MORF4L1, encoding a chromatin remodeler, is mutated in a recognizable dysmorphic neurodevelopmental disorder.
TL;DR
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, and provides a cautionary tale about overreliance on animal models as a screening tool for variant classification.
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 morf4l1KI/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.