Exome Sequence Analysis to Characterize Undiagnosed Family Segregating Motor Impairment and Dystonia.

: Hypermanganesemia with dystonia 1 (HMNDYT1) is a rare genetic disorder characterized by elevated blood manganese levels. This condition is associated with polycythemia, motor neurodegeneration with extrapyramidal features, and hepatic dysfunction, which can progress to cirrhosis in some patients. : In this study, a consanguineous Saudi family with two affected individuals exhibiting symptoms of severe motor impairment, spastic paraparesis, postural instability, and dystonia was studied. Clinical and radiographic evaluations were conducted on the affected individuals. Whole exome sequencing (WES) was performed to diagnose the disease and to determine the causative variant underlying the phenotype. Moreover, Sanger sequencing was used for validation and segregation analysis of the identified variant. Bioinformatics tools were utilized to predict the pathogenicity of candidate variants based on ACMG criteria. : Exome sequencing detected a recurrent homozygous missense variant (c.266T>C; p.L89P) in exon 1 of the gene. Sanger sequencing was employed to validate the segregation of the discovered variant in all available family members. Bioinformatics tools predicted that the variant is potentially pathogenic. Moreover, conservation analysis showed that the variant is highly conserved in vertebrates. : This study shows that exome sequencing is instrumental in diagnosing undiagnosed neurodevelopmental disorders. Moreover, this study expands the mutation spectrum of in distinct populations.