MORF4L1, encoding a chromatin remodeler, is mutated in a recognizable dysmorphic neurodevelopmental disorder
6 affiliations
- 1Department of Translational Genomics, Genomic Medicine Centre of Excellence, King Faisal Specialist Hospital and Research Center
- 2Department of Pediatrics, Faculty of Medicine, Kuwait University
- 3Neuroscience Centre, King Faisal Specialist Hospital and Research Centre
- 4Program in Developmental and Stem Cell Biology, SickKids Research Institute
- 5Kuwait Medical Genetics Centre, Ministry of Health
- 6Zebrafish Genetics and Disease Model Core, SickKids Research Institute
Abstract
Chromatin remodelers are increasingly recognized as key contributors to neurodevelopmental disorders, usually through de novo dominant variants. Mortality Factor 4 Like 1 (MORF4L1) is recognized for its role in chromatin organization and transcriptional regulation. We identified a consanguineous Middle Eastern family in which a neurodevelopmental disorder with a distinctive dysmorphic phenotype segregated with a homozygous variant in MORF4L1. The autosomal recessive inheritance sets it apart from most other chromatin remodeling disorders. Consistent with its epigenetic role, we also observed a disruption in DNA methylation patterns in patient blood compared to controls. We modelled both the patient variant and a predicted loss of function variant in zebrafish and found that biallelic loss of function fish exhibited growth restriction and craniofacial/skeletal defects consistent with the patients’ phenotypes. Surprisingly, larvae with knock in of the mutant morf4l1 KI/KI appeared phenotypically normal with respect to jaw development suggesting that the impact of the variant is less severe in zebrafish. Functional modelling in zebrafish confirms a loss‑of‑function mechanism and highlights species‑dependent differences specifically in the impact of the missense variant on protein function. The tolerance of zebrafish to the human variant provides a cautionary tale about overreliance on animal models as a screening tool for variant classification.
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BibTeX
@article{shamseldin2026morf4l1,
title = {{MORF4L1, encoding a chromatin remodeler, is mutated in a recognizable dysmorphic neurodevelopmental disorder}},
author = {Hanan E. Shamseldin and Dana Marafi and Mohammed AlMuhaizea and C’airah Ceolin and Firdous Abdulwahab and Tarfa Alshidi and Buthaina Albash and Fatemah Alabdulrazzaq and Harsha R. Murthy and Jenica L. M. Van Gennip and Isabella M. Harmic and Rebecca Simonian and Xiucheng Cui and Jason Burgess and Brian Ciruna and Ashish R. Deshwar and Fowzan S. Alkuraya and Lama AlAbdi},
journal = {Scientific Reports},
year = {2026},
month = jul,
doi = {10.1038/s41598-026-61907-7},
url = {https://doi.org/10.1038/s41598-026-61907-7},
note = {CC BY},
}
RIS
TY - JOUR
TI - MORF4L1, encoding a chromatin remodeler, is mutated in a recognizable dysmorphic neurodevelopmental disorder
AU - Hanan E. Shamseldin
AU - Dana Marafi
AU - Mohammed AlMuhaizea
AU - C’airah Ceolin
AU - Firdous Abdulwahab
AU - Tarfa Alshidi
AU - Buthaina Albash
AU - Fatemah Alabdulrazzaq
AU - Harsha R. Murthy
AU - Jenica L. M. Van Gennip
AU - Isabella M. Harmic
AU - Rebecca Simonian
AU - Xiucheng Cui
AU - Jason Burgess
AU - Brian Ciruna
AU - Ashish R. Deshwar
AU - Fowzan S. Alkuraya
AU - Lama AlAbdi
PY - 2026
DA - 2026/07/01
JO - Scientific Reports
DO - 10.1038/s41598-026-61907-7
UR - https://doi.org/10.1038/s41598-026-61907-7
AB - Chromatin remodelers are increasingly recognized as key contributors to neurodevelopmental disorders, usually through de novo dominant variants. Mortality Factor 4 Like 1 (MORF4L1) is recognized for its role in chromatin organization and transcriptional regulation. We identified a consanguineous Middle Eastern family in which a neurodevelopmental disorder with a distinctive dysmorphic phenotype segregated with a homozygous variant in MORF4L1. The autosomal recessive inheritance sets it apart from most other chromatin remodeling disorders. Consistent with its epigenetic role, we also observed a disruption in DNA methylation patterns in patient blood compared to controls. We modelled both the patient variant and a predicted loss of function variant in zebrafish and found that biallelic loss of function fish exhibited growth restriction and craniofacial/skeletal defects consistent with the patients’ phenotypes. Surprisingly, larvae with knock in of the mutant morf4l1 KI/KI appeared phenotypically normal with respect to jaw development suggesting that the impact of the variant is less severe in zebrafish. Functional modelling in zebrafish confirms a loss‑of‑function mechanism and highlights species‑dependent differences specifically in the impact of the missense variant on protein function. The tolerance of zebrafish to the human variant provides a cautionary tale about overreliance on animal models as a screening tool for variant classification.
SN - 2045-2322
ER -