Non-Mendelian Genetics

Fragile X Syndrome

Fragile X syndrome is the most common inherited form of intellectual disability, with a prevalence of approximately 16–25/100,000 in males and half of that for females. Clinical characteristics can be variable and include intellectual disability, which is typically moderate for males and more mild for females. Males with fragile X syndrome have characteristic facial features, connective tissue findings such as lax joints, and macroorchidism, although some have few or no physical findings. About 25% of individuals with fragile X syndrome also meet criteria for autism spectrum disorder (ASD).

Fragile X syndrome is a trinucleotide repeat disorder that results from expansion of a trinucleotide cytosine-guanine-guanine (CGG) segment of DNA of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome (Xq27.3). If the region expands to include greater than 200 CGG repeats, this leads to hypermethylation and inactivation of the gene product (fragile X mental retardation protein), which is expressed in many tissues but most abundantly in neurons.

Normally, noncarrier individuals have fewer than 45 CGG repeats in this gene; the average is approximately 29 repeats. Individuals with 55–200 repeats are referred to as “premutation carriers” and are at risk of expansion to a full mutation (more than 200 repeats) in their offspring ( Fig. 2.1 ). Although premutation carriers have a 50% chance of passing on the abnormal allele, whether it expands to a full mutation and results in a child with fragile X syndrome depends on the size of the premutation. The chance of expansion of the gene, if it is passed on, ranges from about 3% with premutations that are 55–65 repeats, to nearly 100% if the premutation is larger than 100 repeats. Although premutation size alleles can be present in either parent, they only expand when passed on by the mother and are stable in size when passed on by the father. Individuals with 45–54 repeats are referred to as intermediate or “gray zone” carriers, as their gene may expand to the carrier or premutation size range but will not expand to a full mutation. Therefore, they are at risk to have grandchildren with fragile X syndrome, but not children. Expansion of less than 55 repeats to a full mutation has not been reported in a single generation. In families affected by fragile X syndrome, it is common to see more affected family members in subsequent generations due to genetic anticipation.

Unlike most autosomal recessive diseases, there are risks associated with being a premutation carrier in both men and women. Female premutation carriers are at risk for premature ovarian insufficiency (POI), defined as menopause earlier than 40 years old. Male, and sometimes female, premutation carriers are also at risk for fragile X–associated tremor/ataxia syndrome (FXTAS), a progressive, neurodegenerative disease that can lead to cerebellar symptoms and memory loss, as well as other neurologic deficits that increase with age. Individuals who have fragile X syndrome do not develop ataxia—it only affects premutation carriers.

Testing for fragile X syndrome can be performed on DNA from blood (to identify female carriers or affected individuals) or on amniotic fluid or chorionic villi (to identify affected fetuses) through a combination of polymerase chain reaction (PCR) and Southern blot analysis. Ideally, carrier screening for fragile X syndrome should be done in the preconception period, although it can also be performed during pregnancy. The American College of Obstetricians and Gynecologists (ACOG) recommends carrier screening for fragile X syndrome for women who are pregnant or considering pregnancy who have a family history of a fragile X–related disorder or of intellectual disability. ACOG also recommends testing for fragile X syndrome for women with unexplained premature ovarian failure or insufficiency, but at the present time, ACOG does not recommend universal screening for fragile X syndrome.

Myotonic Dystrophy

Myotonic dystrophy 1 (DM1) is a neuromuscular condition with symptoms that include muscle spasm (myotonia) and muscle weakness. It affects a variety of organ systems, leading to cardiac conduction defects, testicular atrophy, insulin resistance, cataracts, and in the congenital form, intellectual disability. The pathogenesis of DM1 is expansion (to 50 repeats or greater) of a cytosine-thymine-guanine (CTG) repeat in the 3′ untranslated region of the DMPK gene. DM1 has a severe, lethal congenital form that includes severe neonatal hypotonia and weakness, respiratory failure, death, and intellectual disability in those that survive the neonatal period.

Myotonic dystrophy 2 (DM2) shares many of the clinical features of DM1 but occurs due to a tetranucleotide (CCTG) repeat expansion in the gene CNBP. Clinically, the presentations of DM1 and DM2 are very similar, except that DM2 does not have a congenital form. With both forms of myotonic dystrophy, the chance of passing on the abnormal allele is 50%, so the genetics are similar to classical autosomal dominant inheritance. However, the expansion demonstrates anticipation and increased severity of symptoms with repeat size and through generations, as is seen with other trinucleotide repeat disorders. The congenital form of myotonic dystrophy results from anticipation and expansion to greater than 1000 repeats. There is also a mild, late onset adult form, a more classical adult form, as well as a childhood form.

Huntington Disease

Huntington disease is a neurodegenerative disorder that follows an autosomal dominant pattern of inheritance, leading to chorea, uncontrolled limb writhing movements, psychiatric abnormalities, dementia, and death usually by age 60 years. In this disorder, the expanding repeat sequence is a cytosine-adenine-glycine (CAG) repeat (to greater than or equal to 40 repeats) in the HTT gene. When this expansion occurs, it results in formation of an abnormal form of a protein called huntingtin that becomes toxic to neurons. As with other trinucleotide repeat disorders, Huntington disease demonstrates anticipation, with increasing number of repeats seen in subsequent generations and associated with younger age of onset. Inheritance through the father can lead to greater repeat expansion and earlier onset of symptoms.

Huntington disease is 100% penetrant, and essentially all affected individuals develop symptoms, usually at the same age or somewhat earlier than their affected parent. In most cases, individuals do not become symptomatic until age 40 years or older, generally after they have had children. Many patients wish to have unaffected children but prefer not to learn their own status given that treatment is not available. In such situations, a form of nondisclosure preimplantation genetic testing can be performed, in which only unaffected embryos are implanted, but the parents are not informed as to whether any of the embryos are affected. It is also possible in some cases to perform prenatal diagnosis through linkage analysis without revealing the status of the parent.