Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature

被引：91

作者：

Bena, Frederique ^{[1
]}

Bruno, Damien L. ^{[2
,3
]}

Eriksson, Mats ^{[4
]}

van Ravenswaaij-Arts, Conny ^{[5
]}

Stark, Zornitza ^{[2
,3
]}

Dijkhuizen, Trijnie ^{[5
]}

Gerkes, Erica ^{[5
]}

Gimelli, Stefania ^{[1
]}

Ganesamoorthy, Devika ^{[2
,3
]}

Thuresson, Ann Charlotte ^{[6
]}

Labalme, Audrey ^{[7
]}

Till, Marianne ^{[7
]}

Bilan, Frederic ^{[8
,9
]}

Pasquier, Laurent ^{[10
]}

Kitzis, Alain ^{[8
,9
]}

Dubourgm, Christele ^{[10
]}

Rossi, Massimiliano ^{[7
]}

Bottani, Armand ^{[1
]}

Gagnebin, Maryline ^{[1
]}

Sanlaville, Damien ^{[7
,11
]}

Gilbert-Dussardier, Brigitte ^{[8
,9
]}

Guipponi, Michel ^{[1
]}

van Haeringen, Arie ^{[12
]}

Kriek, Marjolein ^{[12
]}

Ruivenkamp, Claudia ^{[12
]}

Antonarakis, Stylianos E. ^{[1
,13
]}

Anderlid, Britt Marie ^{[14
,15
]}

Slater, Howard R. ^{[2
,3
]}

Schoumans, Jacqueline ^{[15
,16
]}

机构：

[1] Univ Hosp Geneva, Serv Genet Med, Geneva, Switzerland

[2] Murdoch Childrens Res Inst, Victorian Clin Genet Serv, Parkville, Vic, Australia

[3] Univ Melbourne, Dept Paediat, Royal Childrens Hosp, Parkville, Vic 3052, Australia

[4] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden

[5] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[6] Uppsala Univ, Rudbeck Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden

[7] Grp Hosp Est, Hosp Civils Lyon, Serv Cytogenet Constitut, Lyon, France

[8] Ctr Hosp Univ Poitiers, Serv Genet, Poitiers, France

[9] Univ Poitiers, Poitiers, France

[10] CHU Rennes, Hop Sud, Serv Genet Med, Rennes, France

[11] Univ Lyon 1, INSERM, U1028, CNRS,UMR5292,Equipe TIGER, F-69365 Lyon, France

[12] Leiden Univ, Med Ctr LUMC, Ctr Human & Clin Genet, Leiden, Netherlands

[13] Univ Geneva, Dept Genet Med & Dev, Geneva, Switzerland

[14] Astrid Lindgren Childrens Hosp, Dept Neuropediat, Stockholm, Sweden

[15] Karolinska Inst, Dept Mol Med & Surg, CMM, Stockholm, Sweden

[16] Univ Lausanne Hosp, Dept Med Genet, CH-1011 Lausanne, Switzerland

来源：

AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS | 2013年 / 162B卷 / 04期

基金：

瑞典研究理事会;

关键词：

NRXN1; neurexin; exon; deletion; autism; seizures; review; COPY NUMBER VARIATION; STRUCTURAL VARIATION; RARE DELETIONS; HIGH-FREQUENCY; SPECTRUM; AUTISM; SCHIZOPHRENIA; VARIANTS; GENES; NEUREXINS;

D O I：

10.1002/ajmg.b.32148

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the -isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders. (c) 2013 Wiley Periodicals, Inc.

引用

页码：388 / 403

页数：16

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