Objective: To identify the underlying genetic cause of a childhood-onset spasticity-ataxia-tremor syndrome in a 31-year-old woman.

Background: Biallelic variants in VPS13D have been linked to spastic ataxia or spastic paraplegia depending on the severity of the variants. Intronic variants were described previously; however, no splice analysis has as yet been performed. Cells of mutation carriers have been shown to harbor enlarged mitochondria.

Method: Exome sequencing data of our index patient (P1) and her parents were included in the GPAP platform of the SolveRD project (https://solve-rd.eu/) since the initial analysis in 2016 did not reveal a genetic cause in a diagnostic setting. Re-analysis of the exome data was performed. Prompted by the identification of biallelic variants in VPS13D in P1, we searched the GPAP platform for additional cases. In P1, cDNA from blood and cultured fibroblasts was sequenced and the form factor of the mitochondrial network will be determined by immunostaining with GRP75.

Results: We identified biallelic VPS13D variants in P1; both were located at splice sites. The paternally inherited variant affected a canonical splice site (c.2237-1G>A) and resulted in the skipping of Exon 18. The maternally inherited variant, c.941+3A>G, located in the splice region led to a partial skipping of Exon 8. One additional patient (P2), a 60-year old male, who developed spastic paraplegia at the age of 45 years, was homozygous for the c.941+3A>G variant. This variant has previously been reported in one patient in the compound heterozygous state [1] but has not been investigated at the expression level. In P1, bilateral thalamic deep brain stimulation (DBS) significantly improved her Holmes-like tremor of trunk and extremities.

Conclusion: Here, we present the first two patients carrying two intronic VPS13D variants and showed, for the first time, an exon skipping in a subset of transcripts for the recurrent splice region variant affecting position +3 in Intron 9. The different phenotypes in both patients are in line with previous reports showing that homozygous carriers of “mild” variants present a late-onset spastic paraplegia phenotype and compound heterozygous patients with one “severe” (truncating) variant present with more severe early-onset spastic ataxia. Importantly, Holmes-like tremor is a new clinical feature, and DBS a potential treatment option in VPS13D-related disease.

References: [1] Seong E, Insolera R, Dulovic M, Kamsteeg E, Trinh J, Brüggemann N, Sandford E, Li S, Ozel AB, Li JZ, Jewett T, Kievit AJA, Münchau A, Shakkottai V, Klein C, Collins CA, Lohmann K, Warrenburg BP, Burmeister M. Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects. Ann Neurol. 2018;83:1075–88.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-of-two-novel-patients-with-vps13d-related-disease-and-characterization-of-a-3-splice-site-variant/