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

Lucilla Pizzo, Matthew Jensen, Andrew Polyak, Jill A. Rosenfeld, Katrin Mannik, Arjun Krishnan, Elizabeth McCready, Olivier Pichon, Cedric Le Caignec, Anke Van Dijck, Kate Pope, Els Voorhoeve, Jieun Yoon, Paweł Stankiewicz, Sau Wai Cheung, Damian Pazuchanics, Emily Huber, Vijay Kumar, Rachel L. Kember, Francesca MariAurora Curró, Lucia Castiglia, Ornella Galesi, Emanuela Avola, Teresa Mattina, Marco Fichera, Luana Mandarà, Marie Vincent, Mathilde Nizon, Sandra Mercier, Claire Bénéteau, Sophie Blesson, Dominique Martin-Coignard, Anne Laure Mosca-Boidron, Jean Hubert Caberg, Maja Bucan, Susan Zeesman, Małgorzata J.M. Nowaczyk, Mathilde Lefebvre, Laurence Faivre, Patrick Callier, Cindy Skinner, Boris Keren, Charles Perrine, Paolo Prontera, Nathalie Marle, Alessandra Renieri, Alexandre Reymond, R. Frank Kooy, Bertrand Isidor, Charles Schwartz, Corrado Romano, Erik Sistermans, David J. Amor, Joris Andrieux, Santhosh Girirajan

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 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 other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Conclusion: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

Original languageEnglish
JournalGenetics in Medicine
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Phenotype
Genes
Exome
Gene Dosage
Autistic Disorder
Siblings
Parents
Head
Genetic Background
Cognitive Dysfunction

Keywords

  • 16p11.2 deletion
  • autism
  • CNV
  • modifier
  • phenotypic variability

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants. / Pizzo, Lucilla; Jensen, Matthew; Polyak, Andrew; Rosenfeld, Jill A.; Mannik, Katrin; Krishnan, Arjun; McCready, Elizabeth; Pichon, Olivier; Le Caignec, Cedric; Van Dijck, Anke; Pope, Kate; Voorhoeve, Els; Yoon, Jieun; Stankiewicz, Paweł; Cheung, Sau Wai; Pazuchanics, Damian; Huber, Emily; Kumar, Vijay; Kember, Rachel L.; Mari, Francesca; Curró, Aurora; Castiglia, Lucia; Galesi, Ornella; Avola, Emanuela; Mattina, Teresa; Fichera, Marco; Mandarà, Luana; Vincent, Marie; Nizon, Mathilde; Mercier, Sandra; Bénéteau, Claire; Blesson, Sophie; Martin-Coignard, Dominique; Mosca-Boidron, Anne Laure; Caberg, Jean Hubert; Bucan, Maja; Zeesman, Susan; Nowaczyk, Małgorzata J.M.; Lefebvre, Mathilde; Faivre, Laurence; Callier, Patrick; Skinner, Cindy; Keren, Boris; Perrine, Charles; Prontera, Paolo; Marle, Nathalie; Renieri, Alessandra; Reymond, Alexandre; Kooy, R. Frank; Isidor, Bertrand; Schwartz, Charles; Romano, Corrado; Sistermans, Erik; Amor, David J.; Andrieux, Joris; Girirajan, Santhosh.

In: Genetics in Medicine, 01.01.2018.

