Identification of two novel pathogenic mutations in the SKOR2 gene linked to cerebellar hypoplasia and a broad spectrum of neurodevelopmental delay in two Iranian families.

SKOR2 is a transcriptional repressor expressed in central nervous system tissues, mainly in the Purkinje cells (PCs). This is essential for the proper migration, development, and differentiation of PCs at embryonic stages, and its disruption can affect cerebellar function. SKOR2 protein has two DHD and SAND domains, which play an important role in the TGF-β signaling pathway by binding to Smad transcriptional regulators. Herein, we report nine patients from two unrelated Iranian families suffering from a distinctive combination of learning disability, facial dysmorphisms, and motor and speech impairments. Whole exome sequencing (WES) was employed to identify pathogenic variants in the probands. Sanger sequencing was conducted to confirm the mutations found in the patients, their healthy parents, and relatives. A range of bioinformatics tools was utilized to assess the impact of the identified mutations on the function and structure of the related proteins. WES identified two novel missense (c.374 G > C: p.Arg125Pro) and frameshift (c.1271_1274del: p.K424Rfs*71) mutations in exon 2 of the SKOR2 gene. After segregation and in-silico studies, autosomal recessive inheritance and pathogenic nature of the identified mutation were confirmed. In addition, the studied patients had distinct phenotypes such as clumsiness, dysarthria, and severe hypotonia compared to previous studies, which we named Skor2-related syndrome. These findings indicated a novel SKOR2-related syndrome characterized by neurodevelopmental delay and ataxia. Our findings, given the limited previous studies on the SKOR2 gene, expanded the pathogenic mutations and phenotypic spectrum of SKOR2-associated disorders, provided criteria facilitating early diagnosis and supported genetic counseling for prognosis and family planning.