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• W2994828253 abstract "The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%–70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64–4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10−5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression. The 22q11.2 deletion syndrome (22q11.2DS) results from non-allelic homologous recombination between low-copy repeats termed LCR22. About 60%–70% of individuals with the typical 3 megabase (Mb) deletion from LCR22A-D have congenital heart disease, mostly of the conotruncal type (CTD), whereas others have normal cardiac anatomy. In this study, we tested whether variants in the hemizygous LCR22A-D region are associated with risk for CTDs on the basis of the sequence of the 22q11.2 region from 1,053 22q11.2DS individuals. We found a significant association (FDR p < 0.05) of the CTD subset with 62 common variants in a single linkage disequilibrium (LD) block in a 350 kb interval harboring CRKL. A total of 45 of the 62 variants were associated with increased risk for CTDs (odds ratio [OR) ranges: 1.64–4.75). Associations of four variants were replicated in a meta-analysis of three genome-wide association studies of CTDs in affected individuals without 22q11.2DS. One of the replicated variants, rs178252, is located in an open chromatin region and resides in the double-elite enhancer, GH22J020947, that is predicted to regulate CRKL (CRK-like proto-oncogene, cytoplasmic adaptor) expression. Approximately 23% of patients with nested LCR22C-D deletions have CTDs, and inactivation of Crkl in mice causes CTDs, thus implicating this gene as a modifier. Rs178252 and rs6004160 are expression quantitative trait loci (eQTLs) of CRKL. Furthermore, set-based tests identified an enhancer that is predicted to target CRKL and is significantly associated with CTD risk (GH22J020946, sequence kernal association test (SKAT) p = 7.21 × 10−5) in the 22q11.2DS cohort. These findings suggest that variance in CTD penetrance in the 22q11.2DS population can be explained in part by variants affecting CRKL expression. The vast majority of individuals with 22q11.2 deletion syndrome (22q11.2DS [MIM: 192430]) have a 3 megabase (Mb) hemizygous deletion of chromosome 22q11.2.1McDonald-McGinn D.M. Sullivan K.E. Marino B. Philip N. Swillen A. Vorstman J.A. Zackai E.H. Emanuel B.S. Vermeesch J.R. Morrow B.E. et al.22q11.2 deletion syndrome.Nat. Rev. Dis. Primers. 2015; 1: 15071Crossref PubMed Scopus (393) Google Scholar Occuring in 1/4,000 live births2Botto L.D. May K. Fernhoff P.M. Correa A. Coleman K. Rasmussen S.A. Merritt R.K. O’Leary L.A. Wong L.Y. Elixson E.M. et al.A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population.Pediatrics. 2003; 112: 101-107Crossref PubMed Scopus (469) Google Scholar,3Oskarsdóttir S. Vujic M. Fasth A. Incidence and prevalence of the 22q11 deletion syndrome: a population-based study in Western Sweden.Arch. Dis. Child. 2004; 89: 148-151Crossref PubMed Scopus (296) Google Scholar and 1/1,000 fetuses,4Grati F.R. Molina Gomes D. Ferreira J.C. Dupont C. Alesi V. Gouas L. Horelli-Kuitunen N. Choy K.W. García-Herrero S. de la Vega A.G. et al.Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies.Prenat. Diagn. 2015; 35: 801-809Crossref PubMed Scopus (163) Google Scholar,5Maisenbacher M.K. Merrion K. Pettersen B. Young M. Paik K. Iyengar S. Kareht S. Sigurjonsson S. Demko Z.P. Martin K.A. Incidence of the 22q11.2 deletion in a large cohort of miscarriage samples.Mol. Cytogenet. 