Runs of Homozygosity Analysis Reveals 1,900-Year-Old ECEL1 Arthrogryposis Mexican Founder Variant

Abstract ECEL1 -related distal arthrogryposis type 5D is characterized by distal joint contractures, ocular abnormalities, and absence of central nervous system involvement. We investigated the genetic basis of arthrogryposis multiplex congenita (AMC) and explored the ancestry and origin of recurrent ECEL1 variants. The study included 93 individuals with AMC residing in Mexico. Genome sequencing identified biallelic ECEL1 variants in 37 individuals (40%). Twenty unrelated individuals were homozygous for a 46-bp frameshift deletion, c.110_155del (p.Phe37CysfsTer151), and eight additional individuals were compound heterozygous for c.110_155del; the remaining nine individuals carried other pathogenic ECEL1 variants. Overall, c.110_155del accounted for 50 of 74 disease-causing ECEL1 alleles (68%). Analysis of population genomic data from the Mexico City Prospective Study estimated a carrier frequency of 1 in 600 among individuals with Indigenous Mexican ancestry, or approximately 30-fold enrichment relative to European and African ancestries. To investigate a potential founder effect, runs of homozygosity analysis, haplotype dating, and ancestry inference were performed. Eighteen of 20 homozygotes shared a 272-kb ancestral haplotype encompassing ECEL1 , and the most recent common ancestor was estimated to have lived ~ 1,900 years ago. ADMIXTURE and local ancestry inference demonstrated predominantly Indigenous Mexican ancestry among homozygous individuals (median ancestry proportion 0.81), while all 40 deletion-bearing chromosomes carried Indigenous Mexican ancestry at the c.110_155del locus. ECEL1 -related distal arthrogryposis is a common genetic cause of AMC in Mexico. The high frequency of c.110_155del, extensive haplotype sharing, and uniform Indigenous Mexican local ancestry at the deletion locus support an Indigenous Mexican founder effect.