Feasibility of Follow-Up Studies and Reclassification in Spinocerebellar Ataxia Gene Variants of Unknown Significance

Fatemeh Ghorbani; Mohamed Z Alimohamed; Juliana F Vilacha; Krista K Van Dijk; Jelkje De Boer-Bergsma; Michiel R Fokkens; Henny Lemmink; Rolf H Sijmons; Birgit Sikkema-Raddatz; Matthew R Groves; Corien C Verschuuren-Bemelmans; Dineke S Verbeek; Cleo C Van Diemen; Helga Westers

doi:10.3389/fgene.2022.782685

Feasibility of Follow-Up Studies and Reclassification in Spinocerebellar Ataxia Gene Variants of Unknown Significance

Front Genet. 2022 Mar 25:13:782685. doi: 10.3389/fgene.2022.782685. eCollection 2022.

Authors

Fatemeh Ghorbani¹, Mohamed Z Alimohamed^{1

2

3}, Juliana F Vilacha⁴, Krista K Van Dijk¹, Jelkje De Boer-Bergsma¹, Michiel R Fokkens¹, Henny Lemmink¹, Rolf H Sijmons¹, Birgit Sikkema-Raddatz¹, Matthew R Groves⁵, Corien C Verschuuren-Bemelmans¹, Dineke S Verbeek¹, Cleo C Van Diemen¹, Helga Westers¹

Affiliations

¹ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.
² Department of Hematology and Blood Transfusion, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
³ Shree Hindu Mandal Hospital, Dar es Salaam, Tanzania.
⁴ Groningen Biomolecular Sciences and Biotechnology Institute, Zernike Institute for Advanced Materials, University of Groningen, Groningen, Netherlands.
⁵ Structural Biology in Drug Design, Department of Drug Design, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, Netherlands.

Abstract

Spinocerebellar ataxia (SCA) is a heterogeneous group of neurodegenerative disorders with autosomal dominant inheritance. Genetic testing for SCA leads to diagnosis, prognosis and risk assessment for patients and their family members. While advances in sequencing and computing technologies have provided researchers with a rapid expansion in the genetic test content that can be used to unravel the genetic causes that underlie diseases, the large number of variants with unknown significance (VUSes) detected represent challenges. To minimize the proportion of VUSes, follow-up studies are needed to aid in their reclassification as either (likely) pathogenic or (likely) benign variants. In this study, we addressed the challenge of prioritizing VUSes for follow-up using (a combination of) variant segregation studies, 3D protein modeling, in vitro splicing assays and functional assays. Of the 39 VUSes prioritized for further analysis, 13 were eligible for follow up. We were able to reclassify 4 of these VUSes to LP, increasing the molecular diagnostic yield by 1.1%. Reclassification of VUSes remains difficult due to limited possibilities for performing variant segregation studies in the classification process and the limited availability of routine functional tests.

Keywords: functional studies; gene panel; genetic diagnostics; protein modeling; segregation; spinocerebellar ataxia; variant of unknown significance.