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Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis
  1. Yvonne J Vos1,*,
  2. Hermien E K de Walle1,
  3. Krista K Bos1,
  4. Jenneke A. Stegeman1,
  5. Annelies M ten Berge1,
  6. Martijn Bruining2,
  7. Merel C van Maarle3,
  8. Mariet W Elting4,
  9. Nicolette S den Hollander5,
  10. Ben Hamel6,
  11. Ana Maria Fortuna7,
  12. Lone E M Sunde8,
  13. Irene Stolte-Dijkstra1,
  14. Connie T R M Schrander-Stumpel9,
  15. Robert M W Hofstra1
  1. 1 Department of Genetics, University Medical Centre Groningen, University of Groningen, Netherlands;
  2. 2 Internal Medicine, Medical Centre Leeuwarden, Leeuwarden, Netherlands;
  3. 3 Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands;
  4. 4 Department of Clinical Genetics, VU University Medical Center, Amsterdam, Netherlands;
  5. 5 Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands;
  6. 6 Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands;
  7. 7 Medical Genetics Center Jacinto Magalhães, National Health Institute, Porto, Netherlands;
  8. 8 Department of Clinical Genetics, Aalborg Sygehus, Aarhus University Hospital, Aalborg, Netherlands;
  9. 9 Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
  1. Correspondence to: Yvonne J. Vos, Department of Genetics, University Medical Centre Groningen, Hanzeplein 1, Groningen, 9713 GZ, Netherlands; y.j.vos{at}


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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