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

Yvonne J Vos^1,*, Hermien E K de Walle¹, Krista K Bos¹, Jenneke A. Stegeman¹, Annelies M ten Berge¹, Martijn Bruining², Merel C van Maarle³, Mariet W Elting⁴, Nicolette S den Hollander⁵, Ben Hamel⁶, Ana Maria Fortuna⁷, Lone E M Sunde⁸, Irene Stolte-Dijkstra¹, Connie T R M Schrander-Stumpel⁹, Robert M W Hofstra¹

¹ Department of Genetics, University Medical Centre Groningen, University of Groningen, Netherlands;
² Internal Medicine, Medical Centre Leeuwarden, Leeuwarden, Netherlands;
³ Department of Clinical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands;
⁴ Department of Clinical Genetics, VU University Medical Center, Amsterdam, Netherlands;
⁵ Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands;
⁶ Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands;
⁷ Medical Genetics Center Jacinto Magalhães, National Health Institute, Porto, Netherlands;
⁸ Department of Clinical Genetics, Aalborg Sygehus, Aarhus University Hospital, Aalborg, Netherlands;
⁹ Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands

Correspondence to: Yvonne J. Vos, Department of Genetics, University Medical Centre Groningen, Hanzeplein 1, Groningen, 9713 GZ, Netherlands; y.j.vos{at}medgen.umcg.nl

Accepted 3 September 2009

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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