The clinical relevance of intragenic NRXN1 deletions
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| Názov: | The clinical relevance of intragenic NRXN1 deletions |
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| Autori: | Nele Cosemans, Laura Vandenhove, Annick Vogels, Koenraad Devriendt, Hilde Van Esch, Griet Van Buggenhout, Hilde Olivié, Thomy de Ravel, Els Ortibus, Eric Legius, Peter Aerssens, Jeroen Breckpot, Joris R. Vermeesch, Sanbing Shen, Jacqueline Fitzgerald, Louise Gallagher, Hilde Peeters |
| Prispievatelia: | Medical Genetics |
| Zdroj: | Journal of Medical Genetics. 57:347-355 |
| Informácie o vydavateľovi: | BMJ, 2020. |
| Rok vydania: | 2020 |
| Predmety: | Male, 0301 basic medicine, Calcium-Binding Proteins/genetics, 0303 health sciences, Neural Cell Adhesion Molecules/genetics, Calcium-Binding Proteins, Schizophrenia/epidemiology, Neurodevelopmental Disorders/epidemiology, Exons, 3. Good health, 03 medical and health sciences, Neurodevelopmental Disorders, Intellectual Disability, Schizophrenia, Humans, Abnormalities, Multiple/epidemiology, Intellectual Disability/epidemiology, Abnormalities, Multiple, Female, Genetic Predisposition to Disease, 10. No inequality, Neural Cell Adhesion Molecules, Gene Deletion |
| Popis: | BackgroundIntragenic 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 Therefore, a literature study and an analysis of 43 previously unpublished deletions are provided.MethodsThe literature cohort covered 629 heterozygous NRXN1 deletions: 148 in controls, 341 in probands and 140 in carrier relatives,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.ResultsThe 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.ConclusionExon 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. |
| Druh dokumentu: | Article |
| Jazyk: | English |
| ISSN: | 1468-6244 0022-2593 |
| DOI: | 10.1136/jmedgenet-2019-106448 |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/31932357 https://pubmed.ncbi.nlm.nih.gov/31932357/ https://jmg.bmj.com/content/early/2020/01/13/jmedgenet-2019-106448.abstract https://jmg.bmj.com/content/jmedgenet/early/2020/01/13/jmedgenet-2019-106448.full.pdf https://www.ncbi.nlm.nih.gov/pubmed/31932357 https://jmg.bmj.com/content/57/5/347 https://jmg.bmj.com/content/early/2020/01/13/jmedgenet-2019-106448 |
| Prístupové číslo: | edsair.doi.dedup.....24c857a9e8bca50014a388e16fe900e5 |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | BackgroundIntragenic 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.MethodsThe 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.ResultsThe 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.ConclusionExon 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. |
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| ISSN: | 14686244 00222593 |
| DOI: | 10.1136/jmedgenet-2019-106448 |