Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease

Mutations in L1CAM, the gene encoding the LI neuronal cell adhesion molecul e, lead to an X-linked trait characterized by one or mofe of the symptoms o f hydrocephalus, adducted thumbs, agenesis or hypoplasia of corpus callosum , spastic paraplegia, and mental retardation (L1-disease). We screened 153 cases with prenatally or clinically suspected X-chromosomal hydrocephalus f or L1CAM mutations by SSCP analysis of the 28 coding exons and regulatory e lements in the 5'-untranslated region of the gene. Forty-six pathogenic mut ations were found (30.1% detection rate), the majority consisting of nonsen se, frameshift, and splice site mutations. In eight cases, segregation anal ysis disclosed recent de novo mutations. Statistical analysis of the data i ndicates a significant effect on mutation detection rate of (i) family hist ory, (ii) number of L1-disease typical clinical findings, and (iii) presenc e or absence of signs not typically associated with L1CAM-disease. Whereas mutation detection rate was 74.2% for patients with at least two additional cases in the family, only 16 mutations were found in the 102 eases with ne gative family history (15.7% detection rate). Our data suggest a higher tha n previously assumed contribution of L1CAM mutations in the pathogenesis of the heterogeneous group of congenital hydrocephalus. Am. J, Med, Genet. 92 :40-46, 2000, (C) 2000 Wiley-Liss, Inc.