The Genetic Basis of Neurological Disorders: Missense and Nonsense Variants in Three Pakistani Families With...

Neurological disorders affect both the central and peripheral nervous systems, exhibiting broad genetic and clinical variability and posing a significant public health concern. These conditions range from common disorders, such as attention deficit disorder and epilepsy, to rare diseases like intellectual disability (ID) and white matter disorders. Exome sequencing (ES) has emerged as a powerful tool in diagnosing the genetic underpinnings of these disorders. ES demonstrated its feasibility as a cost-effective diagnostic pathway by identifying pertinent diagnostic outcomes in 29.4% of cases and being noticeably more cost-effective than conventional genetic diagnostic techniques.

This study investigated the genetic basis of three rare neurological disorders in three unrelated Pakistani families using ES. Each family presents with a distinct syndromic form of ID, associated with bilateral frontoparietal polymicrogyria (BFPP) (Family-1), Li-Ghorbani-Weisz-Hubshman syndrome (LIGOWS) (Family-2), or hypomyelination and congenital cataract (HCC) (Family-3). The functional consequences of the missense variants were investigated using bioinformatic prediction tools to confirm the pathogenicity.

In Family-1 with BFPP, ES identified a novel homozygous missense variant ((NM_001145771.3): c.1579C > T; (NP_001139243.1): p.Pro527Ser) in ADGRG1, predicted to impact protein function. In Family-2 with LIGOWS, a novel homozygous missense variant ((NM_182958.4): c.649A > C; (NP_892003.2): p.Met217Leu) was found in KAT8. In Family-3 with HCC, a novel homozygous nonsense variant ((NM_032581.4): c.722T > G; (NP_115970.2): p.Leu241Ter) was identified in FAM126A, likely resulting in a truncated, nonfunctional protein. Families' structures and segregation analysis confirm disease condition segregating with autosomal recessive mode of inheritance. The functional consequences of the ADGRG1 and KAT8 missense variants were revealed as deleterious using bioinformatic prediction tools.

We have identified novel pathogenic variants in ADGRG1, KAT8, and FAM126A in individuals with rare neurological disorders, thereby expanding the genetic and clinical spectrum of these conditions. This study reports, for the first time, an autosomal recessive inheritance pattern for a KAT8-related disorder, providing new insights into its genetic architecture.