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

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 sequen...

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Bibliographic Details
Published in:American journal of medical genetics. Part A 2021-10, Vol.185 (10), p.3028-3041
Main Authors: 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.
Format: Article
Language:English
Subjects:
Adult
birth defects
Bladder
bladder exstrophy
Bladder Exstrophy - genetics
Bladder Exstrophy - pathology
Cell Adhesion - genetics
Cell migration
Cell Movement - genetics
Children
Children & youth
Etiology
Exome - genetics
Female
Gene frequency
Genetic diversity
Genetic Predisposition to Disease
genetics
Heredity
Humans
Infant, Newborn
Male
Mutation - genetics
Pregnancy
Tetraspanins - genetics
TSPAN4
TUBE1
Tubulin - genetics
Urethra
ventral body wall closure
Whole Exome Sequencing
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Summary: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.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.62439