Genetic Homogeneity of a TDP1 Variant, c.1478A>G, as the Main Disease-Causing Variant of Spinocerebellar Ataxia With Axonal Neuropathy 1 (SCAN1) in the Middle East: A Systematic Review.

Abstract

Background: Spinocerebellar ataxia with axonal neuropathy 1 (SCAN1) is an ultrarare neurodegenerative disorder inherited in an autosomal recessive manner, mainly marked by progressive ataxia and axonal polyneuropathy. SCAN1 is mainly caused by the c.1478A>G:p.His493Arg mutation in the TDP1 gene. In this study, we present the first Iranian family, and the fifth family totally, diagnosed with the SCAN1, which carries the common variant c.1478A>G. Additionally, we conducted a systematic review to identify all reported probably disease-related variants of TDP1.

Methods: Whole exome sequencing was performed on the proband, who was initially diagnosed with axonal neuropathy. The data were analyzed, and the variant was confirmed via Sanger sequencing. Cosegregation analysis was used to validate the variant within the family. Following PRISMA 2020 guidelines, we performed a systematic review using the terms TDP1, tyrosyl-DNA phosphodiesterase, SCAN1, and spinocerebellar ataxia with axonal neuropathy in four major databases.

Results: Whole exome sequencing results identified the known TDP1:c.1478A>G variant, which correlated with the disease status in the family. Clinical and paraclinical findings were consistent with SCAN1. Our systematic review identified 16 variants in 20 families associated with various neurological or non-neurological disorders. Among these families, four were SCAN1. Although four of five families with SCAN1, including our family, shared the same TDP1 variant, c.1478A>G, they exhibited some clinical heterogeneity.

Conclusions: Given that all these cases were from the Middle East, we suggested this mutation may be a founder mutation in this region. Since only a few families with SCAN1 have been reported, further research is needed to fully understand this disorder.