title: Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.
abstract: 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 β-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.
authors.affiliation: Service of Genetic Medicine, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Béna
authors.forename: Damien L
authors.initials: DL
authors.lastname: Bruno
authors.forename: Mats
authors.initials: M
authors.lastname: Eriksson
authors.forename: Conny
authors.initials: C
authors.lastname: van Ravenswaaij-Arts
authors.forename: Zornitza
authors.initials: Z
authors.lastname: Stark
authors.forename: Trijnie
authors.initials: T
authors.lastname: Dijkhuizen
authors.forename: Erica
authors.initials: E
authors.lastname: Gerkes
authors.forename: Stefania
authors.initials: S
authors.lastname: Gimelli
authors.forename: Devika
authors.initials: D
authors.lastname: Ganesamoorthy
authors.forename: Ann Charlotte
authors.initials: AC
authors.lastname: Thuresson
authors.forename: Audrey
authors.initials: A
authors.lastname: Labalme
authors.forename: Marianne
authors.initials: M
authors.lastname: Till
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bilan
authors.forename: Laurent
authors.initials: L
authors.lastname: Pasquier
authors.forename: Alain
authors.initials: A
authors.lastname: Kitzis
authors.forename: Christele
authors.initials: C
authors.lastname: Dubourgm
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Rossi
authors.forename: Armand
authors.initials: A
authors.lastname: Bottani
authors.forename: Maryline
authors.initials: M
authors.lastname: Gagnebin
authors.forename: Damien
authors.initials: D
authors.lastname: Sanlaville
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gilbert-Dussardier
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.forename: Arie
authors.initials: A
authors.lastname: van Haeringen
authors.forename: Marjolein
authors.initials: M
authors.lastname: Kriek
authors.forename: Claudia
authors.initials: C
authors.lastname: Ruivenkamp
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Britt Marie
authors.initials: BM
authors.lastname: Anderlid
authors.forename: Howard R
authors.initials: HR
authors.lastname: Slater
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Schoumans
mesh_terms: D001321:Autistic Disorder / Q000235:genetics*; D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D015331:Cohort Studies; D005091:Exons; D006579:Heterozygote; D006801:Humans; D007621:Karyotyping; D009419:Nerve Tissue Proteins / Q000235:genetics*; D019006:Neural Cell Adhesion Molecules; D012640:Seizures / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D002135:Calcium-Binding Proteins; D015816:Cell Adhesion Molecules, Neuronal; C539628:NRXN1 protein, human; D009419:Nerve Tissue Proteins; D019006:Neural Cell Adhesion Molecules