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
Autosomal dominant familial spastic paraplegia
Autosomal dominant polycystic kidney disease (PKD1)
Autosomal dominant rolandic epilepsy
Behçet syndrome
Bipolar affective disorder
Crohn disease
Facioscapulohumeral muscular dystrophy
Familial adenomatous polyposis
Familial breast cancer
Familial chronic myeloproliferative disorders
Familial Hodgkin lymphoma
Familial intracranial aneurysms
Familial pancreatic cancer
Familial paraganglioma
Familial Parkinson disease
Familial primary pulmonary hypertension
Familial rheumatoid arthritis
Graves disease
Hodgkin and non‐Hodgkin lymphoma
Holt–Oram syndrome
Idiopathic pulmonary fibrosis
Lattice corneal dystrophy type I (LCD1)
Li–Fraumeni syndrome
Ménière disease
Obsessive–compulsive spectrum disorders
Oculodentodigital syndrome
Paroxysmal kinesigenic dyskinesia (PKD)
Restless legs syndrome
Schizophrenia
Total anomalous pulmonary venous return
Unipolar affective disorder
Recognition in the last decade of hexanucleotide repeat expansions in the C9orf72 gene reveal additional challenges that have raised consideration of prenatal diagnosis, as discussed under “Accurate diagnosis.” Mutations in C9orf72 have been reported in 40–50 percent of cases with familial amyotrophic lateral sclerosis, between 3.5 percent and 8 percent of sporadic ALS cases,792–795 and in 25 percent of familial frontotemporal lobar degeneration, with about 7 percent in sporadic cases.793, 794 The clinical spectrum includes patients with frontotemporal dementia and ALS as well as those with a corticobasal syndrome.796 The real burden and likely involvement of prenatal diagnosis is the recognition of C9orf72 expansions noted in Western Europe as occurring in 18.52 percent of familial cases and 6.26 percent in sporadic cases of frontotemporal lobar degeneration.797 Overall frequencies of these expansions in Finland, Sweden, and Spain were much higher, being 29.33 percent, 20.73 percent, and 25.49 percent, respectively.797 A further distressing aspect of the C9orf72 expansion is the symptomatology that extends to family members who do not have the expansion. In a study of 1,414 first‐ and second‐degree relatives, a statistically
