De novo truncating variant in the FBRSL1 gene caused neurodevelopmental disorders, epilepsy, congenital heart disease, and facial dysmorphism.

AIM: This study aims to investigate the causative role of FBRSL1, a paralog of the established neurodevelopmental disorder (NDD) gene AUTS2, in developmental disorders.

METHOD: Whole-exome sequencing was conducted to identify possible pathogenic variants. Functional studies were conducted in zebrafish models with fbrsl1 knockdown to investigate the gene-disease association. The role of FBRSL1 in development was studied via single-cell RNA sequencing and spatio-temporal expression.

RESULTS

We identified a de novo FBRSL1 variant p.Ala128Cysfs*5 in a patient with neurodevelopmental delay, epilepsy, congenital heart disease, and facial dysmorphism. Further analysis of four patients with FBRSL1 variants revealed an emerging syndromic NDD, characterized by microcephaly, global developmental delay, autism, facial dysmorphism, and skeletal contractures. Zebrafish knockdown models recapitulated neurodevelopmental abnormalities, epileptiform discharges, and cardiac dysfunction, consistent with the patient's phenotypes. FBRSL1 is highly expressed in the developing brain and heart, potentially explaining its multisystem phenotypes. Single-cell RNA sequencing revealed a high expression of FBRSL1 in neural progenitors of 1-month-old organoids, suggesting its vital role in neurodevelopment.

INTERPRETATION: This study suggested FBRSL1 as a causative gene of syndromic developmental disorders with multisystem involvement, bridged gaps in understanding shared genetic mechanisms underlying multisystem developmental pathologies, and offered novel avenues for precision medicine approaches.