A novel mutation in TARDBP segregates with amyotrophic lateral sclerosis in a large family with early onset and fast progression

Abstract

Objective: To identify the genetic background of ALS segregating in a large Bedouin family in Israel. Methods: Exome sequencing was carried out on three siblings in a family segregating ALS, two affected and one without neurological symptoms. Filtering for causative variants and for modifiers was carried out. Eight variants were confirmed by Sanger sequencing and genotyped on nine available members of the family (three affected and six unaffected). Results: We report the identification of a novel mutation in TARDBP, p.Ala321Asp, segregating in the family. The patients are affected with early onset (average age 34.5, 21–43 years old) and fast progressive disease. The mutation is in exon 6, in the glycin-rich domain, and is predicted to be deleterious. Additional rare, potentially deleterious variants were observed in the three patients, only one of them, PLEKHG5-Phe538Leu, which is located 4.5 Mb upstream to the TARDBP, was also fully segregating in the family. Conclusion: We identified a novel mutation in TARDBP which segregates with the disease in a large family. Additional rare variants were identified, and the combination of next-generation-sequencing together with linkage analysis was optimal to identify causality and modification, emphasizing the importance of combining the two analyses. Burden of deleterious variants may be associated with early age at onset.

Keywords:

• Whole-exome-sequencing
• TARDBP
• familial ALS

Acknowledgement

The authors would like to thank the Project MinE GWAS Consortium. The authors would like to thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at https://gnomad.broadinstitute.org/about.

We thank Danielle Cohen-Avinoam, MSc and Hila Meltzer Fridrich, BSc for technical help.

Disclosure of interest

Orly Goldstein reports no conflict of interest; Merav Kedmi reports no conflict of interest; Mali Gana-Weisz reports no conflict of interest; Beatrice Nefussy reports no conflict of interest; Danielle Cohen-Avinoam reports no conflict of interest; Batel Vainer reports no conflict of interest; Yaara Fainmesser reports no conflict of interest; Vivian E Drory received research support from ALS Association and from Adelis Foundation; Avi Orr-Urtreger received research support from ALS Association and from Kahn and Adelis Foundations.

Additional information

Funding

This work was supported by Adelis Foundation, by ALS Association grant number 47717 and by Kahn Foundation.