期刊
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
卷 185, 期 10, 页码 3028-3041出版社
WILEY
DOI: 10.1002/ajmg.a.62439
关键词
birth defects; bladder exstrophy; genetics; TSPAN4; TUBE1; ventral body wall closure
资金
- Centers for Disease Control and Prevention [U01 DD001035, U01 DD001223]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [HHSN27500005, HHSN275201100001I]
- National Human Genome Research Institute [HG006493]
Bladder exstrophy (BE) is a rare defect with genetic variations possibly playing a role. A study involving exome sequencing of 26 child/mother/father trios identified several rare variants in genes such as TSPAN4, TUBE1, WNT3, CRKL, MYH9, and LZTR1 associated with BE. Furthermore, de novo variants and rare compound heterozygous variants were also detected, suggesting a complex genetic basis for this defect.
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.
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