Intermediate-45 to 54 repeats
Full mutations are expressed (penetrant) in all males and many females. When a full mutation is present, males typically have significant cognitive and behavioral abnormalities and phenotypic features. In females, random X-inactivation, however, results in variable expression, and the disability may be much less severe. With rare exception, the parent of origin of repeat expansion that leads to a full mutation is female (Monaghan, 2013).
For individuals with a premutation, evaluation and counseling are more complex. A female with the fragile X premutation is at risk to have ofspring with the full mutation, depending on the repeat number. The risk ofa full mutation in an ofspring is 5 percent or less if the CGG repeat number is <70 but exceeds 95 percent with 100 to 200 CGG repeats (Nolin, 2003). Expansion is extremely unlikely in a male premutation carrier, but all of his daughters will carry the premutation. Among women with no risk factors, approximately 1 in 250 carries a fragile X premutation, and the risk approximates 1 in 90 in those with a family history of intellectual disability (Cronister, 2008). Premutation carriers may themselves experience significant health consequences. Males with the premutation are at increased risk for the fragile X tremor ataxia syndrome (FXTAS). his syndrome is characterized by memory loss, executive function deficits, anxiety, and dementia (Monaghan, 2013). Females are at risk for FXTAS as well, although less so. hey also have a 20-percent risk for fragile X-associated primary ovarian insuficiency.
he American College of Obstetricians and Gynecologists (2016c, 2017a) recommends carrier screening for women with a family histof) of fragile X syndrome; individuals with unexplained intellectual disability, developmental delay, or autism; and women with primary ovarian insuiciency.
Prenatal diagnosis can be accomplished by amniocentesis or chorionic villus sampling. Specimens obtained by either can define the CGG repeat number, although chorionic villus sampling may not accurately determine FMRl gene methylation status.
his term describes some genes that are inherited but not expressed, depending on whether they are inherited from the mother or father. hus, the resulting phenotype varies according to the parent of origin. Imprinting afects gene expression by epigenetic control, which modiies genetic structure using methods other than altering the underlying nucleotide sequence. For example, methyl group addition may alter gene expression and thereby afect the phenotype without changing the genotype. Importantly, the efect may be reversed in a subsequent generation, because a female who inherits an imprinted gene from her father will pass it in her oocytes with a maternal-rather than paternal-imprint, and vice versa.
Selected diseases that can involve imprinting are shown in
Table 13-5. A useful example includes two very diferent dis eases that afect the same region of DNA. First, Prader-Willi syndrome is characterized by obesity and hyperphagia; short stature; small hands, feet, and external genitalia; and mild mental retardation. In more than 70 percent of cases, PraderWilli syndrome is caused by microdeletion or disruption for the paternal 15q 11.2-q 13. The remaining cases are due to maternal uniparental disomy or due to maternal gene imprinting with the paternal gene inactivated.
In contrast, Angelman syndrome includes severe intellectual disability; normal stature and weight; absent speech; seizure disorder; ataxia and jerky arm movements; and paroxysms of inappropriate laughter. In approximately 70 percent of cases, Angelman syndrome is caused by microdeletion for the maternal 15q 11.2-q 13. In 2 percent, the syndrome is caused by paternal uniparental disomy, and another 2 to 3 percent is due to paternal gene imprinting with the maternal genes inactivated.