Identification of novel candidate disease genes from de novo exonic copy number variants

Tomasz Gambin, Bo Yuan, Weimin Bi, Pengfei Liu, Jill A. Rosenfeld, Zeynep Coban-Akdemir, Amber N. Pursley, Sandesh C.S. Nagamani, Ronit Marom, Sailaja Golla, Lauren Dengle, Heather G. Petrie, Reuben Matalon, Lisa Emrick, Monica B. Proud, Diane Treadwell-Deering, Hsiao Tuan Chao, Hannele Koillinen, Chester Brown, Nora Urraca & 32 others Roya Mostafavi, Saunder Bernes, Elizabeth R. Roeder, Kimberly M. Nugent, Patricia I. Bader, Gary Bellus, Michael Cummings, Hope Northrup, Myla Ashfaq, Rachel Westman, Robert Wildin, Anita E. Beck, La Donna Immken, Lindsay Elton, Shaun Varghese, Edward Buchanan, Laurence Faivre, Mathilde Lefebvre, Christian P. Schaaf, Magdalena Walkiewicz, Yaping Yang, Sung Hae L. Kang, Seema R. Lalani, Carlos A. Bacino, Arthur L. Beaudet, Amy M. Breman, Janice L. Smith, Sau Wai Cheung, James R. Lupski, Ankita Patel, Chad A. Shaw, Paweł Stankiewicz

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. Methods: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. Results: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. Conclusions: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.

Original languageEnglish (US)
Article number83
JournalGenome Medicine
Volume9
Issue number1
DOIs
StatePublished - Sep 21 2017

Fingerprint

Genes
Exons
Microarray Analysis
Exome
Gene Dosage
Genetic Association Studies
Genome
Nucleotides
Alleles
Databases
Research
Population

Keywords

  • CNVs
  • De novo variants
  • Exon targeted array CGH
  • Intragenic copy number variants

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Gambin, T., Yuan, B., Bi, W., Liu, P., Rosenfeld, J. A., Coban-Akdemir, Z., ... Stankiewicz, P. (2017). Identification of novel candidate disease genes from de novo exonic copy number variants. Genome Medicine, 9(1), [83]. https://doi.org/10.1186/s13073-017-0472-7

Identification of novel candidate disease genes from de novo exonic copy number variants. / Gambin, Tomasz; Yuan, Bo; Bi, Weimin; Liu, Pengfei; Rosenfeld, Jill A.; Coban-Akdemir, Zeynep; Pursley, Amber N.; Nagamani, Sandesh C.S.; Marom, Ronit; Golla, Sailaja; Dengle, Lauren; Petrie, Heather G.; Matalon, Reuben; Emrick, Lisa; Proud, Monica B.; Treadwell-Deering, Diane; Chao, Hsiao Tuan; Koillinen, Hannele; Brown, Chester; Urraca, Nora; Mostafavi, Roya; Bernes, Saunder; Roeder, Elizabeth R.; Nugent, Kimberly M.; Bader, Patricia I.; Bellus, Gary; Cummings, Michael; Northrup, Hope; Ashfaq, Myla; Westman, Rachel; Wildin, Robert; Beck, Anita E.; Immken, La Donna; Elton, Lindsay; Varghese, Shaun; Buchanan, Edward; Faivre, Laurence; Lefebvre, Mathilde; Schaaf, Christian P.; Walkiewicz, Magdalena; Yang, Yaping; Kang, Sung Hae L.; Lalani, Seema R.; Bacino, Carlos A.; Beaudet, Arthur L.; Breman, Amy M.; Smith, Janice L.; Cheung, Sau Wai; Lupski, James R.; Patel, Ankita; Shaw, Chad A.; Stankiewicz, Paweł.

In: Genome Medicine, Vol. 9, No. 1, 83, 21.09.2017.

