Loss of function of FAM177A1, a Golgi complex localized protein, causes a novel neurodevelopmental disorder

Purpose The function of FAM177A1 and its relationship to human disease is largely unknown. Recent studies have demonstrated FAM177A1 to be a critical immune-associated gene. One previous case study has linked FAM177A1 to a neurodevelopmental disorder in four siblings. Methods We identified five individuals from three unrelated families with biallelic variants in FAM177A1. The physiological function of FAM177A1 was studied in a zebrafish model organism and human cell lines with loss-of-function variants similar to the affected cohort. Results These individuals share a characteristic phenotype defined by macrocephaly, global developmental delay, intellectual disability, seizures, behavioral abnormalities, hypotonia, and gait disturbance. We show that FAM177A1 localizes to the Golgi complex in mammalian and zebrafish cells. Intersection of the RNA-seq and metabolomic datasets from FAM177A1-deficient human fibroblasts and whole zebrafish larvae demonstrated misregulation of pathways associated with apoptosis, inflammation, and negative regulation of cell proliferation. Conclusion Our data sheds light on the emerging function of FAM177A1 and defines FAM177A1-related neurodevelopmental disorder as a new clinical entity. Overall design: RNA profile comparison of 8dp fam177a1a 700 homozygote, fam177a1a/b 700;746 double homozygote and WT