West-Central African Ancestry of the Repeat-Expansion Founder Mutation on the JPH3 Gene in Mexican Patients With Huntington's Disease-Like 2.

BACKGROUND

A trinucleotide repeat expansion of the JPH3 gene causes Huntington disease-like 2 (HDL2), clinically indistinguishable from Huntington's disease and is considered a disease unique to African and Afro-descendant populations. We identified five HDL2 families from the Costa Chica region of southern Pacific Mexico. Because the Mexican population is admixed, we aimed to determine the ancestral origin of the expansion and define the mutation-carrying haplotype using microarray genomic data.

METHODS

Sixteen individuals (Nine symptomatic, three asymptomatic mutation carriers and four healthy non-carriers) were included. Global and local ancestry were estimated using whole-genome microarray data. Principal component and quadratic discriminant analysis (QDA) were used to infer the most likely origin of the haplotypes, complemented by the SMOTE-Tomek sampling strategy.

RESULTS

Mean ancestry proportions were 16.26, 27.33, and 56.39% for African, European, and Native American components, respectively. A 1.1 Mb segment inferred as African flanking the JPH3 mutation locus was shared by at least one of the homologous chromosomes of all mutation carriers. Phased genotype analysis revealed a common 746 Kb haplotype containing the mutation that includes 412 SNPs. This shared haplotype was consistently inferred to be of African origin. QDA classified this haplotype as Yoruba in 78.3% of the resampling iterations.

CONCLUSIONS

Ancestry analysis suggests that the JPH3 repeat expansion identified in our patients is a founder mutation of African origin. Other founder mutations causing rare genetic diseases in Mexico show how the admixture process in Latin America has contributed to the high prevalence of disease in certain geographical regions.