Objective: We report three siblings with late-onset, slowly progressive cerebellar ataxia associated with a c.475G>A (p.Gly159Arg) missense variant in the PRKCG gene.

Background: Spinocerebellar ataxia type 14 (SCA14) is an autosomal dominant disease characterized by slowly progressive cerebellar degeneration and ataxia. Other symptoms may include myoclonus, dystonia, tremor, and cognitive impairment. It is caused by mutations in the PRKCG gene, which encodes protein kinase C gamma and is expressed highly in cerebellar Purkinje cells [1]. To date, ~40 PRKCG variants are considered pathogenic or likely pathogenic for SCA14. PRKCG c.475G>A (p.Gly159Arg) is currently considered a variant of uncertain significance (VUS) [2].

Method: Case report, bioinformatic analyses

Results: A 54-year-old man presented to our clinic complaining of worsening balance, coordination, and dysarthria since age 50. Exam revealed hypometric saccades, slight dysarthria, upper and lower extremity dysmetria and ataxia, and wide-based gait, but was otherwise normal. An MRI brain showed cerebellar atrophy.  The patient has a twin brother, reportedly identical, who had onset of similar symptoms at age 50 and an older brother who had onset of progressive gait imbalance at age 54. Given this shared familial phenotype, we suspected a genetic cerebellar ataxia. On genetic ataxia panel testing, all three brothers were found to have a PRKCG c.475G>A (p.Gly159Arg) missense variant. Additionally, we found a single report in the literature of an individual with a similar phenotype found to have the same variant, currently considered a VUS [3]. Bioinformatic analyses predict a deleterious effect of this missense mutation (CADD: 32.0, PolyPhen (max): 1.00, REVEL: 0.662) and molecular dynamics analyses have suggested that it may destabilize the protein kinase C gamma regulatory domain [4-7]. We propose it likely that this PRKCG variant is pathogenic for SCA14, as it has now been associated with a progressive cerebellar ataxia phenotype in multiple individuals, whereas it is very rare overall (one occurrence in 1,575,764 alleles in the gnomAD reference population [8]).

Conclusion: We report, to our knowledge, the first familial cases of progressive cerebellar ataxia associated with a PRKCG 475G>A (p.Gly159Arg) variant. These cases add to the evidence for the pathogenicity of this variant for SCA14.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/three-siblings-with-progressive-cerebellar-ataxia-associated-with-a-rare-prkcg-variant/