Challenges in genomic variant interpretation within Pakistani populations due to genomic healthcare inequalities

Accurate classification of genomic variants is crucial to ensure correct diagnosis, genetic counseling, and clinical management of monogenic inherited disorders. Variant interpretation can be hindered in populations that are significantly underrepresented in large reference genomic databases, leading to genomic healthcare inequalities. Despite a relatively high prevalence of inherited autosomal recessive diseases within Pakistan, this population remains significantly underrepresented in reference genomic databases. This genomic data disparity, alongside other population characteristics, including limited access to genomic healthcare, high rates of consanguineous unions, tribal, ethnic, and geographical isolation leading to increased autozygosity, can result in frequent challenges in rare variant interpretation. Here, we describe four Pakistani families with rare monogenic disorders in which whole-exome sequencing identified previously unpublished candidate biallelic variants of uncertain significance (VUS) in four genes: INTS1, PPFIBP1, HSPG2, and ACOX3. Our studies highlight the challenges of rare variant interpretation within the Pakistani community, leading to an increased proportion of variants being classified as VUS. Collectively, our findings highlight the need for increased diversity within genomic research to effectively tackle healthcare inequities faced by underrepresented communities.