Founder alleles and clonal hematopoiesis, not missing diversity, confound variant interpretation in an underrepresented population
- 1Lebanese American University
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.
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BibTeX
@misc{elhaddad2026founder,
title = {{Founder alleles and clonal hematopoiesis, not missing diversity, confound variant interpretation in an underrepresented population}},
author = {M. El-Haddad and N. Hendi and G. Ghada El-Hajj Fuleihan and G. Nemer and N. El-Hachem},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.28.26366687},
url = {https://www.medrxiv.org/content/10.64898/2026.10.28.26366687v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Founder alleles and clonal hematopoiesis, not missing diversity, confound variant interpretation in an underrepresented population
AU - M. El-Haddad
AU - N. Hendi
AU - G. Ghada El-Hajj Fuleihan
AU - G. Nemer
AU - N. El-Hachem
PY - 2026
DA - 2026/10/28
PB - medRxiv
DO - 10.64898/2026.10.28.26366687
UR - https://www.medrxiv.org/content/10.64898/2026.10.28.26366687v1
AB - 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.
ER -