aware of all these issues, have discouraged the use of DTC genetic testing. Position statements have accordingly been issued by the American College of Obstetricians and Gynecologists,584 the American College of Medical Genetics and Genomics,585 the Joint Society of Obstetricians and Gynecologists, and the Canadian College of Medical Genetics.586 A range of laws exist in Europe, with France and Germany banning DTC genetic testing.587 Serious concern has been expressed about the ethical, legal, and regulatory challenges of DTC testing in Ireland588 and Europe.589
A family history of a genetic disorder
The explicit naming of a specific genetic disorder when the family history is being discussed facilitates evaluation and any possible testing. Difficulties are introduced when neither family nor previous physicians have recognized a genetic disorder within the family, sometimes revealed by expanded carrier screening591 or whole‐exome sequencing.592 Such a disorder may be common (e.g. factor V Leiden deficiency) but nevertheless unrecognized. Clinical clues would include individuals in the family with deep‐vein thrombosis, sudden death possibly due to a pulmonary embolus, and yet other individuals with recurrent pregnancy loss.593 Venous thromboembolism is the third leading cause of cardiovascular death in the United States, and provides additional insights into the genetic basis of unprovoked pulmonary embolism. Using whole‐exome sequencing in 393 affected individuals and 6,114 controls, Desch et al.594 identified four genes (PROS1, STAB2, PROC, SERPINC1) with pathogenic variants, expanding the need for genetic testing given the history of thromboembolism.
For some families, individuals with quite different apparent clinical features may, in fact, have the same disorder. Seventeen cancers in different organs in family members may not be recognized as manifestations of the same common mutation. In hereditary nonpolyposis colon/rectal cancer, various family members may suffer from other cancers including the uterus, ovary, breast, stomach, small bowel, ureter, melanoma, or salivary glands. Analysis of the five culprit genes in the proband would enable detection of the mutation, which could then be assayed in other family members at risk. In another example, there may be two or more deceased family members who died from “kidney failure,” and another one or two who died from a cerebral aneurysm or a sudden brain hemorrhage. Adult polycystic kidney disease (APKD) may be the diagnosis, which will require further investigation by both ultrasound and DNA analysis. Moreover, two different genes for APKD have been identified (about 85 percent of cases due to APKD1 and close to 15 percent due to APKD2),595 and a rare third locus is known. In yet other families, a history of hearing impairment/deafness in some members and sudden death in others may translate to the autosomal recessive Jervell and Lange–Nielsen syndrome.596 This disorder is characterized by severe congenital deafness, a long QT interval, and large T waves, together with a tendency for syncope and sudden death due to ventricular fibrillation. Given that a number of genetic cardiac conduction defects have been recognized, a history of an unexplained sudden death in a family should lead to a routine electrocardiogram at the first preconception visit and possibly mutation analysis of at least 15 long QT syndrome genes.597 Other disorders in which sudden death due to a conduction defect might have occurred, with or without a family history of cataract or muscle weakness, should raise the suspicion of myotonic muscular dystrophy (see Chapter 31).
Rare named disorders in a pedigree should automatically raise the question of the need for genetic counseling. We have seen instances (e.g. pancreatitis) in which, in view of its frequency, the disorder was simply ascribed to alcohol or idiopathic categories. Hereditary pancreatitis, although rare, is an autosomal dominant disorder for which several genes are known.598
Awareness of the clinical manifestations in carrier females of X‐linked disorders is important given health and risk implications (Table 1.7). The pattern of inheritance of an unnamed disorder may signal a specific monogenic form of disease. For example, unexplained intellectual disability on either side of the female partner's family calls for fragile X DNA carrier testing. Moreover, unexpected segregation of a maternal premutation may have unpredicted consequences, including reversion of the triplet repeat number to the normal range.671 Genetic counseling may be valuable, more especially because the phenomena of pleiotropism (several different effects from a single gene) and heterogeneity (a specific effect from several genes) may confound interpretation in any of these families.
Table 1.7 Signs in females who are carriers of selected X‐linked recessive disease pertinent to prenatal diagnosis.
| Selected disorders | Key feature(s) that may occur | Selected references |
|---|---|---|
| Aarskog–Scott syndrome allelic with XLMR 16 | Widow's peak or short stature | 599 |
| Achromatopsia | Decreased visual acuity and myopia | 600 |
| Adrenoleukodystrophy | Neurologic and adrenal dysfunction | 601 , 602 |
| Alport syndrome | Microscopic hematuria and hearing impairment | 603 |
| Ameliogenesis imperfecta, hypomaturation type | Mottled enamel vertically arranged | 604 |
| Arthrogryposis multiplex congenita | Club foot, contractures, hyperkyphosis | 605 |
| ATRX syndrome α‐thalessemia/ID syndrome | Mild intellectual disability, hemoglobin H inclusions | 599 , 606 |
| Borjeson–Forssman–Lehmann syndrome | Tapered fingers, short, widely spaced, flexed toes, mild mental retardation | 607 |
| Choroideremia a | Chorioretinal dystrophy | 608 |
| Chondrodysplasia punctata 1 | Mild intellectual disability, possible bone defects and short stature | 599 |
| Chronic granulomatous disease | Cutaneous and mucocutaneous lesions | 609 – 611 |
| Cleft palate | Bifid uvula | 612 |
| Conductive deafness with stapes fixation | Mild hearing loss | 613 |
| Deafness X‐linked 1 allelic with Charcot‐Marie‐Tooth 5 |
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