title: Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract.
abstract: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the leading cause of CKD in children, featuring a broad variety of malformations. A monogenic cause can be detected in around 12% of patients. However, the morphologic clinical phenotype of CAKUT frequently does not indicate specific genes to be examined. To determine the likelihood of detecting causative recessive mutations by whole-exome sequencing (WES), we analyzed individuals with CAKUT from 33 different consanguineous families. Using homozygosity mapping and WES, we identified the causative mutations in nine of the 33 families studied (27%). We detected recessive mutations in nine known disease-causing genes: ZBTB24, WFS1, HPSE2, ATRX, ASPH, AGXT, AQP2, CTNS, and PKHD1 Notably, when mutated, these genes cause multiorgan syndromes that may include CAKUT as a feature (syndromic CAKUT) or cause renal diseases that may manifest as phenocopies of CAKUT. None of the above monogenic disease-causing genes were suspected on clinical grounds before this study. Follow-up clinical characterization of those patients allowed us to revise and detect relevant new clinical features in a more appropriate pathogenetic context. Thus, applying WES to the diagnostic approach in CAKUT provides opportunities for an accurate and early etiology-based diagnosis and improved clinical management.
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.|Talpiot Medical Leadership Program, Sheba Medical Center, Tel-Hashomer, Israel.
authors.forename: Asaf
authors.initials: A
authors.lastname: Vivante
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.|Division of Nephrology, Department of Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Daw-Yang
authors.initials: DY
authors.lastname: Hwang
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Pediatrics, Cologne Children's Hospital, Cologne, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kohl
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shirlee
authors.initials: S
authors.lastname: Shril
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Julian
authors.initials: J
authors.lastname: Schulz
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Amelie
authors.initials: A
authors.lastname: van der Ven
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ghaleb
authors.initials: G
authors.lastname: Daouk
authors.affiliation: Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt.|Egyptian Group for Orphan Renal Diseases, Cairo, Egypt.
authors.forename: Neveen A
authors.initials: NA
authors.lastname: Soliman
authors.affiliation: Pediatric Nephrology Department, Institute of Child Health and Hospital for Children, Chennai, Tamil Nadu, India.
authors.forename: Aravind Selvin
authors.initials: AS
authors.lastname: Kumar
authors.affiliation: Pediatric Nephrology Department, Institute of Child Health and Hospital for Children, Chennai, Tamil Nadu, India.
authors.forename: Prabha
authors.initials: P
authors.lastname: Senguttuvan
authors.affiliation: Division of Urology, Department of Surgery, Kuwait University, Safat, Kuwait.
authors.forename: Elijah O
authors.initials: EO
authors.lastname: Kehinde
authors.affiliation: Medical Faculty Skopje, University Children's Hospital, Skopje, Macedonia; and.
authors.forename: Velibor
authors.initials: V
authors.lastname: Tasic
authors.affiliation: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts; friedhelm.hildebrandt@childrens.harvard.edu.|Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: D059472:Exome / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D013577:Syndrome; D014564:Urogenital Abnormalities / Q000235:genetics*; D014718:Vesico-Ureteral Reflux / Q000235:genetics*
keywords: CAKUT; WES; monogenic disease