RT Journal Article
SR Electronic
T1 X-linked variations in <em>SHROOM4</em> 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 Kolvenbach, Caroline M
A1 Felger, Tim
A1 Schierbaum, Luca
A1 Thiffault, Isabelle
A1 Pastinen, Tomi
A1 Szczepańska, Maria
A1 Zaniew, Marcin
A1 Adamczyk, Piotr
A1 Bayat, Allan
A1 Yilmaz, Öznur
A1 Lindenberg, Tobias T
A1 Thiele, Holger
A1 Hildebrandt, Friedhelm
A1 Hinderhofer, Katrin
A1 Moog, Ute
A1 Hilger, Alina C
A1 Sullivan, Bonnie
A1 Bartik, Lauren
A1 Gnyś, Piotr
A1 Grote, Phillip
A1 Odermatt, Benjamin
A1 Reutter, Heiko M
A1 Dworschak, Gabriel C
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.