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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. 1Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
  2. 2Internal Medicine, Medical Centre Leeuwarden, Leeuwarden, The Netherlands
  3. 3Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
  4. 4Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
  5. 5Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  6. 6Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
  7. 7Medical Genetics Center Jacinto Magalhães, National Health Institute, Porto, Portugal
  8. 8Department of Clinical Genetics, Aalborg Sygehus, Aarhus University Hospital, Aalborg, Denmark
  9. 9Department of Clinical Genetics, and GROW School for Oncology & Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
  1. Correspondence to Yvonne J Vos, University Medical Centre Groningen, Department of Genetics, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; y.j.vos{at}


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.

  • L1 syndrome
  • L1CAM gene
  • mutation analysis
  • genotype–phenotype correlation
  • X-linked hydrocephalus
  • molecular genetics
  • hydrocephalus

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  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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