Work

Reference calibration, autozygosity and blood-derived variant interpretation in older adults

Year: 2026

Type: preprint

Abstract: Population exomes contain signals of demographic history, inherited disease alleles and, when derived from blood, possible acquired variation. Distinguishing these signals is important in underrepresented populations, where reference absence can reflect both sampling and local frequency differences. To the best of our knowledge, this study represents the first Levantine old-age cohort characterized by whole exomes. We reanalyzed blood-derived exomes from 199 Lebanese trial participants aged 65-91 years, including 187 unrelated participants for frequency and recessive analyses. Twenty-nine participants (14.6%) reached the autozygosity expected for offspring of first cousins. Although 13.8% of observed autosomal alleles were absent at callable gnomAD Middle Eastern reference sites, size matching gave a reference-to-cohort single-nucleotide variant absence ratio of 0.98. Excess absence was concentrated among recurrent alleles; 360 were absent from the full reference, none classified as pathogenic or likely pathogenic in ClinVar. Separately, regional disease alleles showed nominal frequency differences, including MEFV p.Val726Ala (0.051 versus 0.012). Qualifying recessive alleles occurred in 55.1% of unrelated participants, decreasing to 45.5% after severity-related exclusions. Conditional qualifying biallelic genotype estimates increased from 2.0 to 27.7 per 1,000 offspring between unrelated-parent and first-cousin inbreeding coefficients. Twelve participants had clonal-driver candidates, but only five met both binomial and empirical allele-fraction criteria for the probable tier; a TP53 frameshift remained unresolved. Eight participants (4.0%) had unconfirmed, condition-matched candidate secondary findings. These observations distinguish reference sampling from allele-specific frequency differences and genotype expectations from clinical outcomes. They support complementary checks on population exome interpretation, while leaving generalizability, variant origin and clinical reportability to independent evaluation.

Source: medRxiv

DOI: 10.64898/2026.10.28.26366687

Authors: Myriam El-Haddad, Nagham Hendi, Ghada El-Hajj Fuleihan, Georges Nemer, Nehme El-Hachem

Institutions: American University of Beirut, Applied Science Private University, Hamad bin Khalifa University, Lebanese American University

Language: English

Topic: Genomics and Rare Diseases

Subfield: Genetics

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funder: American University of Beirut