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Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

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 Kember, Francesca Mari, Aurora 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
doi: https://doi.org/10.1101/257758
Lucilla Pizzo
1Department of Biochemistry and Molecular Biology. The Pennsylvania State University, University Park, Pennsylvania, USA.
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Matthew Jensen
1Department of Biochemistry and Molecular Biology. The Pennsylvania State University, University Park, Pennsylvania, USA.
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Andrew Polyak
1Department of Biochemistry and Molecular Biology. The Pennsylvania State University, University Park, Pennsylvania, USA.
2St. Georges University School of Medicine, Grenada.
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Jill A. Rosenfeld
3Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
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Katrin Mannik
4Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
5Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.
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Arjun Krishnan
6Department of Computational Mathematics, Science and Engineering, Michigan State University, East Lansing, Michigan, USA.
7Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michingan, USA.
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Elizabeth McCready
8Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.
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Olivier Pichon
9CHU Nantes, Medical genetics department, Nantes, France.
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Cedric Le Caignec
9CHU Nantes, Medical genetics department, Nantes, France.
10INSERM, UMR1238, Bone sarcoma and remodeling of calcified tissue, Nantes, France.
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Anke Van Dijck
11Department of Medical Genetics, University and University Hospital Antwerp, Antwerp, Belgium.
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Kate Pope
12Murdoch Children’s Research Institute and University of Melbourne, Department of Paediatrics, Royal Children’s Hospital, Melbourne, Australia.
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Els Voorhoeve
13Department of Clinical Genetics, VU University Medical Center Amsterdam, The Netherlands.
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Jieun Yoon
1Department of Biochemistry and Molecular Biology. The Pennsylvania State University, University Park, Pennsylvania, USA.
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Paweł Stankiewicz
3Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
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Sau Wai Cheung
3Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
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Damian Pazuchanics
1Department of Biochemistry and Molecular Biology. The Pennsylvania State University, University Park, Pennsylvania, USA.
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Emily Huber
1Department of Biochemistry and Molecular Biology. The Pennsylvania State University, University Park, Pennsylvania, USA.
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Vijay Kumar
1Department of Biochemistry and Molecular Biology. The Pennsylvania State University, University Park, Pennsylvania, USA.
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Rachel Kember
14Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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Francesca Mari
15Medical Genetics, University of Siena, Siena, Italy.
16Medical Genetics, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
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Aurora Curró
15Medical Genetics, University of Siena, Siena, Italy.
16Medical Genetics, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
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Lucia Castiglia
17Oasi Research Institute – IRCCS, Troina, Italy.
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Ornella Galesi
17Oasi Research Institute – IRCCS, Troina, Italy.
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Emanuela Avola
17Oasi Research Institute – IRCCS, Troina, Italy.
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Teresa Mattina
18Medical Genetics, University of Catania School of Medicine, Catania, Italy.
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Marco Fichera
18Medical Genetics, University of Catania School of Medicine, Catania, Italy.
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Luana Mandarà
19Medical Genetics, ASP Ragusa, Ragusa, Italy.
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Marie Vincent
9CHU Nantes, Medical genetics department, Nantes, France.
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Mathilde Nizon
9CHU Nantes, Medical genetics department, Nantes, France.
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Sandra Mercier
9CHU Nantes, Medical genetics department, Nantes, France.
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Claire Bénéteau
9CHU Nantes, Medical genetics department, Nantes, France.
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Sophie Blesson
20Department of genetics, Bretonneau university hospital, Tours, France.
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Dominique Martin-Coignard
21Service de Cytogénétique, CHU de Le Mans, Le Mans, France.
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Anne-Laure Mosca-Boidron
22Laboratoire de Génétique Chromosomique et Moléculaire, CHU Dijon, France.
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Jean-Hubert Caberg
23Centre Hospitalier Universitaire de Liège. Domaine Universitaire du Sart Tilman, Liège, Belgium.
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Maja Bucan
14Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
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Susan Zeesman
24McMaster University, Hamilton, Ontario, Canada.
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Małgorzata J.M. Nowaczyk
24McMaster University, Hamilton, Ontario, Canada.
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Mathilde Lefebvre
25Centre de Génétique. Hôpital d’Enfants Dijon, France.
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Laurence Faivre
26Center for Rare Diseases and Reference Developmental Anomalies and Malformation Syndromes. Dijon, France.
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Patrick Callier
22Laboratoire de Génétique Chromosomique et Moléculaire, CHU Dijon, France.
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Cindy Skinner
27Greenwood Genetic Center. Greenwood, South Carolina, USA.
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Boris Keren
28Hôpital La Pitié Salpêtrière. Paris, France.
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Charles Perrine
28Hôpital La Pitié Salpêtrière. Paris, France.
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Paolo Prontera
29Medical Genetics Unit, Hospital “Santa Maria della Misericordia”, Perugia, Italy.
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Nathalie Marle
22Laboratoire de Génétique Chromosomique et Moléculaire, CHU Dijon, France.
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Alessandra Renieri
15Medical Genetics, University of Siena, Siena, Italy.
16Medical Genetics, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
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Alexandre Reymond
4Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
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R Frank Kooy
11Department of Medical Genetics, University and University Hospital Antwerp, Antwerp, Belgium.
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Bertrand Isidor
9CHU Nantes, Medical genetics department, Nantes, France.
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Charles Schwartz
27Greenwood Genetic Center. Greenwood, South Carolina, USA.
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Corrado Romano
17Oasi Research Institute – IRCCS, Troina, Italy.
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Erik Sistermans
13Department of Clinical Genetics, VU University Medical Center Amsterdam, The Netherlands.
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David J. Amor
12Murdoch Children’s Research Institute and University of Melbourne, Department of Paediatrics, Royal Children’s Hospital, Melbourne, Australia.
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Joris Andrieux
30Institut de Génétique Médicale, Hôpital Jeanne de Flandre, CHRU de Lille, Lille, France.
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Santhosh Girirajan
1Department of Biochemistry and Molecular Biology. The Pennsylvania State University, University Park, Pennsylvania, USA.
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  • For correspondence: sxg47@psu.edu
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Abstract

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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 18, 2018.
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Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders
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 Kember, Francesca Mari, Aurora 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
bioRxiv 257758; doi: https://doi.org/10.1101/257758
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Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders
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 Kember, Francesca Mari, Aurora 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
bioRxiv 257758; doi: https://doi.org/10.1101/257758

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