Abstract
BACKGROUND: Oral-facial-digital (OFD) syndrome comprises a number of genetically and clinically heterogeneous ciliopathies characterized by distinctive craniofacial, oral cavity and extremities abnormalities. Recently, SCNM1, encoding a protein component of the minor spliceosome, was associated with OFD syndrome. Until now, only three families had been described with pathogenic variants in this gene. RESULTS: Using exome sequencing, we identified biallelic variants in SCNM1 in five additional patients diagnosed with OFD syndrome from four unrelated families. Clinical evaluation of these patients revealed novel features linked to SCNM1 including neurodevelopmental disorders, oculomotor apraxia and skeletal abnormalities. The pathogenicity of a missense variant affecting the C2H2 zinc finger domain of SCNM1, p.(His68Arg), was verified in fibroblasts from a patient with this variant in the homozygous state. These cells exhibited comparable defects to those previously reported in cells lacking SCNM1, including diminished expression of several U12-intron containing genes such as TMEM107 and CIBAR1, two ciliary genes previously associated with OFD syndrome and postaxial polydactyly, respectively, and abnormal primary cilia. In addition, the mutant version of SCNM1 harboring the p.(His68Arg) change was unable to rescue the phenotype of SCNM1-deficient cells. CONCLUSIONS: This work expands the molecular and clinical landscape of the SCNM1-related condition and shows that pathogenic variants in this gene cause a complex phenotype overlapping with OFD types II and VI. Our data improves understanding of the ciliopathy linked to SCNM1, which is of paramount importance in terms of genetic counselling, particularly with regard to the risks associated with neurodevelopmental disorders. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40246-025-00868-w.