Exome Survey and Candidate Gene Re-Sequencing Identifies Novel Exstrophy Candidate Genes and Implicates <i>LZTR1</i> in Disease Formation
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
Affiliations
Ricarda Köllges
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
Jil Stegmann
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
Sophia Schneider
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
Lea Waffenschmidt
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
Julia Fazaal
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
Katinka Breuer
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
Alina C. Hilger
Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, 91054 Erlangen, Germany
Gabriel C. Dworschak
Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, 53127 Bonn, Germany
Enrico Mingardo
Institute of Anatomy and Cell Biology, Medical Faculty, University of Bonn, 53127 Bonn, Germany
Wolfgang Rösch
Department of Pediatric Urology, Clinic St. Hedwig, University Medical Center Regensburg, 93053 Regensburg, Germany
Aybike Hofmann
Department of Pediatric Urology, Clinic St. Hedwig, University Medical Center Regensburg, 93053 Regensburg, Germany
Claudia Neissner
Department of Pediatric Urology, Clinic St. Hedwig, University Medical Center Regensburg, 93053 Regensburg, Germany
Anne-Karolin Ebert
Department of Urology and Pediatric Urology, University Hospital Ulm, 89081 Ulm, Germany
Raimund Stein
Center for Pediatric, Adolescent and Reconstructive Urology, University Medical Center Mannheim, University Heidelberg, 69117 Mannheim, Germany
Nina Younsi
Center for Pediatric, Adolescent and Reconstructive Urology, University Medical Center Mannheim, University Heidelberg, 69117 Mannheim, Germany
Karin Hirsch-Koch
Division of Pediatric Urology, Department of Urology, University Hospital Erlangen, 91054 Erlangen, Germany
Eberhard Schmiedeke
Clinic for Pediatric Surgery and Pediatric Urology, Klinikum Bremen-Mitte, 28205 Bremen, Germany
Nadine Zwink
Department of Child and Adolescent Psychiatry, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
Ekkehart Jenetzky
Department of Child and Adolescent Psychiatry, University Medical Center of the Johannes Gutenberg University Mainz, 55131 Mainz, Germany
Holger Thiele
Cologne Center for Genomics, University of Cologne, 50923 Cologne, Germany
Kerstin U. Ludwig
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany
Heiko Reutter
Division of Neonatology and Pediatric Intensive Care, Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, 91054 Erlangen, Germany
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 (NR1H2, GKAP1), four candidate genes with autosomal-recessive biallelic variants (AKR1B10, CLSTN3, NDST4, PLEKHB1) and one candidate gene with suggestive uniparental disomy (SVEP1). 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 LZTR1 (c.978_985del, p.Ser327fster6) and in SLC7A4 (c.1087delC, p.Arg363fster68). Conclusions: According to previous studies, our study further implicates LZTR1 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.
