Evidence for Ancestral History Shaping Neuromuscular Latino Disease Heritage


Pre-Clinical Research

Poster Number: T399


Daniel Calame, MD, PhD, Baylor College of Medicine, Haowei Du, PhD, Baylor College of Medicine, Zeynep Coban-Akdemir, PhD, Baylor College of Medicine, University of Texas Health Science Center at Houston, Farida Abid, MD, Baylor College of Medicine, Tim Lotze, MD, Baylor College of Medicine/Texas Children's Hospital, Lisa Emrick, MD, Baylor College of Medicine, Davut Pehlivan, MD, Baylor College of Medicine, Richard Gibbs, PhD, Baylor College of Medicine, Jennifer Posey, MD, PhD, Baylor College of Medicine, James lupski, MD, PhD, DSc (hon), Baylor College of Medicine

Latinos are underrepresented in human genomics studies despite comprising 20% of the United States and 8.2% of global populations. ‘Latino genetics’ has been shaped by admixture of Indigenous Americans, Africans, and Europeans with resulting complexity due to migration patterns, population bottlenecks, founder events, and genetic drift. These historical events can influence rare disease risk through propagation of population-specific disease alleles, as seen in the Finnish and Ashkenazi Jewish populations.

We searched for evidence of Latino neuromuscular disease (NMD) heritage, i.e., recessive disease-associated variant alleles enriched in, or unique to, the Latino population, via a cohort-wide analysis of exome sequencing (ES) data including absence of heterozygosity (AOH) analysis as a surrogate measure of runs of homozygosity (ROH) (>12,000 individuals with rare diseases in a research dataset). We identified five homozygous pathogenic variant alleles in non-consanguineous Latinos which mapped within AOH blocks with low genome-wide total AOH, consistent with identity-by-state (IBS) rather than identity-by-descent (IBD) due to consanguinity. These variant alleles include ASCC3(NM_006828.4):c.5063G>T;p.(Gly1688Val) (congenital myopathy), TNNT3(NM_006757.4):c.481-1G>A (congenital myopathy), GDAP1(NM_018972.4):c.487C>T;p.(Gln163Ter) (demyelinating neuropathy), TANGO2(NM_152906.7):c.460G>A;p.(Gly154Arg) (rhabdomyolysis), and HPDL(NM_032756.3):c.859T>C;p.(Tyr287His) (hereditary spastic paraplegia). Three additional homozygous pathogenic variant alleles, ATP13A2(NM_022089.4):c.2529+1G>A (axonal neuropathy, amyotrophic lateral sclerosis) and ENTPD1(NM_001776.6):c.574-6_574-3del and c.770_771del;p.(Gly257GlufsTer18) (hereditary spastic paraplegia), were each found in multiple unrelated consanguineous Latino families suggestive of founder alleles rendered homozygous through IBD consanguinity. Of the variant alleles present in gnomAD v2.1.1, each occurred exclusively in individuals of Latino or unassigned ancestry. Variant allele frequencies ranged from 0 to 8e-4 (average allele frequency 2.6e-4 ± 2.6e-4).

In summary, we identify eight candidate Latino NMD heritage variant alleles within a disease-focused genomic dataset. Although rare, the identification of these Latino neuromuscular disease (NMD) heritage alleles illustrates the imperative of fully representing each human population group in studies aimed at disease gene discovery.