Document Type
Article
Publication Date
6-2023
Identifier
DOI: 10.1136/jmg-2022-108738
Abstract
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.
Journal Title
Journal of medical genetics
Volume
60
Issue
6
First Page
587
Last Page
596
MeSH Keywords
Pregnancy; Female; Humans; Animals; Mice; Zebrafish; DNA Copy Number Variations; Morpholinos; Urinary Tract; Central Nervous System; Cardiovascular System
Keywords
congenital, hereditary, and neonatal diseases and abnormalities; digestive system abnormalities; genetic counseling; heart defects, congenital; nervous system malformations
Recommended Citation
Kolvenbach CM, Felger T, Schierbaum L, et al. X-linked variations in SHROOM4 are implicated in congenital anomalies of the urinary tract and the anorectal, cardiovascular and central nervous systems. J Med Genet. 2023;60(6):587-596. doi:10.1136/jmg-2022-108738
Comments
Grant support
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
Publisher's Link: https://jmg.bmj.com/content/60/6/587.long