Unravelling homozygous PLA2G6 variants in Pakistani individuals with diverse clinical manifestations via whole exome sequencing.

Whole Exome Sequencing (WES) was performed on 265 Pakistani individuals with suspected neurodevelopmental disorders, revealing that seven of them carried homozygous mutations in the PLA2G6 gene, which is linked to neurodegenerative diseases such as Infantile Neuroaxonal Dystrophy (INAD) and Parkinson's disease 14 (PD14). These patients presented with a typical cluster of symptoms, including ataxia, gait instability, cognitive decline, motor regression, and psychiatric manifestations like autistic features, impulsive behaviour, and emotional lability. However, the clinical presentation varied across patients, underscoring the phenotypic diversity associated with PLA2G6 mutations. We identified six distinct variants in the PLA2G6 gene (NM_003560.4) across seven affected individuals. These comprised two pathogenic variants (c.2370T > G and c.1427 + 1G > T), three likely pathogenic variants c.929T > A (observed in two patients), c.1591 + 5G > C, and c.2276G > T, and one variant of uncertain significance c.905T > G. All these mutations were predicted to be disease-related by in silico tools, confirming their likely role in disease causation. This study elucidates the variety of clinical features due to PLA2G6 mutations, with manifestations ranging from motor-cognitive to psychiatric features. Our results emphasize the importance of new homozygous variants for the genetic heterogeneity of these diseases. We want to underscore the value of genetic testing in patients with progressive neurodevelopmental signs, like in the case of our patient, which may result in early diagnosis and help in deciding treatment later. Furthermore, this study provides additional insight into genotype-phenotype correlations of PLA2G6-associated diseases and offers directions for future studies to develop tailored therapeutics.