2017; 10: 6Crossref PubMed Scopus (8) Google Scholar this syndrome is the most frequent chromosomal microdeletion disorder The 22q11.2DS results from de novo non-allelic homologous recombination events between four low-copy repeats (LCRs) termed LCR22A, B, C, and D.6Edelmann L. Pandita R.K. Spiteri E. Funke B. Goldberg R. Palanisamy N. Chaganti R.S. Magenis E. Shprintzen R.J. Morrow B.E. A common molecular basis for rearrangement disorders on chromosome 22q11.Hum. Mol. Genet. 1999; 8: 1157-1167Crossref PubMed Scopus (337) Google Scholar,7Shaikh T.H. Kurahashi H. Saitta S.C. O’Hare A.M. Hu P. Roe B.A. Driscoll D.A. McDonald-McGinn D.M. Zackai E.H. Budarf M.L. Emanuel B.S. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis.Hum. Mol. Genet. 2000; 9: 489-501Crossref PubMed Scopus (398) Google Scholar More than 85% of affected individuals carry a 3 Mb hemizygous deletion between LCR22A and LCR22D.8Edelmann L. Pandita R.K. Morrow B.E. Low-copy repeats mediate the common 3-Mb deletion in patients with velo-cardio-facial syndrome.Am. J. Hum. Genet. 1999; 64: 1076-1086Abstract Full Text Full Text PDF PubMed Scopus (254) Google Scholar However, nested proximal (LCR22A– LCR22B, 1.5 Mb, 5%; LCR22A–LCR22C, 2 Mb, 2%;6Edelmann L. Pandita R.K. Spiteri E. Funke B. Goldberg R. Palanisamy N. Chaganti R.S. Magenis E. Shprintzen R.J. Morrow B.E. A common molecular basis for rearrangement disorders on chromosome 22q11.Hum. Mol. Genet. 1999; 8: 1157-1167Crossref PubMed Scopus (337) Google Scholar,7Shaikh T.H. Kurahashi H. Saitta S.C. O’Hare A.M. Hu P. Roe B.A. Driscoll D.A. McDonald-McGinn D.M. Zackai E.H. Budarf M.L. Emanuel B.S. Chromosome 22-specific low copy repeats and the 22q11.2 deletion syndrome: genomic organization and deletion endpoint analysis.Hum. Mol. Genet. 2000; 9: 489-501Crossref PubMed Scopus (398) Google Scholar) and distal (LCR22B–LCR22D, 1.5 Mb, 4%; LCR22C–LCR22D, 0.7 Mb, 1%) deletions are present in some individuals with 22q11.2DS.1McDonald-McGinn D.M. Sullivan K.E. Marino B. Philip N. Swillen A. Vorstman J.A. Zackai E.H. Emanuel B.S. Vermeesch J.R. Morrow B.E. et al.22q11.2 deletion syndrome.Nat. Rev. Dis. Primers. 2015; 1: 15071Crossref PubMed Scopus (393) Google Scholar In patients with the LCR22A–LCR22D and proximal nested LCR22A–LCR22B and LCR22A–LCR22C deletions the prevalence of congenital heart disease (CHD) is approximately 65%.9Burn J. Goodship J. Developmental genetics of the heart.Curr. Opin. Genet. Dev. 1996; 6: 322-325Crossref PubMed Scopus (53) Google Scholar,10Unolt M. Versacci P. Anaclerio S. Lambiase C. Calcagni G. Trezzi M. Carotti A. Crowley T.B. Zackai E.H. Goldmuntz E. et al.Congenital heart diseases and cardiovascular abnormalities in 22q11.2 deletion syndrome: From well-established knowledge to new frontiers.Am. J. Med. Genet. A. 2018; 176: 2087-2098Crossref PubMed Scopus (19) Google Scholar A somewhat lower prevalence (∼32%) is observed in individuals with distal nested deletions.11Burnside R.D. 22q11.21 Deletion Syndromes: A Review of Proximal, Central, and Distal Deletions and Their Associated Features.Cytogenet. Genome Res. 2015; 146: 89-99Crossref PubMed Scopus (76) Google Scholar, 12Verhagen J.M. Diderich K.E. Oudesluijs G. Mancini G.M. Eggink A.J. Verkleij-Hagoort A.C. Groenenberg I.A. Willems P.J. du Plessis F.A. de Man S.A. et al.Phenotypic variability of atypical 22q11.2 deletions not including TBX1.Am. J. Med. Genet. A. 2012; 158A: 2412-2420Crossref PubMed Scopus (40) Google Scholar, 13Rump P. de Leeuw N. van Essen A.J. Verschuuren-Bemelmans C.C. Veenstra-Knol H.E. Swinkels M.E. Oostdijk W. Ruivenkamp C. Reardon W. de Munnik S. et al.Central 22q11.2 deletions.Am. J. Med. Genet. A. 2014; 164A: 2707-2723Crossref PubMed Scopus (36) Google Scholar, 14Racedo S.E. McDonald-McGinn D.M. Chung J.H. Goldmuntz E. Zackai E. Emanuel B.S. Zhou B. Funke B. Morrow B.E. Mouse and human CRKL is dosage sensitive for cardiac outflow tract formation.Am. J. Hum. Genet. 