represents Case 1. The patient (proband) presents at 10 weeks’ gestation with a history that her sister has adult-onset MD. Neither of her parents, both in their mid-60s have any symptoms to suggest that either is affected with MD. Based on the absence of any symptoms in the patient or her parents, we might assume that the sister’s disease represents a new dominant mutation. Molecular testing of the family, however, indicates a much different scenario:

• 
  

  The sister has 150 trinucleotide repeats, consistent with her clinical symptoms.

  
  
• 
  

  Her mother has 40 repeats, which is in the range of what is called a premutation (35–100 repeats).

  
  
• 
  

  The proband also has 150 repeats and can be expected to experience MD symptoms in the future.

  
  
• 
  

  Molecular evaluation reveals that the fetus has 2000 repeats, consistent with the diagnosis of congenital MD.

Trinucleotide repeat disorders are characterized by the presence of unstable premutations that may remain unchanged or may amplify during spermatogenesis or oogenesis. In the case of MD, marked amplification can occur when the gene is passed from the mother, but not from the father. Therefore, the congenital form of MD is seen only when the gene is passed from the mother to the fetus. Determination of the status of a person with a family history of MD (ie, normal, premutation, full mutation) is quite precise with the use of modern molecular techniques.

Huntington disease (HD) is a late-onset, progressive, and fatal disease, inherited in a classic autosomal-dominant fashion. The early symptoms of the disease are subtle loss of muscle coordination, forgetfulness, and personality changes. The disease progresses in stages, from choreiform movements (hence the older name of Huntington chorea) to hypokinesis and then to rigidity. Ultimately, the patient is bedridden with dysphagia, dysarthria, and impairment of gait and coordination. Onset of the disease occurs most commonly between the ages of 30 and 50 years.

Like MD, HD has been found to be caused by a mutation involving a trinucleotide repeat sequence. Normal persons have between 11 and 31 copies of a CAG repeat. The full mutation range is between 38 and 100 copies. There is an intermediate range of 32 to 38 repeats, and there are examples of both affected and unaffected persons with this number of repeats.² Therefore, there does not appear to be a true premutation in HD. Unlike MD, inheritance of HD from the father is associated with expansion of the repeats and an earlier age of onset. In approximately one-third of cases where the father passes on the gene to his offspring, there is an expansion resulting in juvenile-onset HD.

The ability to diagnose HD precisely by molecular techniques offers both the possibility of presymptomatic (predictive) testing and prenatal detection of an affected fetus. Although predictive testing can offer freedom from the psychological burdens associated with being at risk if the person does not carry the mutation, the impact on persons found to have the gene can be devastating. Those found to carry the gene face the inevitability of developing a disease for which there is currently no treatment.

Most commonly the obstetrician-gynecologist will be presented with the request for prenatal testing by an at-risk patient. It must be emphasized to the couple that testing will determine precisely whether the fetus has the HD gene. Thus, a positive result gives an at-risk patient a presymptomatic diagnosis of HD. Direct prenatal testing should not be performed unless an at-risk patient has already undergone predictive testing. One option to avoid the difficulties of direct prenatal testing is the use of preimplantation genetic diagnosis, which only provides information regarding unaffected embryos, and does not reveal the status of the at-risk parent.^3,4