Huntingtin Haplotypes Provide Prioritized Target Panels for Allele-specific Silencing in Huntington Disease Patients of European Ancestry

Abstract

Huntington disease (HD) is a dominant neurodegenerative disorder caused by a CAG repeat expansion in the Huntingtin gene (HTT). Heterozygous polymorphisms in cis with the mutation allow for allele-specific suppression of the pathogenic HTT transcript as a therapeutic strategy. To prioritize target selection, precise heterozygosity estimates are needed across diverse HD patient populations. Here we present the first comprehensive investigation of all common target alleles across the HTT gene, using 738 reference haplotypes from the 1000 Genomes Project and 2364 haplotypes from HD patients and relatives in Canada, Sweden, France, and Italy. The most common HD haplotypes (A1, A2, and A3a) define mutually exclusive sets of polymorphisms for allele-specific therapy in the greatest number of patients. Across all four populations, a maximum of 80% are treatable using these three target haplotypes. We identify a novel deletion found exclusively on the A1 haplotype, enabling potent and selective silencing of mutant HTT in approximately 40% of the patients. Antisense oligonucleotides complementary to the deletion reduce mutant A1 HTT mRNA by 78% in patient cells while sparing wild-type HTT expression. By suppressing specific haplotypes on which expanded CAG occurs, we demonstrate a rational approach to the development of allele-specific therapy for a monogenic disorder.

REVIEW-ARTICLE Intermediate alleles of Huntington’s disease HTT gene in different populations worldwide: a systematic review

“…Some SNPs (single nucleotide polymorphisms) were reported as factors that could interfere in genetic stability of the CAG polymorphic region (HTT). It is believed that a specific SNP profile can determine the degree of predisposition in the event of CAG expansion at the HTT gene (Warby et al, 2009;Kay et al, 2015). Different SNP haplogroups have been built in order to categorize individuals with normal CAG alleles and expanded ones in different ancestral origin populations (Warby et al, 2009).…”

“…According to each genetic profile, these subjects are classified in haplogroups A, B, or C. In a sample of the European population, as known as of a high HD prevalence, it was observed that the haplogroup A is found in 95% of the affected individuals and, interestingly, the haplogroup A is also present in 53% of chromosomes of the general population (<27 CAG) (Warby et al, 2009). The haplogroups B and C have been found in populations that had low HD prevalence (Warby et al, 2009;Kay et al, 2015).…”

The targetable A1 Huntington disease haplotype has distinct Amerindian and European origins in Latin America

“…4,5 In populations of European ancestry where prevalence is highest, the expanded CAG repeat occurs preferentially on haplotypes A1, A2, and A3a, whereas in African and East Asian patients the HD mutation occurs on a heterogeneous mix of local haplotypes. [6][7][8][9] European HD haplotypes A1 and A2 do not occur in African and East Asian populations, suggesting that these haplotypes may account in part for higher HD prevalence rates in populations of European ancestry. 4,7 HD has been reported in many countries of Latin America, but detailed genetic investigations are lacking.…”

“…[6][7][8][9] European HD haplotypes A1 and A2 do not occur in African and East Asian populations, suggesting that these haplotypes may account in part for higher HD prevalence rates in populations of European ancestry. 4,7 HD has been reported in many countries of Latin America, but detailed genetic investigations are lacking. 10 Early clinical descriptions were reported in Cuba and Brazil, and subsequently in Argentina, Mexico, Peru, Chile, and Colombia.…”

“…10,12 Limited haplotyping studies of HD in Latin America suggest that the HD mutation occurs on specific haplotypes, although not necessarily from European founders. 10 HTT haplotypes in Venezuelan patients, including the CCG repeat in exon 1 (GRCh37 chr4:g.3076673_3076675 [7]) and Δ2642 codon deletion in exon 58 (GRCh37 chr4: g.3230411_3230413delGAG), 13 suggest a common origin of the HD mutation among affected families of Venezuela, but without definitive data of European ancestry. 14 (HTT exon numbering follows Ensembl transcript HTT-001/ENST00000355072.9, NCBI reference mRNA NM_002111.8, and exon numbering originally described in Ambrose et al 13 )…”