2015; 96: 235-244Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Hence, both nested proximal and distal hemizygous deletions are associated with the occurrence of CHD. Most 22q11.2DS patients with CHD have conotruncal heart defects (CTDs [MIM: 217095]15Peyvandi S. Lupo P.J. Garbarini J. Woyciechowski S. Edman S. Emanuel B.S. Mitchell L.E. Goldmuntz E. 22q11.2 deletions in patients with conotruncal defects: data from 1,610 consecutive cases.Pediatr. Cardiol. 2013; 34: 1687-1694Crossref PubMed Scopus (60) Google Scholar), affecting the development of the cardiac outflow tract, including the aortic arch. Such defects that occur in 22q11.2DS patients include tetralogy of Fallot (TOF [MIM: 187500]), persistent truncus arteriosus (PTA), interrupted aortic arch type B (IAAB), right-sided aortic arch (RAA), and abnormal branching of the subclavian arteries. Some have isolated atrial septal defects (ASD), ventricular septal defects (VSD), and rarely, other cardiac malformations. Among the known coding genes in the LCR22A–LCR22B region, TBX1 (T-box 1 [MIM: 602054]), which encodes a T-box transcription factor,16Merscher S. Funke B. Epstein J.A. Heyer J. Puech A. Lu M.M. Xavier R.J. Demay M.B. Russell R.G. Factor S. et al.TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome.Cell. 2001; 104: 619-629Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar,17Lindsay E.A. Vitelli F. Su H. Morishima M. Huynh T. Pramparo T. Jurecic V. Ogunrinu G. Sutherland H.F. Scambler P.J. et al.Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice.Nature. 2001; 410: 97-101Crossref PubMed Scopus (761) Google Scholar is the strongest candidate gene for CTDs, as first suggested by gene inactivation studies in mouse models.16Merscher S. Funke B. Epstein J.A. Heyer J. Puech A. Lu M.M. Xavier R.J. Demay M.B. Russell R.G. Factor S. et al.TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome.Cell. 2001; 104: 619-629Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar, 17Lindsay E.A. Vitelli F. Su H. Morishima M. Huynh T. Pramparo T. Jurecic V. Ogunrinu G. Sutherland H.F. Scambler P.J. et al.Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice.Nature. 2001; 410: 97-101Crossref PubMed Scopus (761) Google Scholar, 18Papaioannou V.E. The T-box gene family: emerging roles in development, stem cells and cancer.Development. 2014; 141: 3819-3833Crossref PubMed Scopus (130) Google Scholar Inactivation of one allele of Tbx1 resulted in mild aortic-arch anomalies, whereas inactivation of both alleles resulted in a PTA and perinatal lethality.16Merscher S. Funke B. Epstein J.A. Heyer J. Puech A. Lu M.M. Xavier R.J. Demay M.B. Russell R.G. Factor S. et al.TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome.Cell. 2001; 104: 619-629Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar, 17Lindsay E.A. Vitelli F. Su H. Morishima M. Huynh T. Pramparo T. Jurecic V. Ogunrinu G. Sutherland H.F. Scambler P.J. et al.Tbx1 haploinsufficieny in the DiGeorge syndrome region causes aortic arch defects in mice.Nature. 