The copy number variation landscape of congenital anomalies of the kidney and urinary tract.
Miguel VerbitskyRik WestlandAlejandra PerezKrzysztof KirylukQingxue LiuPriya KrithivasanAdele MitrottiDavid A FaselEkaterina BatourinaMatthew Gordon SampsonMonica BodriaMax WerthCharlly KaoJeremiah MartinoValentina P CaponeAsaf VivanteShirlee ShrilByum Hee KilMaddalena MarasàJun Y ZhangYoung-Ji NaTze Y LimDina AhramPatricia L WengErin L HeinzenAlba CarreaGiorgio PiaggioLoreto GesualdoValeria MancaGiuseppe MasnataMargherita GiganteDaniele CusiClaudia IzziFrancesco ScolariJoanna A E van WijkMarijan SaragaDomenico SantoroGiovanni ContiPasquale ZamboliHope WhiteDorota DrozdzKatarzyna ZachwiejaMonika MiklaszewskaMarcin TkaczykDaria TomczykAnna KrakowskaPrzemyslaw SikoraTomasz JarmolińskiMaria K Borszewska-KornackaRobert PawluchMaria SzczepanskaPiotr AdamczykMalgorzata Mizerska-WasiakGrazyna KrzemienAgnieszka SzmigielskaMarcin ZaniewMark G DobsonJohn M DarlowPrem PuriDavid E BartonSusan L FurthBradley A WaradyZoran GucevVladimir J LozanovskiVelibor TasicIsabella PisaniLandino AllegriLida M RodasJosep M CampistolCécile JeanpierreShumyle AlamPasquale CasaleCraig S WongFangming LinDébora M MirandaEduardo A OliveiraAna Cristina Simões-E-SilvaJonathan M BaraschBrynn LevyNan WuFriedhelm HildebrandtGian Marco GhiggeriAnna Latos-BielenskaAnna Materna-KirylukFeng ZhangHakon HakonarsonVirginia E PapaioannouCathy Lee MendelsohnAli G GharaviSimone Sanna-CherchiPublished in: Nature genetics (2018)
Congenital anomalies of the kidney and urinary tract (CAKUT) are a major cause of pediatric kidney failure. We performed a genome-wide analysis of copy number variants (CNVs) in 2,824 cases and 21,498 controls. Affected individuals carried a significant burden of rare exonic (that is, affecting coding regions) CNVs and were enriched for known genomic disorders (GD). Kidney anomaly (KA) cases were most enriched for exonic CNVs, encompassing GD-CNVs and novel deletions; obstructive uropathy (OU) had a lower CNV burden and an intermediate prevalence of GD-CNVs; and vesicoureteral reflux (VUR) had the fewest GD-CNVs but was enriched for novel exonic CNVs, particularly duplications. Six loci (1q21, 4p16.1-p16.3, 16p11.2, 16p13.11, 17q12 and 22q11.2) accounted for 65% of patients with GD-CNVs. Deletions at 17q12, 4p16.1-p16.3 and 22q11.2 were specific for KA; the 16p11.2 locus showed extensive pleiotropy. Using a multidisciplinary approach, we identified TBX6 as a driver for the CAKUT subphenotypes in the 16p11.2 microdeletion syndrome.