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

University of Washington Center for Mendelian Genomics, NISC Comparative Sequencing Program and the National Birth Defects Prevention Study

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1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3028-3041
Number of pages14
JournalAmerican Journal of Medical Genetics, Part A
Volume185
Issue number10
DOIs
StatePublished - Oct 2021

Bibliographical note

Funding Information:
We thank the NBDPS participants, scientists, staff, and Genetics Collaborative Working Group. We also thank Dr. Marilyn Browne at the Birth Defects Research Section, New York State Department of Health, and the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about. This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, the National Institutes of Health, or the California Department of Public Health. This work was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract numbers HHSN275201100001I and HHSN27500005) and by the Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health. This work was also supported through Centers for Disease Control and Prevention (CDC) cooperative agreements under PA #96043, PA #02081, FOA #DD09-001, FOA #DD13-003, and NOFO #DD18-001 to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study (NBDPS) and/or the Birth Defects Study To Evaluate Pregnancy exposureS (BD-STEPS), and the Iowa Center for Birth Defects Research and Prevention U01 DD001035 and U01 DD001223 (PAR). The University of Washington Center for Mendelian Genomics (UW-CMG) was funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956.

Funding Information:
We thank the NBDPS participants, scientists, staff, and Genetics Collaborative Working Group. We also thank Dr. Marilyn Browne at the Birth Defects Research Section, New York State Department of Health, and the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about . This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention, the National Institutes of Health, or the California Department of Public Health. This work was funded by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract numbers HHSN275201100001I and HHSN27500005) and by the Division of Intramural Research of the National Human Genome Research Institute, National Institutes of Health. This work was also supported through Centers for Disease Control and Prevention (CDC) cooperative agreements under PA #96043, PA #02081, FOA #DD09‐001, FOA #DD13‐003, and NOFO #DD18‐001 to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study (NBDPS) and/or the Birth Defects Study To Evaluate Pregnancy exposureS (BD‐STEPS), and the Iowa Center for Birth Defects Research and Prevention U01 DD001035 and U01 DD001223 (PAR). The University of Washington Center for Mendelian Genomics (UW‐CMG) was funded by NHGRI and NHLBI grants UM1 HG006493 and U24 HG008956.

Publisher Copyright:
© 2021 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Keywords

  • TSPAN4
  • TUBE1
  • birth defects
  • bladder exstrophy
  • genetics
  • ventral body wall closure

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.
  • Research Support, N.I.H., Intramural

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