Exome sequencing reveals broad genetic heterogeneity for neuromuscular disorders in consanguineous Pakistani Families

Neuromuscular disorders comprise the majority of neurogenetic conditions, generally characterized by overlapping clinical symptoms, such as spastic paraplegia, muscular abnormalities, and ataxia. In low- and middle-income countries (LMICs), many patients remain undiagnosed or are misdiagnosed. For many NMDs, early diagnosis helps reduce the impact and mortality of the disorder, particularly in LMICs such as Pakistan, and reduces the burden on the healthcare system. The aim of this study was to use exome sequencing as a first line of diagnostic approach to identify the cause of disease. Here, we present five consanguineous families from different remote villages in Pakistan with an undiagnosed neuromuscular disorder, in whom whole-exome sequencing was able to provide a diagnosis. We identified novel variants in known reported disease genes SPEN (c.351_356del) and POMT1 (c.1583A > G) and three previously reported variants in MMP2 (c.1287del), ARL13B (c.599 G > A), and SPG11 (c.6811_6812del). In one family, homozygous pathogenic variants in two different genes (SPEN and NPHP4) were identified; to our knowledge, this is the first report of nephronophthisis and Radio-Tartaglia syndrome co- segregating in a family. In all cases, Sanger sequencing was performed on available family members to confirm segregation. Our study highlights the importance of whole-exome sequencing as a first-line diagnostic approach in undiagnosed individuals with neuromuscular disorders in LMICs, where access to healthcare is limited.