Research output: Contribution to journalArticle

Gambin, T, Yuan, B, Bi, W, Liu, P, Rosenfeld, JA, Coban-Akdemir, Z, Pursley, AN, Nagamani, SCS, Marom, R, Golla, S, Dengle, L, Petrie, HG, Matalon, R, Emrick, L, Proud, MB, Treadwell-Deering, D, Chao, HT, Koillinen, H, Brown, C, Urraca, N, Mostafavi, R, Bernes, S, Roeder, ER, Nugent, KM, Bader, PI, Bellus, G, Cummings, M, Northrup, H, Ashfaq, M, Westman, R, Wildin, R, Beck, AE, Immken, LD, Elton, L, Varghese, S, Buchanan, E, Faivre, L, Lefebvre, M, Schaaf, CP, Walkiewicz, M, Yang, Y, Kang, SHL, Lalani, SR, Bacino, CA, Beaudet, AL, Breman, AM, Smith, JL, Cheung, SW, Lupski, JR, Patel, A, Shaw, CA & Stankiewicz, P 2017, 'Identification of novel candidate disease genes from de novo exonic copy number variants', Genome Medicine, vol. 9, no. 1, 83. https://doi.org/10.1186/s13073-017-0472-7
Gambin, Tomasz ; Yuan, Bo ; Bi, Weimin ; Liu, Pengfei ; Rosenfeld, Jill A. ; Coban-Akdemir, Zeynep ; Pursley, Amber N. ; Nagamani, Sandesh C.S. ; Marom, Ronit ; Golla, Sailaja ; Dengle, Lauren ; Petrie, Heather G. ; Matalon, Reuben ; Emrick, Lisa ; Proud, Monica B. ; Treadwell-Deering, Diane ; Chao, Hsiao Tuan ; Koillinen, Hannele ; Brown, Chester ; Urraca, Nora ; Mostafavi, Roya ; Bernes, Saunder ; Roeder, Elizabeth R. ; Nugent, Kimberly M. ; Bader, Patricia I. ; Bellus, Gary ; Cummings, Michael ; Northrup, Hope ; Ashfaq, Myla ; Westman, Rachel ; Wildin, Robert ; Beck, Anita E. ; Immken, La Donna ; Elton, Lindsay ; Varghese, Shaun ; Buchanan, Edward ; Faivre, Laurence ; Lefebvre, Mathilde ; Schaaf, Christian P. ; Walkiewicz, Magdalena ; Yang, Yaping ; Kang, Sung Hae L. ; Lalani, Seema R. ; Bacino, Carlos A. ; Beaudet, Arthur L. ; Breman, Amy M. ; Smith, Janice L. ; Cheung, Sau Wai ; Lupski, James R. ; Patel, Ankita ; Shaw, Chad A. ; Stankiewicz, Paweł. / Identification of novel candidate disease genes from de novo exonic copy number variants. In: Genome Medicine. 2017 ; Vol. 9, No. 1.
@article{001ced4ef32542a887a2f7b0c28f6366,
title = "Identification of novel candidate disease genes from de novo exonic copy number variants",
abstract = "Background: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. Methods: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. Results: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11{\%}), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. Conclusions: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.",
keywords = "CNVs, De novo variants, Exon targeted array CGH, Intragenic copy number variants",
author = "Tomasz Gambin and Bo Yuan and Weimin Bi and Pengfei Liu and Rosenfeld, {Jill A.} and Zeynep Coban-Akdemir and Pursley, {Amber N.} and Nagamani, {Sandesh C.S.} and Ronit Marom and Sailaja Golla and Lauren Dengle and Petrie, {Heather G.} and Reuben Matalon and Lisa Emrick and Proud, {Monica B.} and Diane Treadwell-Deering and Chao, {Hsiao Tuan} and Hannele Koillinen and Chester Brown and Nora Urraca and Roya Mostafavi and Saunder Bernes and Roeder, {Elizabeth R.} and Nugent, {Kimberly M.} and Bader, {Patricia I.} and Gary Bellus and Michael Cummings and Hope Northrup and Myla Ashfaq and Rachel Westman and Robert Wildin and Beck, {Anita E.} and Immken, {La Donna} and Lindsay Elton and Shaun Varghese and Edward Buchanan and Laurence Faivre and Mathilde Lefebvre and Schaaf, {Christian P.} and Magdalena Walkiewicz and Yaping Yang and Kang, {Sung Hae L.} and Lalani, {Seema R.} and Bacino, {Carlos A.} and Beaudet, {Arthur L.} and Breman, {Amy M.} and Smith, {Janice L.} and Cheung, {Sau Wai} and Lupski, {James R.} and Ankita Patel and Shaw, {Chad A.} and Paweł Stankiewicz",
year = "2017",
month = "9",
day = "21",
doi = "10.1186/s13073-017-0472-7",
language = "English (US)",
volume = "9",
journal = "Genome Medicine",
issn = "1756-994X",
publisher = "BioMed Central",
number = "1",

}

TY - JOUR

T1 - Identification of novel candidate disease genes from de novo exonic copy number variants

AU - Gambin, Tomasz

AU - Yuan, Bo

AU - Bi, Weimin

AU - Liu, Pengfei

AU - Rosenfeld, Jill A.

AU - Coban-Akdemir, Zeynep

AU - Pursley, Amber N.

AU - Nagamani, Sandesh C.S.

AU - Marom, Ronit

AU - Golla, Sailaja

AU - Dengle, Lauren

AU - Petrie, Heather G.

AU - Matalon, Reuben

AU - Emrick, Lisa

AU - Proud, Monica B.

AU - Treadwell-Deering, Diane

AU - Chao, Hsiao Tuan

AU - Koillinen, Hannele

AU - Brown, Chester

AU - Urraca, Nora

AU - Mostafavi, Roya

AU - Bernes, Saunder

AU - Roeder, Elizabeth R.

AU - Nugent, Kimberly M.

AU - Bader, Patricia I.

AU - Bellus, Gary

AU - Cummings, Michael

AU - Northrup, Hope

AU - Ashfaq, Myla

AU - Westman, Rachel

AU - Wildin, Robert

AU - Beck, Anita E.

AU - Immken, La Donna

AU - Elton, Lindsay

AU - Varghese, Shaun

AU - Buchanan, Edward

AU - Faivre, Laurence

AU - Lefebvre, Mathilde

AU - Schaaf, Christian P.

AU - Walkiewicz, Magdalena

AU - Yang, Yaping

AU - Kang, Sung Hae L.

AU - Lalani, Seema R.

AU - Bacino, Carlos A.

AU - Beaudet, Arthur L.

AU - Breman, Amy M.

AU - Smith, Janice L.

AU - Cheung, Sau Wai

AU - Lupski, James R.

AU - Patel, Ankita

AU - Shaw, Chad A.

AU - Stankiewicz, Paweł

PY - 2017/9/21

Y1 - 2017/9/21

N2 - Background: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. Methods: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. Results: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. Conclusions: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.

AB - Background: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. Methods: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. Results: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. Conclusions: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.

KW - CNVs

KW - De novo variants

KW - Exon targeted array CGH

KW - Intragenic copy number variants

UR - http://www.scopus.com/inward/record.url?scp=85029750433&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85029750433&partnerID=8YFLogxK

U2 - 10.1186/s13073-017-0472-7

DO - 10.1186/s13073-017-0472-7

M3 - Article

VL - 9

JO - Genome Medicine

JF - Genome Medicine

SN - 1756-994X

IS - 1

M1 - 83

ER -