to us providing requested prenatal diagnosis. Mothers with such mutations who have seen their own mothers and sisters die have made the difficult personal decision to terminate pregnancy.763 DudokdeWit et al. laid out a detailed and systematic approach to counseling and testing in these families.764 In their model approach, important themes and messages emerge:
Each person may have a different method of coping with threatening information and treatment options.
Predictive testing should not harm the family unit.
Special care and attention are necessary to obtain informed consent, protect privacy and confidentiality and safeguard “divergent and conflicting intrafamilial and intergenerational interests.”
A French study noted that 87.7 percent of women who were first‐degree relatives of patients with breast cancer were in favor of predictive testing.765 Two specific groups of women are especially involved. The first are those who, at a young age, have already had breast cancer, with or without a family history, and in whom a specific mutation has been identified. Recognizing their high risk for breast and/or ovarian cancer,766, 767 these women have grappled with decisions about elective bilateral mastectomy and oophorectomy and mastectomy of a contralateral breast. Current estimates of penetrance are 36–85 percent lifetime risk for breast cancer and 16–60 percent lifetime risk for ovarian cancer, depending upon the population studied.768
The second group of women are of Ashkenazi Jewish ancestry. These women have about a 2 percent risk of harboring two common mutations in BRCA1 (c.68 69delAG and c.5266dupC) and one in BRCA2 (c.5946delT) that account for the majority of breast cancers in this ethnic group.768, 769 Regardless of a family history of breast or ovarian cancer, the lifetime risk of breast cancer among Jewish female mutation carriers was 82 percent in a study of 1,008 index cases.770 Breast cancer risk by 50 years of age among mutation carriers born before 1940 was 24 percent, but 67 percent for those born after 1940.770 Lifetime ovarian cancer risks were 54 percent for BRCA1 and 23 percent for BRCA2 mutation carriers.770
It can easily be anticipated that, with identification of mutations for more and more serious/fatal monogenic genetic disorders (including cardiovascular, cerebrovascular, neurodegenerative, connective tissue, and renal disorders, among others), prospective parents may well choose prenatal diagnosis in an effort to avoid at least easily determinable serious or fatal genetic disorders. Discovery of the high frequency (28 percent) of a mutation (T to A at APC nucleotide 3920) in the familial adenomatous polyposis coli gene among Ashkenazi Jews with a family history of colorectal cancer771 is also likely to be followed by thoughts of avoidance through prenatal diagnosis. This mutation has been found in 6 percent of Ashkenazi Jews.771 Because of the ability to determine whether a specific cancer will develop in the future, given identification of a particular mutation, much agonizing can be expected for many years. These quandaries will not and cannot be resolved in rushed visits to the physician's office as part of preconception or any other care. Moreover, developing knowledge about genotype–phenotype associations and many other aspects of genetic epidemiology will increasingly require referral to clinical geneticists.
Expansion mutations and anticipation
In 1991 the first reports appeared of dynamic mutations resulting from the unstable expansion of trinucleotide repeats.772 Thus far, at least 40 proven disorders with these unstable repeats have been described (see Chapter 14).773 All disorders described thus far are autosomal dominant or X‐linked, except for Friedreich ataxia and progressive myoclonic epilepsy with myoclonic tremor,774–776 which are autosomal recessive and also unique in having intronic involvement.777 Typically for these disorders (except for Friedreich ataxia), the carrier will have one normal allele and a second expanded allele. The repeat expansion disorders, although diverse, share many basic features. They arise from normally existing polymorphic repeats, are unstable, changing size on transmission, with longer repeats associated with severe and earlier onset disease, and highly variable phenotypes.773
These disorders (except for Friedreich ataxia and progressive myoclonic epilepsy type 1)774 are also generally characterized by progressively earlier manifestations and/or more severe expression with succeeding generations. This genetic mechanism, called anticipation, is associated with further expansion (rarely contraction) of the specific triplet repeat (Box 1.2). These disorders characteristically have a direct relation between the number of repeats and the severity of disease with an inverse relation between the number of repeats and age of onset. These aspects of anticipation weigh heavily in preconception counseling when it becomes clear that the relatively mild‐to‐moderate status of a mother with myotonic muscular dystrophy type 1, for example, with a 50 percent risk, could have an affected child with severe congenital myotonic muscular dystrophy.778 Triplet size in this disorder correlates significantly with muscular disability as well as intellectual and gonadal dysfunction.779 These authors also noted that triplet repeat size did not correlate with the appearance of cataract, myotonia, gastrointestinal dysfunction, and cardiac abnormalities. For myotonic dystrophy type 2 there is no correlation between disease severity and tetranucleotide (CCTG) repeat length.780 Women with myotonic dystrophy type 2 have an increased risk of ovarian and endometrial cancer.781, 782 Somatic mosaicism with different amplification rates in various tissues may be one possible explanation for variable phenotypes. Fortunately, in very few repeat expansion disorders, including Huntington disease, do de novo mutations occur.783 Parent‐of‐origin effects influencing anticipation are also recognized (see fragile X syndrome discussion in Chapter 16). The offspring of fathers with Huntington disease, spinocerebellar ataxias types 2 and 7, for example, may present clinically, and on occasion even before the father has become symptomatic.784 For myotonic muscular dystrophy, paternally transmitted small expansions have a higher risk of symptomatic offspring compared with females.785 Rarely, two triplet repeat disorders occur concurrently, as reported in a patient with both oculopharyngeal muscular dystrophy and Huntington disease.786 Anticipation does occur in Huntington disease, but not in oculopharyngeal muscular dystrophy. It is well documented that the paradoxical effects of repeat interruptions in the ATTCT expansion alleles in spinocerebellar ataxia type 10 result in a contraction in intergenerational repeat size.787 De novo repeat interruptions may also be associated with less somatic instability and few or no symptoms and signs in myotonic muscular dystrophy type 1.788, 789 Spinocerebellar ataxia type 2 has also been associated with Parkinsonism and an increased risk for amyotrophic lateral sclerosis (ALS).790 Almost all of the 59 autosomal recessive spinocerebellar ataxias791 are not characterized by repeat expansions. Marked heterogeneity in the clinical features are common.
Box 1.2 Selected genetic disorders with anticipation
Disorders with anticipation
All autosomal dominant disorders with repeat expansion mutations listed in Chapter 14 Table 14.2
Charcot–Marie–Tooth disease type 1A
Dyskeratosis congenita
Familial amyloid polyneuropathy
Hereditary nonpolyposis colorectal cancer (Lynch syndrome)
Disorders with suspected anticipation
Ablepharon–macrostomia syndrome
Adult‐onset idiopathic dystonia
Autosomal dominant acute myelogenous leukemia