2001; 410: 97-101Crossref PubMed Scopus (761) Google Scholar, 18Papaioannou V.E. The T-box gene family: emerging roles in development, stem cells and cancer.Development. 2014; 141: 3819-3833Crossref PubMed Scopus (130) Google Scholar Furthermore, missense variants in TBX1 have been found in individuals without a known genetic condition; these individuals partially phenocopied those with 22q11.2DS, implicating TBX1 as a human CTD gene.19Gong W. Gottlieb S. Collins J. Blescia A. Dietz H. Goldmuntz E. McDonald-McGinn D.M. Zackai E.H. Emanuel B.S. Driscoll D.A. Budarf M.L. Mutation analysis of TBX1 in non-deleted patients with features of DGS/VCFS or isolated cardiovascular defects.J. Med. Genet. 2001; 38: E45Crossref PubMed Scopus (122) Google Scholar, 20Yagi H. Furutani Y. Hamada H. Sasaki T. Asakawa S. Minoshima S. Ichida F. Joo K. Kimura M. Imamura S. et al.Role of TBX1 in human del22q11.2 syndrome.Lancet. 2003; 362: 1366-1373Abstract Full Text Full Text PDF PubMed Scopus (606) Google Scholar, 21Paylor R. Glaser B. Mupo A. Ataliotis P. Spencer C. Sobotka A. Sparks C. Choi C.H. Oghalai J. Curran S. et al.Tbx1 haploinsufficiency is linked to behavioral disorders in mice and humans: implications for 22q11 deletion syndrome.Proc. Natl. Acad. Sci. USA. 2006; 103: 7729-7734Crossref PubMed Scopus (223) Google Scholar, 22Torres-Juan L. Rosell J. Morla M. Vidal-Pou C. García-Algas F. de la Fuente M.A. Juan M. Tubau A. Bachiller D. Bernues M. et al.Mutations in TBX1 genocopy the 22q11.2 deletion and duplication syndromes: a new susceptibility factor for mental retardation.Eur. J. Hum. Genet. 2007; 15: 658-663Crossref PubMed Scopus (48) Google Scholar, 23Rauch R. Hofbeck M. Zweier C. Koch A. Zink S. Trautmann U. Hoyer J. Kaulitz R. Singer H. Rauch A. Comprehensive genotype-phenotype analysis in 230 patients with tetralogy of Fallot.J. Med. Genet. 2010; 47: 321-331Crossref PubMed Scopus (99) Google Scholar, 24Ogata T. Niihori T. Tanaka N. Kawai M. Nagashima T. Funayama R. Nakayama K. Nakashima S. Kato F. Fukami M. et al.TBX1 mutation identified by exome sequencing in a Japanese family with 22q11.2 deletion syndrome-like craniofacial features and hypocalcemia.PLoS ONE. 2014; 9: e91598Crossref PubMed Scopus (29) Google Scholar There is another gene, CRKL (CRK-like protooncogene adaptor protein [MIM: 602007]), that has been considered as a candidate. CRKL, mapping to the LCR22C-D region, is also of strong interest because inactivation of both alleles in mouse models results in CTDs with late gestational lethality.25Guris D.L. Fantes J. Tara D. Druker B.J. Imamoto A. Mice lacking the homologue of the human 22q11.2 gene CRKL phenocopy neurocristopathies of DiGeorge syndrome.Nat. Genet. 2001; 27: 293-298Crossref PubMed Scopus (228) Google ScholarInterestingly, a genetic interaction was observed between Tbx1 and Crkl in mouse models, suggesting that they might participate in the same functional pathway during embryogenesis.26Guris D.L. Duester G. Papaioannou V.E. Imamoto A. Dose-dependent interaction of Tbx1 and Crkl and locally aberrant RA signaling in a model of del22q11 syndrome.Dev. Cell. 2006; 10: 81-92Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar In contrast to CHD’s prevalence of about 0.5%–1% in the general population,27van der Linde D. Konings E.E. Slager M.A. Witsenburg M. Helbing W.A. Takkenberg J.J. Roos-Hesselink J.W. Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis.J. Am. Coll. Cardiol. 