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Clinical geneticists, obstetricians, or pediatricians are frequently the specialists most confronted by patients seeking guidance because of genetic diseases in their families. Given the huge advances made in the recognition of thousands of culprit genes for genetic disorders seen in virtually all specialties, all physicians need to be aware of precise molecular diagnosis tests for monogenic disorders, and the opportunities for avoidance of recurrence. A previous child or a deceased sibling or parent may have had the disease in question. The genetic counseling process depends on an accurate diagnosis. Information about the exact previous diagnosis is important not only for the communication of subsequent risks but also for precise future options. Now whole‐exome or genome sequencing and the demonstrated potential diagnostic yield of 25–52 percent for previously undiagnosed patients with severe intellectual disability^236–240 introduce clinical demands to be up to date and well informed. It is not sufficient to know that the previous child had a mucopolysaccharidosis; exactly which type and even subtype must be determined because each may have different enzymatic deficiencies or genotypes (see Chapter 23). A history of limb‐girdle muscular dystrophy will also not facilitate prenatal diagnosis because there are eight dominant types (1A–1H), at least 23 autosomal recessive types (2A–2W),²⁴¹ and many are still to be molecularly identified. Similarly, a history of epilepsy gives no clear indication of which genes are involved.²⁴² Birth of a previous child with craniosynostosis requires precise determination of the cause (∼20 percent recognized as genetic)²⁴³ before risk counseling is provided. Mutations in at least 13 genes are clearly associated with monogenic syndromic forms of craniosynostosis.^244–246 Moreover, a chromosomal abnormality may be the cause.

Awareness of genetic heterogeneity and of intra‐ and inter‐family phenotypic variation of a specific disorder (e.g. tuberous sclerosis)²⁴⁷ is also necessary. The assumption of a particular predominant genotype as an explanation for a familial disorder is unwarranted. The common adult dominant polycystic kidney disease caused by mutations in the ADPKD1 gene has an early‐infancy presentation in 2–5 percent of cases.²⁴⁸ Moreover, mutations in the ADPKD2 gene may result in polycystic kidney disease and perinatal death²⁴⁹ and, further, should not be confused with the autosomal recessive type caused by mutations in the ARPKD gene. Awareness of contiguous gene syndromes, such as tuberous sclerosis and polycystic kidney disease (TSC2‐PKD1) is important, especially with the availability of microarrays.

Instead of simply accepting the patient's naming of the disease (e.g. muscular dystrophy or a mucopolysaccharidosis), or that a test result was normal (or not), the counselor must obtain and document confirmatory data. The unreliability of the maternal history, in this context, is remarkable, a positive predictive value of 47 percent having been documented.²⁵⁰ Photographs of the deceased, autopsy reports, hospital records, results of carrier detection or other tests performed elsewhere, and other information may provide the crucial confirmation or negation of the diagnosis made previously. Important data after miscarriage may also influence counseling. In a study of 91 consecutive, spontaneously aborted fetuses, almost one‐third had malformations, most associated with increased risks in subsequent pregnancies.²⁵¹

Myotonic muscular dystrophy type 1 (DM), the most common adult muscular dystrophy, with an incidence of about 1 in 8,000,²⁵² serves as the paradigm for preconception, prenatal, and perinatal genetic counseling. Recognition of the pleiomorphism of this disorder will, for example, alert the physician hearing a family history of one individual with DM, another with sudden death (cardiac conduction defect), and yet another relative with cataracts. Awareness of the autosomal dominant nature of this disorder and its genetic basis due to a dynamic mutation in the DMPK gene reflected in the number of trinucleotide (CTG) repeat units, raises issues beyond the 50 percent risk of recurrence in the offspring of an affected parent. As the first disorder characterized with expanding trinucleotide repeats, the observation linking the degree of disease severity and earlier onset to the number of triplet repeats was not long in coming²⁵² (see Chapter 14). In addition, the differences in severity when the mutation was passed via a maternal rather than a paternal gene focused attention on the fact that congenital DM was almost always a sign of the greatest severity when originating through maternal transmission. However, at least one exception has been noted.²⁵³ There is about a 93–94 percent likelihood that the CTG repeat will expand on transmission. This process of genetic anticipation (increasing clinical severity over generations) is not inevitable. An estimated 6–7 percent of cases of DM are associated with a decrease in the number of triplet repeats or no change in number.²⁵⁴ Rare cases also exist in which complete reversal of the mutation occurs with spontaneous correction to a normal range of triplet repeats.^255–262