MORF4L1, encoding a chromatin remodeler, is mutated in a recognizable dysmorphic neurodevelopmental disorder.

Homozygous loss-of-function variant in MORF4L1 (a chromatin remodeler), confirmed in zebrafish; disrupted DNA methylation.

Identification, in a consanguineous Middle Eastern family, of a neurodevelopmental disorder (NDD) with a distinctive dysmorphic phenotype segregating with a homozygous variant in MORF4L1, a chromatin remodeler. The autosomal recessive inheritance sets this apart from most chromatin-remodelling disorders. A disruption of DNA methylation was observed in patient blood. Zebrafish modelling confirms a loss-of-function mechanism, but the animal tolerates the human missense variant — a reminder of the limits of models for variant classification.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A new recessive NDD gene, a target already covered by WES/WGS — the challenge is recognising the dysmorphic phenotype and annotating the variant. The methylation signature adds an interesting functional argument. The authors' caution about zebrafish tolerance to the missense is welcome: a negative model does not exonerate a variant. To be strengthened by further families.

Analysis by Dr Thibaut Benquey