Biallelic Novel SKOR2 Variants in Individuals With Cerebellar Hypoplasia and Intellectual Disability, Expanding the Phenotypic Spectrum of Valence-Farazi Cerebellar Ataxia Syndrome.

PMID 41821366 | DOI 10.1002/ajmg.a.70125 · American journal of medical genetics. Part A · 2026

The embryonic development of the cerebellum is orchestrated through a dynamic process that governs the interplay of Purkinje and granule cell populations. SKOR2 (Fussel 18) is a transcriptional co-repressor that increases SHH (sonic hedgehog) expression which is a potent signal for granule cell proliferation and integration into the complex neuronal network that underlies cerebellar function and development. Complete loss of Skor2 function in a murine model has been shown to result in cerebellar hypoplasia due to severe disruption of the cerebellar vermis. Through GeneMatcher we identified eight individuals from five unrelated families with compound heterozygous or homozygous loss of function, splice site and missense variants in SKOR2 associated with a phenotypic spectrum of cerebellar hypoplasia, microcephaly, ataxia, developmental delays and intellectual disability. Variants identified in SKOR2 included homozygous c.1877delC; p.Pro626Glnfsx156 in the first individual, homozygous c.2752 + 1G>T in the second and third individuals, compound heterozygous c.757T>G p.C253G, c.949T>A p.S317T in the fourth individual, homozygous c.421_424del (p.Asp141Ilefs*118) in the fifth, sixth, and seventh individuals, and a homozygous c.1169C>A; p.Ser390* in the eighth individual. The eight individuals had various degrees of developmental and speech delays, as well as cerebellar hypoplasia identified in some of them. In silico analysis supported pathogenicity of most of SKOR2 variants, except for case 4, and their impact on protein function. Recently, SKOR2 is reported to be associated with Valence-Farazi Cerebellar Ataxia Syndrome (OMIM # 621386) (Skor2-OMIM-OMIM.ORG). This study expands the phenotypic spectrum for this newly described condition. Additional studies in affected individuals will be needed to refine the phenotypic spectrum and identify genotype-phenotype correlations.