2011; 58: 2241-2247Crossref PubMed Scopus (1412) Google Scholar the dramatically elevated CHD risk in the 22q11.2DS population is attributed largely to the presence of the hemizygous deletion. Phenotypic variability, however, cannot be fully explained by the presence of the 22q11.2 deletion or deletion size and is most likely due to the existence of additional genetic and/or environmental modifiers. Identification of modifiers can provide insight into the biological mechanism of heart development and disease. Although some insights into the genetic architecture of CHD in 22q11.2DS have been gained through array genotyping and whole-exome sequencing efforts, whole-genome sequencing (WGS) methods in large cohorts are needed.28Guo T. McDonald-McGinn D. Blonska A. Shanske A. Bassett A.S. Chow E. Bowser M. Sheridan M. Beemer F. Devriendt K. et al.International Chromosome 22q11.2 ConsortiumGenotype and cardiovascular phenotype correlations with TBX1 in 1,022 velo-cardio-facial/DiGeorge/22q11.2 deletion syndrome patients.Hum. Mutat. 2011; 32: 1278-1289Crossref PubMed Scopus (46) Google Scholar, 29Mlynarski E.E. Sheridan M.B. Xie M. Guo T. Racedo S.E. McDonald-McGinn D.M. Gai X. Chow E.W. Vorstman J. Swillen A. et al.International Chromosome 22q11.2 ConsortiumCopy-Number Variation of the Glucose Transporter Gene SLC2A3 and Congenital Heart Defects in the 22q11.2 Deletion Syndrome.Am. J. Hum. Genet. 2015; 96: 753-764Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 30Mlynarski E.E. Xie M. Taylor D. Sheridan M.B. Guo T. Racedo S.E. McDonald-McGinn D.M. Chow E.W. Vorstman J. Swillen A. et al.International Chromosome 22q11.2 ConsortiumRare copy number variants and congenital heart defects in the 22q11.2 deletion syndrome.Hum. Genet. 2016; 135: 273-285Crossref PubMed Scopus (26) Google Scholar, 31Guo T. Repetto G.M. McDonald McGinn D.M. Chung J.H. Nomaru H. Campbell C.L. Blonska A. Bassett A.S. Chow E.W.C. Mlynarski E.E. et al.International 22q11.2 Consortium/Brain and Behavior Consortium∗Genome-wide association study to find modifiers for tetralogy of Fallot in the 22q11.2 deletion syndrome identifies variants in the GPR98 locus on 5q14.3.Circ Cardiovasc Genet. 2017; 10Crossref Scopus (13) Google Scholar, 32Guo T. Chung J.H. Wang T. McDonald-McGinn D.M. Kates W.R. Hawuła W. Coleman K. Zackai E. Emanuel B.S. Morrow B.E. Histone modifier genes alter conotruncal heart phenotypes in 22q11.2 deletion syndrome.Am. J. Hum. Genet. 2015; 97: 869-877Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 33Lin J.R. Zhang Q. Cai Y. Morrow B.E. Zhang Z.D. Integrated rare variant-based risk gene prioritization in disease case-control sequencing studies.PLoS Genet. 2017; 13: e1007142Crossref PubMed Scopus (4) Google Scholar The remaining 22q11.2 allele is particularly vulnerable to second-hit variants because only one functional copy of genes is present. To test the hypothesis that common and/or rare single-nucleotide variants (SNVs; including small indels) on the remaining allele might be associated with CHD, we used WGS data from 1,053 22q11.2DS subjects, all with the same typical 3 Mb LCR22A–LCR22D deletion. We performed a case-control association study involving 22q11.2-affected individualswith CHD or subtypes within CHD, such as CTDs, and control individuals with 22q11.2DS but who also have a normal heart and/or aortic arch. Furthermore, to determine whether associations identified in the 22q11.2DS cohort were also observed in CTD cases from the general population, we analyzed existing genome-wide association data from a meta-analysis of CTDs in cases without a 22q11.2 deletion.34Agopian A.J. Goldmuntz E. Hakonarson H. Sewda A. Taylor D. Mitchell L.E. Pediatric Cardiac Genomics Consortium∗Genome-wide association studies and meta-analyses for congenital heart defects.Circ Cardiovasc Genet. 