C9orf72 hexanucleotide repeat expansion in Indian patients with ALS: a common founder and its geographical...

Hexanucleotide repeat expansion in C9orf72 is defined as a major causative factor for familial amyotrophic lateral sclerosis (ALS). The mutation frequency varies dramatically among populations of different ethnicity; however, in most cases, C9orf72 mutant has been described on a common founder haplotype. We assessed its frequency in a study cohort involving 593 clinically and electrophysiologically defined ALS cases. We also investigated the presence of reported Finnish haplotype among the mutation carriers. The identified common haplotype region was further screened in 192 (carrying 2-6 G4C2 repeats) and 96 (≥7 repeats) control chromosomes. The G4C2 expansion was observed in 3.2% (19/593) of total cases where 9/19 (47.4%) positive cases belonged to the eastern region of India. Haplotype analysis revealed 11 G4C2-Ex carriers shared the common haplotype (haplo-A) background spanning a region of ∼90 kbp (rs895021-rs11789520) including rs3849942 (a well-known global at-risk loci with T allele for G4C2 expansion). The other 3 G4C2-Ex cases had a different haplotype (haplo-B) with core difference from haplo-A at G4C2-Ex flanking 31 kbp region between rs3849942 and rs11789520 SNPs (allele 'C' of rs3849942 which is a nonrisk allele). Out of other five G4C2-cases, four carried the risk allele T of rs3849942 while one harbored the non-risk allele. This study establishes the prevalence of C9orf72 expansion in Indian ALS cases providing further evidence for geographical predilection. The global core risk haplotype predominated C9orf72 expansion-positive ALS cases, yet the existence of a different haplotype suggests a second lineage (haplo B), which may have been derived from the Finnish core haplotype or may imply a unique haplotype among Asians. The association of risk haplotype with normal intermediate C9orf72 alleles reinforced its role in conferring instability to the C9orf72-G4C2 region. We thus present an effective support to interpret future burden of ALS cases in India.