Objectives: L1 syndrome is an X-linked recessive disorder for which we aimed to: develop a comprehensive mutation analysis system with a high rate of detection, develop a tool to predict the chance of detecting a mutation in the L1CAM gene, and look for genotype-phenotype correlations.
Methods: The DNA of 367 referred cases was analysed for mutations in the coding sequences of the gene. A subgroup of 100 patients was also investigated for mutations in regulatory sequences, and for large duplications. Clinical data for 106 patients was collected and used for statistical analysis.
Results: We detected 68 different mutations in 73 patients. In patients with three or more clinical characteristics of L1 syndrome, our mutation detection rate was 66% compared to 16% in patients with fewer characteristics. The detection rate was 51% in families with more than one affected relative, and 18% in families with one affected male. A combination of these two factors resulted in an 85% detection rate (odds ratio 10.4, confidence interval 3.6–30.1).
The type of mutation has impact on the severity of L1 syndrome. Children with a truncating mutation died more frequently (52%) before the age of three than those with a missense mutation (8%) (p=0.02).
Conclusions: We developed a comprehensive mutation detection system with a detection rate of almost 20% in unselected patients and up to 85% in a selected group. Using the patients’ clinical characteristics and family history, clinicians can accurately predict the chance of finding a mutation. A genotype-phenotype correlation was confirmed. The occurrence of (maternal) germline mosaicism was proven.
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