RT Journal Article
SR Electronic
T1 Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 257758
DO 10.1101/257758
A1 Lucilla Pizzo
A1 Matthew Jensen
A1 Andrew Polyak
A1 Jill A. Rosenfeld
A1 Katrin Mannik
A1 Arjun Krishnan
A1 Elizabeth McCready
A1 Olivier Pichon
A1 Cedric Le Caignec
A1 Anke Van Dijck
A1 Kate Pope
A1 Els Voorhoeve
A1 Jieun Yoon
A1 Paweł Stankiewicz
A1 Sau Wai Cheung
A1 Damian Pazuchanics
A1 Emily Huber
A1 Vijay Kumar
A1 Rachel Kember
A1 Francesca Mari
A1 Aurora Curró
A1 Lucia Castiglia
A1 Ornella Galesi
A1 Emanuela Avola
A1 Teresa Mattina
A1 Marco Fichera
A1 Luana Mandarà
A1 Marie Vincent
A1 Mathilde Nizon
A1 Sandra Mercier
A1 Claire Bénéteau
A1 Sophie Blesson
A1 Dominique Martin-Coignard
A1 Anne-Laure Mosca-Boidron
A1 Jean-Hubert Caberg
A1 Maja Bucan
A1 Susan Zeesman
A1 Małgorzata J.M. Nowaczyk
A1 Mathilde Lefebvre
A1 Laurence Faivre
A1 Patrick Callier
A1 Cindy Skinner
A1 Boris Keren
A1 Charles Perrine
A1 Paolo Prontera
A1 Nathalie Marle
A1 Alessandra Renieri
A1 Alexandre Reymond
A1 R Frank Kooy
A1 Bertrand Isidor
A1 Charles Schwartz
A1 Corrado Romano
A1 Erik Sistermans
A1 David J. Amor
A1 Joris Andrieux
A1 Santhosh Girirajan
YR 2018
UL http://biorxiv.org/content/early/2018/04/18/257758.abstract
AB Purpose To assess the contribution of rare variants in the genetic background towards variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive mutations.Methods We analyzed quantitative clinical information, exome-sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated mutations.Results The number of rare secondary mutations in functionally intolerant genes (second-hits) correlated with the expressivity of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in probands with autism carrying gene-disruptive mutations (n=184, p=0.03) compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of second-hits compared to those with mild/no family history (p=0.001). The number of secondary variants also correlated with the severity of cognitive impairment in probands carrying pathogenic rare CNVs (n=53) or de novo mutations in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These second-hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for genes affecting cellular and developmental processes.Conclusion Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate gene mutation is identified.