ONLINE MUTATION REPORT Somatic mosaicism is rare in unaffected parents of patients with sporadic tuberous sclerosis

T uberous sclerosis is an autosomal dominant hamartoma syndrome with a prevalence of one in 6000 to one in 10 000 births. 2 Most patients with tuberous sclerosis have hamartomas in the brain, skin, kidneys, and heart; involvement of the lung, gastrointestinal tract, bone, retina, and gingiva is less common but is seen often. During early childhood, tuberous sclerosis presents most commonly with seizures that are caused by involvement of the brain by the hallmark cortical tubers. Mental retardation and a variety of developmental disorders including autism are seen often, and specific neurocognitive defects seem to be associated with involvement of the brain in patients with tuberous sclerosis. Tuberous sclerosis occurs because of mutations in either of two genes–TSC1 or TSC2. 5 Sporadic cases because of new mutations account for about two thirds of all patients that are seen. Among families with multiple affected members, about half show linkage to TSC1 on 9q34 and half to TSC2 on 16p13. No evidence suggests a third locus. The TSC1 gene consists of 23 exons and the TSC2 gene of 42 exons; mutations are distributed widely throughout both genes. Mutations in TSC2 are much more common than mutations in TSC1 (4.2:1 ratio); this ratio is higher than that predicted by their relative genomic extents and coding regions. Many different types of mutation are common in the TSC2 gene, including missense, inframe deletion, and large deletion mutations. In contrast, these three types of mutation are relatively rare in TSC1, which possibly contributes to the higher rate of cases because of TSC2 mutations than because of TSC1 mutations. Mosaicism is well known in many autosomal dominant disorders, particularly relatively common diseases with high sporadic case rates (for example, see reference 10 and its cited references). Generalised somatic and confined gonadal mosaicism have been reported previously in families affected by tuberous sclerosis, which has led to the suggestion that it is a relatively common event. We studied a defined cohort of patients with tuberous sclerosis with mutations in TSC1 and TSC2 to explore systematically the occurrence of mosaicism among the parents of sporadic cases of tuberous sclerosis.