SOMATIC MOSAICISM - A COMMON-CAUSE OF CLASSIC DISEASE IN TUMOR-PRONE SYNDROMES - LESSONS FROM TYPE-2 NEUROFIBROMATOSIS

Blood samples from 125 families with classic type 2 neurofibromatosis with bilateral vestibular schwannomas were analyzed for mutations in t he NF2 gene. Causative mutations were identified in 52 families. In fi ve families, the first affected individual in the family (the index ca se) was a mosaic for a disease-causing mutation. Only one of nine chil dren from the three mosaic cases with children are affected. Four of t hese nine children inherited the allele associated with the disease-ca using mutation yet did not inherit the mutation. NF2 mutations were id entified in only 27/79 (34%) of sporadic cases, compared with 25/46 (5 4%) of familiar cases (P < .05). In 48 families in which a mutation ha s not been identified, the index cases have had 125 children, of whom only 29 are affected with NF2 and of whom only a further 21 cases woul d be predicted to be affected by use of life curves. The 50/125 (40%) of cases is significantly less than the 50% expected eventually to dev elop NF2 (P < .05). Somatic mosaicism is likely to be a common cause o f classic NF2 and may well account for a low detection rate for mutati ons in sporadic cases. Degrees of gonosomal mosaicism mean that recurr ence risks may well be < 50% in the index case when a mutation is not identified in lymphocyte DNA.