Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants

L Pizzo; M Jensen; A Polyak; JA Rosenfeld; K Mannik; A Krishnan; E McCready; O Pichon; C Le Caignec; A Van Dijck; K Pope; E Voorhoeve; J Yoon; P Stankiewicz; SW Cheung; D Pazuchanics; E Huber; V Kumar; RL Kember; F Mari; A Curró; L Castiglia; O Galesi; E Avola; T Mattina; M Fichera; L Mandarà; M Vincent; M Nizon; S Mercier; C Bénéteau; S Blesson; D Martin-Coignard; AL Mosca-Boidron; JH Caberg; M Bucan; S Zeesman; MJM Nowaczyk; M Lefebvre; L Faivre; P Callier; C Skinner; B Keren; C Perrine; P Prontera; N Marle; A Renieri; A Reymond; RF Kooy; B Isidor; C Schwartz; C Romano; E Sistermans; DJ Amor; J Andrieux; S Girirajan

Journal article

Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants

L Pizzo, M Jensen, A Polyak, JA Rosenfeld, K Mannik, A Krishnan, E McCready, O Pichon, C Le Caignec, A Van Dijck, K Pope, E Voorhoeve, J Yoon, P Stankiewicz, SW Cheung, D Pazuchanics, E Huber, V Kumar, RL Kember, F Mari Show all

Genetics in Medicine | ELSEVIER SCIENCE INC | Published : 2019

DOI: 10.1038/s41436-018-0266-3

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Abstract

Purpose: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. Methods: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. Results: The number of rare likely deleterious variants in functionally intolerant genes (“other hits”) correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their..

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University of Melbourne Researchers

David Amor Author

Grants

Awarded by National Institutes of Health

Funding Acknowledgements

This work was supported by NIH R01-GM121907, Brain and Behavior Foundation (NARSAD 22535), SFARI Pilot Grant (SFARI 399894, S.G.) and resources from the Huck Institutes of the Life Sciences to S.G. L.P. was supported by Fulbright Commission Uruguay-ANII and the Huck Institutes of the Life Sciences. M.J. was supported by NIH T32-GM102057. C.R., L.C., O.G., and E.A. were supported by the Italian Ministry of Health and "5 per mille" funding. K.M. is a Jacobs Foundation Research Fellow. A.R. is supported by the Swiss National Science Foundation (31003A_160203). Dedicated to the memory of Ethan Francis Schwartz, 1996-1998. We are grateful to all of the families in each cohort (16p12.1 deletion, SVIP and SSC) who participated in the study. We thank the SSC principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman) as well as the Simons VIP Consortium. We appreciate obtaining access to genomic and phenotypic data on SFARI Base. Approved researchers can obtain the SSC and SVIP population data sets described in this study by applying at https://www.base.sfari.org.