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A genetic evaluation and counseling are usually indicated when a previous fetus or child has or had a genetic disorder, unless the matter is straightforward (e.g. previous trisomy 21) and the obstetrician is well informed. Careful inquiry should be made about the health status of a previous child. Failure or delay in the diagnosis of a monogenic disorder leaves the parents without the option of prenatal diagnosis in a subsequent pregnancy. In addition, it deprives them of the option of preimplantation genetic testing for those disorders with known mutations. Failure to make an early diagnosis of a genetic disorder during the first 5 years of life is common. For example, the Rotterdam Clinical Genetics Group reported that 50 percent of children affected by neurofibromatosis had been treated for related symptoms before a specific diagnosis had been made.⁴²⁹ Such delay has become problematic given that the NF1 gene and genes for many other monogenic disorders are routinely sequenced for a precise diagnosis.

Frequently, distressed parents will select a different physician for a subsequent pregnancy and a new or more recent insight may shed light on the cause of the previous disorder. For example, confined placental mosaicism (see Chapter 4) may now serve to explain the discrepancy between reported chromosomal findings at the time of CVS and fetal tissues obtained at elective abortion. Confined placental mosaicism may also be associated with intrauterine growth restriction (see Chapter 4), requiring serial ultrasounds during the pregnancy.

Given the heterogeneous nature of genetic disease, being alert to alternative mechanisms of causation will on occasion be rewarding. For example, during a consultation with a patient who had previously delivered a child with the autosomal recessive Meckel–Gruber syndrome, preparatory discussions about establishing the specific mutation from each parent could reveal that the father is not a carrier of a mutation in the culprit gene. Although nonpaternity is more likely, a judicious approach would also include consideration of uniparental disomy.^{430, 431} This mode of inheritance, in which an offspring can inherit two copies – part or all of a chromosome from one parent and no copy from the other parent – has been seen in a number of disorders, including Prader–Willi syndrome and Angelman syndrome (see discussion later and Chapter 14). About 25 percent of cases of Prader–Willi syndrome are caused by maternal uniparental disomy.⁴³² Involvement of chromosomes 7, 11, 14, and 15 have been notable. Uniparental disomy is caused primarily by meiotic nondisjunction events and followed by trisomy or monosomy “rescue.” Most cases described have been associated with advanced maternal age and have been detected primarily in the process of prenatal genetic studies.^{433, 434}

Recognition of the molecular basis of a disorder from which a previous child died may provide a couple with an opportunity for prenatal diagnosis in a subsequent planned pregnancy. A caveat would be the availability of analyzable tissue from the deceased child. In the recent past this was mostly not done, but with the escalation of new discoveries in genetics, tissues should now be frozen for potential future DNA analysis. The establishment of the molecular basis of recognized syndromes, previously undetectable prenatally, now provides new opportunities for couples seeking prenatal diagnosis. Examples abound and include some of the craniosynostosis syndromes, certain skeletal dysplasias, and many other disorders.

In one of our cases, a father with metaphyseal dysplasia of Schmid, troubled by the indignities and hurts of growing up with severe short stature, elected prenatal diagnosis at a preconception visit. Subsequent mutation analysis of conceived twins yielded a normal prenatal diagnosis result confirmed postnatally.⁴³⁵

Heterogeneity and pleiotropism also require consideration in the context of a previous child's disorder and anticipation of future prenatal diagnosis. For example, a previous child with tuberous sclerosis or a fetus with a cardiac rhabdomyoma would prompt molecular analysis of the TSC1 and TSC2 genes for more precise future prenatal diagnosis.⁴³⁶