Key result
Novel ASPA splicing variant linked to mild Canavan disease clustering in an Indian community.
Why the study?
Mild/juvenile Canavan disease is less frequently reported in the literature, and little is known about its pathogenetic mechanisms.
Observational (n=34)
The study identifies a novel ASPA variant and confirms a founder event responsible for the high clustering of Mild/juvenile Canavan disease in the Telugu Devanga Chettiar community, paving the way for carrier screening.
Supports targeted carrier screening in this founder population; leaves open validation in larger cohorts.
Mild/juvenile Canavan disease (M/JCD) is less frequently reported in literature and little is known about its pathogenetic mechanisms. We report a comprehensive investigation into the pathogenetic mechanism of a novel ASPA (NM_000049.4):c.526G > A(p.Gly176Ser) variant in two families. The families belong to Telugu Devanga Chettiar community (TDC) from southern India. TDC has a complex history of migration from their historical origin centuries ago with high endogamy. TDC probably has the highest clustering M/JCD recorded historically (around 24 cases). The pathogenic variant was shown to cause non-classical splicing defect resulting in two different transcripts. The splicing aberration, a loss of function mechanism coupled with a milder missense effect can explain the milder phenotype compared to the infantile onset CD. The high clustering of an extremely rare form of neurodegenerative disorder with reduced fitness, indicated to a possibility of founder event. Genotyping array of TDC and multiple distinct populations of Indian origin for several population genetic parameters was performed. It yielded robust signatures of a founder event, such as a high fixation index, increased runs of homozygosity and identity-by-descent estimation in TDC in the absence of consanguinity; large haplotype with high linkage disequilibrium comprising the pathogenic variant; presence of a robust population structure; mutation dating, estimating the age of the potential founder of TDC at around 375 years; possibly a high carrier rate in TDC. This study has not only focused its attention on natural history and pathogenetics but also paves way for carrier screening programs in TDC and future therapeutic studies.
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Arunachal et al. (2022) conducted an observational in Mild/juvenile Canavan disease (n=34). Genetic analysis (Whole exome sequencing, genotyping array) vs. Healthy controls and other population groups was evaluated on Identification of the pathogenic variant and genomic signatures of a founder event. A novel homozygous ASPA variant c.526G>A causing a non-classical splicing defect was identified as the cause of mild/juvenile Canavan disease clustering in an Indian community due to a founder event.
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