RT Journal Article
SR Electronic
T1 The clinical relevance of intragenic <em>NRXN1</em> deletions
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 347
OP 355
DO 10.1136/jmedgenet-2019-106448
VO 57
IS 5
A1 Cosemans, Nele
A1 Vandenhove, Laura
A1 Vogels, Annick
A1 Devriendt, Koenraad
A1 Van Esch, Hilde
A1 Van Buggenhout, Griet
A1 Olivié, Hilde
A1 de Ravel, Thomy
A1 Ortibus, Els
A1 Legius, Eric
A1 Aerssens, Peter
A1 Breckpot, Jeroen
A1 R. Vermeesch, Joris
A1 Shen, Sanbing
A1 Fitzgerald, Jacqueline
A1 Gallagher, Louise
A1 Peeters, Hilde
YR 2020
UL http://jmg.bmj.com/content/57/5/347.abstract
AB Background Intragenic NRXN1 deletions are susceptibility variants for neurodevelopmental disorders; however, their clinical interpretation is often unclear. Therefore, a literature study and an analysis of 43 previously unpublished deletions are provided.Methods The literature cohort covered 629 heterozygous NRXN1 deletions: 148 in controls, 341 in probands and 140 in carrier relatives, and was used for clinical hypothesis testing. Exact breakpoint determination was performed for 43 in-house deletions.Results The prevalence of exonic NRXN1 deletions in controls was ~1/3000 as compared with ~1/800 in patients with neurodevelopmental/neuropsychiatric disorders. The differential distribution of deletions across the gene between controls and probands allowed to distinguish distinct areas within the gene. Exon 6–24 deletions appeared only twice in over 100000 control individuals, had an estimated penetrance for neurodevelopmental disorders of 32.43%, a de novo rate of 50% and segregated mainly with intellectual disability (ID) and schizophrenia. In contrast, exon 1–5 deletions appeared in 20 control individuals, had an estimated penetrance of 12.59%, a de novo rate of 32.5% and were reported with a broad range of neurodevelopmental phenotypes. Exact breakpoint determination revealed six recurrent intron 5 deletions.Conclusion Exon 6–24 deletions have a high penetrance and are mainly associated with ID and schizophrenia. In contrast, the actual contribution of exon 1–5 deletions to a neurodevelopmental/neuropsychiatric disorder in an individual patient and family remains very difficult to assess. To enhance the clinical interpretation, this study provides practical considerations for counselling and an interactive table for comparing a deletion of interest with the available literature data.