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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.

ABC (ATP-binding cassette) transporters are members of a large superfamily of proteins that utilize ATP hydrolysis to translocate a wide range of substrates across biological membranes. In general, members of C subfamily (ABCC) are structurally characterized by an additional (N-terminal) transmembrane domain (TMD0). Phylogenetic analysis of plant ABCCs separates their protein sequences into three distinct clusters: I and II are plant specific whereas cluster III contains both human and plant ABCCs. Screening of the Plant Medicinal Genomics Resource database allowed us to identify 16 ABCCs partial sequences in Catharanthus roseus; two of which belong to the unique CrABCC1 transcript that we identified in cluster III. Genomic organization of CrABCC1 TMD0 coding sequence displays an AT-AC U12-type intron that is conserved in higher plant orthologues. We showed that CrABCC1, like its human orthologue ABCC10, produces alternative transcripts that encode protein sequences with a truncated form of TMD0 without the first transmembrane span (TM1). Subcellular localization of CrABCC1 TMD0 variants using yellow fluorescent protein fusions reveals that the TM1 is required for a correct routing of the TMD0 to the tonoplast. Finally, the specific repartition of CrABCC1 orthologues in some species suggests that this gene was lost several times during evolution and that its physiological function may, rely on a common feature of multicellular eukaryotes.