2017; 10: e001449Crossref PubMed Scopus (20) Google Scholar Recruitment of the study subjects has been previously described.31Guo T. Repetto G.M. McDonald McGinn D.M. Chung J.H. Nomaru H. Campbell C.L. Blonska A. Bassett A.S. Chow E.W.C. Mlynarski E.E. et al.International 22q11.2 Consortium/Brain and Behavior Consortium∗Genome-wide association study to find modifiers for tetralogy of Fallot in the 22q11.2 deletion syndrome identifies variants in the GPR98 locus on 5q14.3.Circ Cardiovasc Genet. 2017; 10Crossref Scopus (13) Google Scholar,35Guo T. Diacou A. Nomaru H. McDonald-McGinn D.M. Hestand M. Demaerel W. Zhang L. Zhao Y. Ujueta F. Shan J. et al.International Chromosome 22q11.2, International 22q11.2 Brain and Behavior ConsortiaDeletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2.Hum. Mol. Genet. 2018; 27: 1150-1163Crossref PubMed Scopus (11) Google Scholar In brief, subjects with a known 22q11.2 deletion, existing DNA samples, and approval by institutional research ethics boards (Albert Einstein College of Medicine; Committee of Clinical Investigation; CCI#1999-201) were recruited in part from the International 22q11.2 Brain and Behavior Consortium36Gur R.E. Bassett A.S. McDonald-McGinn D.M. Bearden C.E. Chow E. Emanuel B.S. Owen M. Swillen A. Van den Bree M. Vermeesch J. et al.A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium.Mol. Psychiatry. 2017; 22: 1664-1672Crossref PubMed Scopus (39) Google Scholar (Table S1). A total of 1,595 samples had a clinical diagnosis of 22q11.2DS and carried a laboratory-confirmed 22q11.2 deletion. We obtained cardiac phenotype information from cardiology records, including echocardiography reports, as previously described.35Guo T. Diacou A. Nomaru H. McDonald-McGinn D.M. Hestand M. Demaerel W. Zhang L. Zhao Y. Ujueta F. Shan J. et al.International Chromosome 22q11.2, International 22q11.2 Brain and Behavior ConsortiaDeletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2.Hum. Mol. Genet. 2018; 27: 1150-1163Crossref PubMed Scopus (11) Google Scholar Individuals with missing cardiac records were excluded from these analyses. Individuals with the LCR22A-D deletion and any intracardiac or aortic arch defect were considered to be CHD-affected individuals. Individuals with no heart or aortic arch defect, except for those with only a patent foramen ovale or VSD and/or ASD that spontaneously closed in infancy and/or a bicuspid aortic valve, were considered to be controls. For the CTD subset, any of the following cardiac defects were considered to be CTD-affected individuals in the present study: TOF, PTA, IAAB, RAA, or abnormal origin of the right or left subclavian artery. The difference between CHD- and CTD-afected individuals was that CTD-affected individuals did not have isolated VSD or ASD, but both CHD-affected and CTD-affected individuals had LCR22A-D deletions. CTD can be separated into two different groups based upon differences in embryological origin. These groups are characterized by (1) cardiac outflow tract (OFT) defects that include TOF, PTA, PS (pulmonic stenosis), and/or PA (pulmonary atresia) and (2) aortic-arch defects or defects that affect arterial branching from the aortic arch; such defects include RAA, IAAB, or other aortic-arch defects, such as abnormal origin of the right subclavian artery. We also performed other sub-phenotype comparisons as described. WGS with a median depth of 39-fold was performed on 1,595 subjects as part of the International 22q11.2 Brain and Behavior Consortium.36Gur R.E. Bassett A.S. McDonald-McGinn D.M. Bearden C.E. Chow E. Emanuel B.S. Owen M. Swillen A. Van den Bree M. Vermeesch J. et al.A neurogenetic model for the study of schizophrenia spectrum disorders: the International 22q11.2 Deletion Syndrome Brain Behavior Consortium.Mol. Psychiatry. 