RT Journal Article SR Electronic T1 X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2022-108738 DO 10.1136/jmg-2022-108738 A1 Caroline M Kolvenbach A1 Tim Felger A1 Luca Schierbaum A1 Isabelle Thiffault A1 Tomi Pastinen A1 Maria Szczepańska A1 Marcin Zaniew A1 Piotr Adamczyk A1 Allan Bayat A1 Öznur Yilmaz A1 Tobias T Lindenberg A1 Holger Thiele A1 Friedhelm Hildebrandt A1 Katrin Hinderhofer A1 Ute Moog A1 Alina C Hilger A1 Bonnie Sullivan A1 Lauren Bartik A1 Piotr Gnyś A1 Phillip Grote A1 Benjamin Odermatt A1 Heiko M Reutter A1 Gabriel C Dworschak YR 2022 UL http://jmg.bmj.com/content/early/2022/11/15/jmg-2022-108738.abstract AB Background SHROOM4 is thought to play an important role in cytoskeletal modification and development of the early nervous system. Previously, single-nucleotide variants (SNVs) or copy number variations (CNVs) in SHROOM4 have been associated with the neurodevelopmental disorder Stocco dos Santos syndrome, but not with congenital anomalies of the urinary tract and the visceral or the cardiovascular system.Methods Here, exome sequencing and CNV analyses besides expression studies in zebrafish and mouse and knockdown (KD) experiments using a splice blocking morpholino in zebrafish were performed to study the role of SHROOM4 during embryonic development.Results In this study, we identified putative disease-causing SNVs and CNVs in SHROOM4 in six individuals from four families with congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems (CNS). Embryonic mouse and zebrafish expression studies showed Shroom4 expression in the upper and lower urinary tract, the developing cloaca, the heart and the cerebral CNS. KD studies in zebrafish larvae revealed pronephric cysts, anomalies of the cloaca and the heart, decreased eye-to-head ratio and higher mortality compared with controls. These phenotypes could be rescued by co-injection of human wild-type SHROOM4 mRNA and morpholino.Conclusion The identified SNVs and CNVs in affected individuals with congenital anomalies of the urinary tract, the anorectal, the cardiovascular and the central nervous systems, and subsequent embryonic mouse and zebrafish studies suggest SHROOM4 as a developmental gene for different organ systems.Data are available upon reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. SHROOM4 variants identified in this study were submitted to ClinVar.