The first case of the TARDBP p.G294V mutation in a homozygous state: is a single pathogenic allele sufficient to cause ALS?

Abstract

Here, we described the first amyotrophic lateral sclerosis patient presenting the c.881 G > T p.G294V TARDBP mutation in homozygous status. The patient belongs to a large pedigree from Morocco. Except for one older affected brother his parents and remaining 8 sibs are referred to be healthy and do not show any neurological sign or symptom. The lack of evidence of TARDBP deletions of any sizes, together with the presence of several AOH segments, strongly suggests that the homozygosity status of p.G294V in the proband derived from parental consanguinity. A revision of the literature and our cohorts indicates that the p.G294V mutation has been detected in only 15 additional ALS patients in heterozygosity and, except for one additional Moroccan patient, all were of Italian origin. The analysis of microsatellite markers surrounding the TARDBP gene in 8 individuals carrying the p.G294V mutation showed that the haplotypic context of the Moroccan proband is shared with most patients of European origin indicating that they carry the p.G294V mutation inherited from a common ancestor. The analysis of the 15 ALS pedigrees (from literature data and present study), strongly suggests a reduced penetrance of the p.G294V mutation since for 13 of the 15 described p.G294V ALS cases the parents did not show any neurological symptoms. This result has potentially important implications in genetic counseling, since genetic testing of a reduced penetrance mutation on pre-symptomatic individuals proves very difficult to predict the outcome based on the genotype.

Keywords:

• TARDBP
• mutation
• amyotrophic lateral sclerosis

Declaration of interest

The authors declare no financial or other conflicts of interest.

Additional information

Funding

This work was supported by the Italian Ministry of Research and Education (L.C. and S.D.) [PRIN2015- project 201534HNXC001 and PRIN 2017-project 2017SNW5MB_005]. V.P. and C.G. have been partially supported for this work by Fondazione Regionale per la Ricerca Biomedica – FRRB (Regione Lombardia), [project nr. 2015-0023] and by the Italian Ministry of Health [grant RF 2013-02355764].