2017; 22: 1664-1672Crossref PubMed Scopus (39) Google Scholar In brief, samples were sequenced with the Illumina HiSeq X Ten for the first 100 samples and the Illumina HiSeq 2500 platform for all other samples at Hudson Alpha. Sequence reads were mapped to genome build hg38 (December 2013; GRCh38/hg38) with PEMapper (90% stringency for 2 × 100 bp reads and 95% stringency for 2 × 150 bp reads;37Johnston H.R. Chopra P. Wingo T.S. Patel V. Epstein M.P. Mulle J.G. Warren S.T. Zwick M.E. Cutler D.J. Reply to Plüss et al.: The strength of PEMapper/PECaller lies in unbiased calling using large sample sizes.Proc. Natl. Acad. Sci. USA. 2017; 114: E8323Crossref PubMed Scopus (1) Google Scholar). Deletion sizes were confirmed by the coverage at the 22q11.2 region. Variants on the remaining 22q11.2 allele (LCR22A–LCR22D region; chr22: 18115819–21432004, hg38) were called by PECaller in haploid mode. Variants were called if ≥90% of the variants at the site had a posterior probability ≥95%. Variants were removed if Hardy-Weinberg equilibrium (HWE) p value were < 1.0 × 10−5. Exclusion was based upon the quality-control (QC) results of the dataset from the genome-wide diploid variants. Samples from relatives, those in which sex did not match that revealed by genetic assays, and samples with poor-quality sequence were removed. For all samples with the LCR22A–LCR22D deletion, variants with a genotype call rate of <0.95 and monomorphic variants were removed. Variants within LCR22 regions were removed because of their repetitive nature. Principal-component analysis (PCA) was conducted with PLINK 1.9 beta on the basis of the dataset of genome-wide diploid variants as well as Hapmap 3 r3 (International HapMap project phase III release 3) data. First, shared variants in this dataset and the Hapmap 3 r3 dataset were extracted and combined into one dataset. Of note, we removed variants with A>T, T>A, G>C, and C>G allele types to avoid any potential strand-flip issues. Second, variants with minor-allele frequency <0.05 and variants in the sex chromosome were excluded. After this, we pruned autosomal common variants by using the –indep function to ensure only independent variants were used for PCA. Lastly, PCA was conducted with the –pca function. European Caucasian ancestry of the subjects was determined by the Multidimensional Outlier Detection method as implemented in SVS Golden Helix software. First, a median centroid vector was calculated as [median (column1), median (column2), median (column3)] on the basis of the top three principal components (PCs) for all the samples plus Hapmap CEU (Utah residents with ancestry from northern and western Europe) and TSI (Tuscans in Italy) samples (combined, referred to as Caucasian). A distance score was then calculated for each sample as follows:threshold=∑n=1NQ3n2+M∗∑n=1NIQRn2 The outlier threshold was calculated as follows:distsample=∑n=1N(valuesample,n−mediann)2 Where Q3 and IQR are the third quartile and inner quartile range of each sample (1 … N), respectively, and M is a user-specified multiplier; in this study, 2 was adopted. Outliers