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
N1 - Publisher Copyright:
© 2017 The Author(s).
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
C2 - 28934986
AN - SCOPUS:85029750433
SN - 1756-994X
VL - 9
JO - Genome Medicine
JF - Genome Medicine
IS - 1
M1 - 83
ER -