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Exome Survey and Candidate Gene Re-Sequencing Identifies Novel Exstrophy Candidate Genes and Implicates in Disease Formation.

Biomolecules

Authors: Ricarda Köllges, Jil Stegmann, Sophia Schneider, Lea Waffenschmidt, Julia Fazaal, Katinka Breuer, Alina C Hilger, Gabriel C Dworschak, Enrico Mingardo, Wolfgang Rösch, Aybike Hofmann, Claudia Neissner, Anne-Karolin Ebert, Raimund Stein, Nina Younsi, Karin Hirsch-Koch, Eberhard Schmiedeke, Nadine Zwink, Ekkehart Jenetzky, Holger Thiele, Kerstin U Ludwig, Heiko Reutter

BACKGROUND: The bladder exstrophy-epispadias complex (BEEC) is a spectrum of congenital abnormalities that involves the abdominal wall, the bony pelvis, the urinary tract, the external genitalia, and, in severe cases, the gastrointestinal tract as well.

METHODS: Herein, we performed an exome analysis of case-parent trios with cloacal exstrophy (CE), the most severe form of the BEEC. Furthermore, we surveyed the exome of a sib-pair presenting with classic bladder exstrophy (CBE) and epispadias (E) only. Moreover, we performed large-scale re-sequencing of CBE individuals for novel candidate genes that were derived from the current exome analysis, as well as for previously reported candidate genes within the CBE phenocritical region, 22q11.2.

RESULTS: The exome survey in the CE case-parent trios identified two candidate genes harboring de novo variants (, ), four candidate genes with autosomal-recessive biallelic variants (, , , ) and one candidate gene with suggestive uniparental disomy (). However, re-sequencing did not identify any additional variant carriers in these candidate genes. Analysis of the affected sib-pair revealed no candidate gene. Re-sequencing of the genes within the 22q11.2 CBE phenocritical region identified two highly conserved frameshift variants that led to early termination in two independent CBE males, in (c.978_985del, p.Ser327fster6) and in (c.1087delC, p.Arg363fster68).

CONCLUSIONS: According to previous studies, our study further implicates in CBE formation. Exome analysis-derived candidate genes from CE individuals may not represent a frequent indicator for other BEEC phenotypes and warrant molecular analysis before their involvement in disease formation can be assumed.

PMID: 37509153