of Caucasian samples were examined in the scatterplot of PC1 versus PC2; samples that clustered with the HapMap Gujarati Indians in Houston, Texas (GIH) population or the Mexican ancestry in Los Angeles, California (MEX) population were grouped as Hispanics. Populations dispersed toward Yoruba in Ibadan, Nigeria (YRI) were grouped as African-admixed populations. We also conducted PCA in the three subpopulations to obtain the top several PCs that could serve as covariants so that we could adjust for possible population stratification in the stratified analyses. Logistic regression analyses for common variants were conducted in all 1,053 samples as well as in the Caucasian, African-admixed, and Hispanic subsets; the sex and corresponding number of PCs were adjusted for CHD, CTD, TOF, and TOF-PTA-IAAB risk. We employed the false-discovery rate (FDR) to correct for multiple testing issues. For rare variants, we conducted the Fisher’s exact test in the Caucasian population. Because most genome-wide association studies (GWASs) adopted a suggestive significant threshold at 1.0 × 10−5 for 2.0 × 106 to 1.0 × 106 variants, we set the suggestive significant threshold for this study of a few thousand variants at p = 1.0 × 10−3 for both common and rare variants. PLINK 1.90 was used for SNV-based analyses.38Purcell S. Neale B. Todd-Brown K. Thomas L. Ferreira M.A. Bender D. Maller J. Sklar P. de Bakker P.I. Daly M.J. Sham P.C. PLINK: a tool set for whole-genome association and population-based linkage analyses.Am. J. Hum. Genet. 2007; 81: 559-575Abstract Full Text Full Text PDF PubMed Scopus (16617) Google Scholar For the top variants that were located in the LCR22C–LCR22D region and showed evidence of association with CTD risk in the 22q11.2DS cohort, we analyzed existing data from a meta-analysis of three published GWASs of CTDs in individuals without a 22q11.2 deletion.34Agopian A.J. Goldmuntz E. Hakonarson H. Sewda A. Taylor D. Mitchell L.E. Pediatric Cardiac Genomics Consortium∗Genome-wide association studies and meta-analyses for congenital heart defects.Circ Cardiovasc Genet. 2017; 10: e001449Crossref PubMed Scopus (20) Google Scholar Variants that passed QC were annotated for possible biological function via Bystro,39Kotlar A.V. Trevino C.E. Zwick M.E. Cutler D.J. Wingo T.S. Bystro: Rapid online variant annotation and natural-language filtering at whole-genome scale.Genome Biol. 2018; 19: 14Crossref PubMed Scopus (15) Google Scholar snpEff,40Cingolani P. Platts A. Wang L. Coon M. Nguyen T. Wang L. Land S.J. Lu X. Ruden D.M. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.Fly (Austin). 2012; 6: 80-92Crossref PubMed Scopus (4058) Google Scholar and dbNSFP.41Liu X. Wu C. Li C. Boerwinkle E. dbNSFP v3.0: A one-stop database of functional predictions and annotations for human nonsynonymous and splice-site SNVs.Hum. Mutat. 2016; 37: 235-241Crossref PubMed Scopus (461) Google Scholar We adopted the definition" @default.
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• W2994828253 date "2020-01-01" @default.
• W2994828253 modified "2023-10-17" @default.
• W2994828253 title "Complete Sequence of the 22q11.2 Allele in 1,053 Subjects with 22q11.2 Deletion Syndrome Reveals Modifiers of Conotruncal Heart Defects" @default.
• W2994828253 cites W1482498530 @default.
• W2994828253 cites W1506409704 @default.
• W2994828253 cites W1533942137 @default.
• W2994828253 cites W1816069990 @default.
• W2994828253 cites W1823173687 @default.

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