Research output: Contribution to journalArticle

Pizzo, L, Jensen, M, Polyak, A, Rosenfeld, JA, Mannik, K, Krishnan, A, McCready, E, Pichon, O, Le Caignec, C, Van Dijck, A, Pope, K, Voorhoeve, E, Yoon, J, Stankiewicz, P, Cheung, SW, Pazuchanics, D, Huber, E, Kumar, V, Kember, RL, Mari, F, Curró, A, Castiglia, L, Galesi, O, Avola, E, Mattina, T, Fichera, M, Mandarà, L, Vincent, M, Nizon, M, Mercier, S, Bénéteau, C, Blesson, S, Martin-Coignard, D, Mosca-Boidron, AL, Caberg, JH, Bucan, M, Zeesman, S, Nowaczyk, MJM, Lefebvre, M, Faivre, L, Callier, P, Skinner, C, Keren, B, Perrine, C, Prontera, P, Marle, N, Renieri, A, Reymond, A, Kooy, RF, Isidor, B, Schwartz, C, Romano, C, Sistermans, E, Amor, DJ, Andrieux, J & Girirajan, S 2018, 'Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants', Genetics in Medicine. https://doi.org/10.1038/s41436-018-0266-3
Pizzo, Lucilla ; Jensen, Matthew ; Polyak, Andrew ; Rosenfeld, Jill A. ; Mannik, Katrin ; Krishnan, Arjun ; McCready, Elizabeth ; Pichon, Olivier ; Le Caignec, Cedric ; Van Dijck, Anke ; Pope, Kate ; Voorhoeve, Els ; Yoon, Jieun ; Stankiewicz, Paweł ; Cheung, Sau Wai ; Pazuchanics, Damian ; Huber, Emily ; Kumar, Vijay ; Kember, Rachel L. ; Mari, Francesca ; Curró, Aurora ; Castiglia, Lucia ; Galesi, Ornella ; Avola, Emanuela ; Mattina, Teresa ; Fichera, Marco ; Mandarà, Luana ; Vincent, Marie ; Nizon, Mathilde ; Mercier, Sandra ; Bénéteau, Claire ; Blesson, Sophie ; Martin-Coignard, Dominique ; Mosca-Boidron, Anne Laure ; Caberg, Jean Hubert ; Bucan, Maja ; Zeesman, Susan ; Nowaczyk, Małgorzata J.M. ; Lefebvre, Mathilde ; Faivre, Laurence ; Callier, Patrick ; Skinner, Cindy ; Keren, Boris ; Perrine, Charles ; Prontera, Paolo ; Marle, Nathalie ; Renieri, Alessandra ; Reymond, Alexandre ; Kooy, R. Frank ; Isidor, Bertrand ; Schwartz, Charles ; Romano, Corrado ; Sistermans, Erik ; Amor, David J. ; Andrieux, Joris ; Girirajan, Santhosh. / Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants. In: Genetics in Medicine. 2018.
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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 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 other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Conclusion: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.",
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author = "Lucilla Pizzo and Matthew Jensen and Andrew Polyak and Rosenfeld, {Jill A.} and Katrin Mannik and Arjun Krishnan and Elizabeth McCready and Olivier Pichon and {Le Caignec}, Cedric and {Van Dijck}, Anke and Kate Pope and Els Voorhoeve and Jieun Yoon and Paweł Stankiewicz and Cheung, {Sau Wai} and Damian Pazuchanics and Emily Huber and Vijay Kumar and Kember, {Rachel L.} and Francesca Mari and Aurora Curr{\'o} and Lucia Castiglia and Ornella Galesi and Emanuela Avola and Teresa Mattina and Marco Fichera and Luana Mandar{\`a} and Marie Vincent and Mathilde Nizon and Sandra Mercier and Claire B{\'e}n{\'e}teau and Sophie Blesson and Dominique Martin-Coignard and Mosca-Boidron, {Anne Laure} and Caberg, {Jean Hubert} and Maja Bucan and Susan Zeesman and Nowaczyk, {Małgorzata J.M.} and Mathilde Lefebvre and Laurence Faivre and Patrick Callier and Cindy Skinner and Boris Keren and Charles Perrine and Paolo Prontera and Nathalie Marle and Alessandra Renieri and Alexandre Reymond and Kooy, {R. Frank} and Bertrand Isidor and Charles Schwartz and Corrado Romano and Erik Sistermans and Amor, {David J.} and Joris Andrieux and Santhosh Girirajan",
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T1 - Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants

AU - Pizzo, Lucilla

AU - Jensen, Matthew

AU - Polyak, Andrew

AU - Rosenfeld, Jill A.

AU - Mannik, Katrin

AU - Krishnan, Arjun

AU - McCready, Elizabeth

AU - Pichon, Olivier

AU - Le Caignec, Cedric

AU - Van Dijck, Anke

AU - Pope, Kate

AU - Voorhoeve, Els

AU - Yoon, Jieun

AU - Stankiewicz, Paweł

AU - Cheung, Sau Wai

AU - Pazuchanics, Damian

AU - Huber, Emily

AU - Kumar, Vijay

AU - Kember, Rachel L.

AU - Mari, Francesca

AU - Curró, Aurora

AU - Castiglia, Lucia

AU - Galesi, Ornella

AU - Avola, Emanuela

AU - Mattina, Teresa

AU - Fichera, Marco

AU - Mandarà, Luana

AU - Vincent, Marie

AU - Nizon, Mathilde

AU - Mercier, Sandra

AU - Bénéteau, Claire

AU - Blesson, Sophie

AU - Martin-Coignard, Dominique

AU - Mosca-Boidron, Anne Laure

AU - Caberg, Jean Hubert

AU - Bucan, Maja

AU - Zeesman, Susan

AU - Nowaczyk, Małgorzata J.M.

AU - Lefebvre, Mathilde

AU - Faivre, Laurence

AU - Callier, Patrick

AU - Skinner, Cindy

AU - Keren, Boris

AU - Perrine, Charles

AU - Prontera, Paolo

AU - Marle, Nathalie

AU - Renieri, Alessandra

AU - Reymond, Alexandre

AU - Kooy, R. Frank

AU - Isidor, Bertrand

AU - Schwartz, Charles

AU - Romano, Corrado

AU - Sistermans, Erik

AU - Amor, David J.

AU - Andrieux, Joris

AU - Girirajan, Santhosh

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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 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 other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Conclusion: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

AB - 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 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 other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. Conclusion: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

KW - 16p11.2 deletion

KW - autism

KW - CNV

KW - modifier

KW - phenotypic variability

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