Exome sequencing of child-parent trios with bladder exstrophy: Findings in 26 children

Details

• Alternative Title:
  Am J Med Genet A
• Personal Author:
  Pitsava, Georgia ; Feldkamp, Marcia L. ; Pankratz, Nathan ; Lane, John ; Kay, Denise M. ; Conway, Kristin M. ; Shaw, Gary M. ; Reefhuis, Jennita ; Jenkins, Mary M. ; Almli, Lynn M. ; Olshan, Andrew F. ; Pangilinan, Faith ; Brody, Lawrence C. ; Sicko, Robert J. ; Hobbs, Charlotte A. ; Bamshad, Mike ; McGoldrick, Daniel ; Nickerson, Deborah A. ; Finnell, Richard H. ; Mullikin, James ; Romitti, Paul A. ; Mills, James L.
• Corporate Authors:
  University of Washington Center for Mendelian Genomics, NISC Comparative Sequencing Program and the National Birth Defects Prevention Study
• Description:
  Bladder exstrophy (BE) is a rare, lower ventral midline defect with the bladder and part of the urethra exposed. The etiology of BE is unknown but thought to be influenced by genetic variation with more recent studies suggesting a role for rare variants. As such, we conducted paired-end exome sequencing in 26 child/mother/father trios. Three children had rare (allele frequency ≤ 0.0001 in several public databases) inherited variants in TSPAN4, one with a loss-of-function variant and two with missense variants. Two children had loss-of-function variants in TUBE1. Four children had rare missense or nonsense variants (one per child) in WNT3, CRKL, MYH9, or LZTR1, genes previously associated with BE. We detected 17 de novo missense variants in 13 children and three de novo loss-of-function variants (AKR1C2, PRRX1, PPM1D) in three children (one per child). We also detected rare compound heterozygous loss-of-function variants in PLCH2 and CLEC4M and rare inherited missense or loss-of-function variants in additional genes applying autosomal recessive (three genes) and X-linked recessive inheritance models (13 genes). Variants in two genes identified may implicate disruption in cell migration (TUBE1) and adhesion (TSPAN4) processes, mechanisms proposed for BE, and provide additional evidence for rare variants in the development of this defect.
• Subjects:
  Adult Article Birth Defects Bladder Exstrophy Cell Adhesion Cell Movement Exome Female Genetic Predisposition To Disease Genetics Humans Infant, Newborn Male Mutation Pregnancy Tetraspanins TSPAN4 TUBE1 Tubulin Ventral Body Wall Closure Whole Exome Sequencing

  More +
• Source:
  Am J Med Genet A. 185(10):3028-3041
• Pubmed ID:
  34355505
• Pubmed Central ID:
  PMC8446314
• Document Type:
  Journal Article
• Funding:
  U01 DD001223/DD/NCBDD CDC HHSUnited States/ ; U01 DD001223/CC/CDC HHSUnited States/ ; U01 DD001035/DD/NCBDD CDC HHSUnited States/ ; HHSN27500005/Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; EP-D-18-001/EPA/EPAUnited States/ ; HHSN275201100001I/HD/NICHD NIH HHSUnited States/ ; UM1 HG006493/HG/NHGRI NIH HHSUnited States/ ; HHSN275201100001C/HD/NICHD NIH HHSUnited States/ ; U24 HG008956/HG/NHGRI NIH HHSUnited States/ ; Z01 HD008792/ImNIH/Intramural NIH HHSUnited States/ ; HHSN275201100001G/HD/NICHD NIH HHSUnited States/ ; HG006493/HG/NHGRI NIH HHSUnited States/ ; HG008956/HG/NHGRI NIH HHSUnited States/ ; U01 DD001035/CC/CDC HHSUnited States/ ; CDP 13-003/HX/HSRD VAUnited States/
• Volume:
  185
• Issue:
  10
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:e86bccfe19931bae7afaadcedbd15accacb17dc8a5f0df3aaa22b6827201d3de
• Download URL:
  https://stacks.cdc.gov/view/cdc/110271/cdc_110271_DS1.pdf
• File Type:
  [PDF - 355.16 KB ]