Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder

Martje G. Pauly; Norbert Brüggemann; Stephanie Efthymiou; Anne Grözinger; Sokhna Haissatou Diaw; Viorica Chelban; Valentina Turchetti; Barbara Vona; Vera Tadic; Henry Houlden; Alexander Münchau; Katja Lohmann

doi:10.3390/ijms24031874

Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder

Martje G. Pauly, Norbert Brüggemann, Stephanie Efthymiou, Anne Grözinger, Sokhna Haissatou Diaw, Viorica Chelban, Valentina Turchetti, Barbara Vona, Vera Tadic, Henry Houlden, Alexander Münchau, Katja Lohmann^*

^*Corresponding author for this work

14 Citations (Scopus)

Abstract

VPS13D is one of four human homologs of the vacuolar sorting protein 13 gene (VPS13). Biallelic pathogenic variants in the gene are associated with spastic ataxia or spastic paraplegia. Here, we report two patients with intronic pathogenic variants: one patient with early onset severe spastic ataxia and debilitating tremor, which is compound-heterozygous for a canonical (NM_018156.4: c.2237−1G > A) and a non-canonical (NM_018156.4: c.941+3G>A) splice site variant. The second patient carries the same non-canonical splice site variant in the homozygous state and is affected by late-onset spastic paraplegia. We confirmed altered splicing as a result of the intronic variants and demonstrated disturbed mitochondrial integrity. Notably, tremor in the first patient improved significantly by bilateral deep brain stimulation (DBS) in the ventralis intermedius (VIM) nucleus of the thalamus. We also conducted a literature review and summarized the phenotypical spectrum of reported VPS13D-related disorders. Our study underscores that looking for mutations outside the canonical splice sites is important not to miss a genetic diagnosis, especially in disorders with a highly heterogeneous presentation without specific red flags.

Original language	English
Article number	1874
Journal	International Journal of Molecular Sciences
Volume	24
Issue number	3
ISSN	1661-6596
DOIs	https://doi.org/10.3390/ijms24031874
Publication status	Published - 02.2023

Funding

M.G.P. was supported by the German Research Foundation (DFG) via the Clinician Scientist Program of the Clinical Scientist School Lübeck (CSSL) (DFG-GEPRIS 413535489). N.B. was supported by the DFG (BR4328.2-1). S.E. is supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1′. B.V. is supported by the DFG VO 2138/7-1 grant 469177153. A.M. and K.L. were supported by the Damp Stiftung. The SolveRD project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 779257. This study makes use of data shared/provided through RD-Connect, which received funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 305444. The exome sequencing of P1 and family members was supported by the “Gutes tun” foundation of the University Hospital Schleswig Holstein.

Research Areas and Centers

Research Area: Medical Genetics

DFG Research Classification Scheme

2.23-06 Molecular and Cellular Neurology and Neuropathology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/ijms24031874

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Pauly, M. G., Brüggemann, N., Efthymiou, S., Grözinger, A., Diaw, S. H., Chelban, V., Turchetti, V., Vona, B., Tadic, V., Houlden, H., Münchau, A., & Lohmann, K. (2023). Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder. International Journal of Molecular Sciences, 24(3), Article 1874. https://doi.org/10.3390/ijms24031874

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abstract = "VPS13D is one of four human homologs of the vacuolar sorting protein 13 gene (VPS13). Biallelic pathogenic variants in the gene are associated with spastic ataxia or spastic paraplegia. Here, we report two patients with intronic pathogenic variants: one patient with early onset severe spastic ataxia and debilitating tremor, which is compound-heterozygous for a canonical (NM\_018156.4: c.2237−1G > A) and a non-canonical (NM\_018156.4: c.941+3G>A) splice site variant. The second patient carries the same non-canonical splice site variant in the homozygous state and is affected by late-onset spastic paraplegia. We confirmed altered splicing as a result of the intronic variants and demonstrated disturbed mitochondrial integrity. Notably, tremor in the first patient improved significantly by bilateral deep brain stimulation (DBS) in the ventralis intermedius (VIM) nucleus of the thalamus. We also conducted a literature review and summarized the phenotypical spectrum of reported VPS13D-related disorders. Our study underscores that looking for mutations outside the canonical splice sites is important not to miss a genetic diagnosis, especially in disorders with a highly heterogeneous presentation without specific red flags.",

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AU - Diaw, Sokhna Haissatou

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N2 - VPS13D is one of four human homologs of the vacuolar sorting protein 13 gene (VPS13). Biallelic pathogenic variants in the gene are associated with spastic ataxia or spastic paraplegia. Here, we report two patients with intronic pathogenic variants: one patient with early onset severe spastic ataxia and debilitating tremor, which is compound-heterozygous for a canonical (NM_018156.4: c.2237−1G > A) and a non-canonical (NM_018156.4: c.941+3G>A) splice site variant. The second patient carries the same non-canonical splice site variant in the homozygous state and is affected by late-onset spastic paraplegia. We confirmed altered splicing as a result of the intronic variants and demonstrated disturbed mitochondrial integrity. Notably, tremor in the first patient improved significantly by bilateral deep brain stimulation (DBS) in the ventralis intermedius (VIM) nucleus of the thalamus. We also conducted a literature review and summarized the phenotypical spectrum of reported VPS13D-related disorders. Our study underscores that looking for mutations outside the canonical splice sites is important not to miss a genetic diagnosis, especially in disorders with a highly heterogeneous presentation without specific red flags.

AB - VPS13D is one of four human homologs of the vacuolar sorting protein 13 gene (VPS13). Biallelic pathogenic variants in the gene are associated with spastic ataxia or spastic paraplegia. Here, we report two patients with intronic pathogenic variants: one patient with early onset severe spastic ataxia and debilitating tremor, which is compound-heterozygous for a canonical (NM_018156.4: c.2237−1G > A) and a non-canonical (NM_018156.4: c.941+3G>A) splice site variant. The second patient carries the same non-canonical splice site variant in the homozygous state and is affected by late-onset spastic paraplegia. We confirmed altered splicing as a result of the intronic variants and demonstrated disturbed mitochondrial integrity. Notably, tremor in the first patient improved significantly by bilateral deep brain stimulation (DBS) in the ventralis intermedius (VIM) nucleus of the thalamus. We also conducted a literature review and summarized the phenotypical spectrum of reported VPS13D-related disorders. Our study underscores that looking for mutations outside the canonical splice sites is important not to miss a genetic diagnosis, especially in disorders with a highly heterogeneous presentation without specific red flags.

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Not to Miss: Intronic Variants, Treatment, and Review of the Phenotypic Spectrum in VPS13D-Related Disorder

Abstract

Funding

Research Areas and Centers

DFG Research Classification Scheme

UN SDGs

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