Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis

J Med Genet. 2010 Mar;47(3):169-75. doi: 10.1136/jmg.2009.071688. Epub 2009 Oct 20.


Objectives: To develop a comprehensive mutation analysis system with a high rate of detection, to develop a tool to predict the chance of detecting a mutation in the L1CAM gene, and to look for genotype-phenotype correlations in the X-linked recessive disorder, L1 syndrome.

Methods: DNA from 367 referred patients 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 were collected and used for statistical analysis.

Results: 68 different mutations were detected in 73 patients. In patients with three or more clinical characteristics of L1 syndrome, the mutation detection rate was 66% compared with 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 (OR 10.4, 95% CI 3.6 to 30.1). The type of mutation affects the severity of L1 syndrome. Children with a truncating mutation were more likely to die before the age of 3 than those with a missense mutation (52% vs 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.

MeSH terms

  • Base Sequence
  • Child
  • Child, Preschool
  • DNA Mutational Analysis / methods*
  • Genetic Association Studies*
  • Genetic Counseling / methods*
  • Genetic Diseases, X-Linked / diagnosis
  • Genetic Diseases, X-Linked / genetics*
  • Germ-Line Mutation
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Mosaicism
  • Neural Cell Adhesion Molecule L1 / analysis
  • Neural Cell Adhesion Molecule L1 / genetics*
  • Practice Guidelines as Topic
  • Syndrome


  • Neural Cell Adhesion Molecule L1