Exome sequencing reveals genetic heterogeneity in consanguineous Pakistani families with neurodevelopmental and neuromuscular disorders

There remains a crucial need to address inequalities in genomic research and include populations from low- and middle-income countries (LMIC). Here we present eight consanguineous families from Pakistan, five with neurodevelopmental disorders (NDDs) and three with neuromuscular disorders (NMDs). Affected individuals were clinically characterized, and genetic variants were identified through exome sequencing (ES), followed by family segregation analysis. Affected individuals in six out of eight families (75%) carried homozygous variants that met ACMG criteria for being pathogenic (in the genes ADGRG1, METTL23, SPG11) or likely pathogenic (in the genes GPAA1, MFN2, SGSH). The remaining two families had homozygous candidate variants in the genes (AP4M1 and FAM126A) associated with phenotypes consistent with their clinical presentations, but the variants did not meet the criteria for pathogenicity and were hence classified as variants of unknown significance. Notably, the variants in ADGRG1, AP4M1, FAM126A, and SGSH did not have prior reports in the literature, demonstrating the importance of including diverse populations in genomic studies. We provide clinical phenotyping along with analyses of ES data that support the utility of ES in making accurate molecular diagnoses in these patients, as well as in unearthing novel variants in known disease-causing genes in underrepresented populations from LMIC.