PDE10A encodes a dual cAMP-cGMP phosphodiesterase that is enriched in the medium spiny neurons of the corpus striatum in the brain and plays an important role in basal ganglia circuitry. Three unrelated patients with childhood onset chorea and striatal abnormalities on MRI brain with heterozygous de novo variants in PDE10A have been described previously. Two families with eight affected individuals with biallelic mutations in PDE10A have also been described previously. We report a family with multiple affected individuals with childhood onset chorea, striatal abnormalities, and a novel heterozygous mutation, c.1001T>G(p.F334C) in PDE10A which was identified by exome sequencing.

Spastic Paraplegia-79 (SPG79) is an autosomal recessive type of childhood onset complicated by hereditary spastic paraplegia. SPG79 is characterized by spasticity, paraplegia, optic atrophy, cerebellar signs, and other variable clinical features. Recessive, disease causing variants in Ubiquitin C-terminal hydrolase-L1 (UCHL1) gene have been implicated as a cause for SPG79 in two families till now. In this study, we report on a third family of SPG79 with two similarly affected siblings, harboring a novel homozygous splice-site variant in the UCHL1 gene (NM_004181.4: c.459+2T>C). The variant was identified by whole-exome sequencing and validated by Sanger sequencing in the family.

Pathogenic variations in SMPD1 lead to acid sphingomyelinase deficiency (ASMD), that is, Niemann‐Pick disease (NPD) type A and B (NPA, NPB), which is a recessive lysosomal storage disease. The knowledge of variant spectrum in Indian patients is crucial for early and accurate NPD diagnosis and genetic counseling of families. In this study, we recruited 40 unrelated pediatric patients manifesting symptoms of ASMD and subnormal ASM enzyme activity. Variations in SMPD1 were studied using Sanger sequencing for all exons, followed by interpretation of variants based on American College of Medical Genetics and Genomics & Association for Molecular Pathology (ACMG/AMP) criteria. We identified 18 previously unreported variants and 21 known variants, including missense, nonsense, deletions, duplications, and splice site variations with disease‐causing potential. Eight missense variants were functionally characterized using in silico molecular dynamic simulation and in vitro transient transfection in HEK293T cells, followed by ASM enzyme assay, immunoblot, and immunofluorescence studies. All the variants showed reduced ASM activity in transfected cells confirming their disease‐causing potential. The study provides data for efficient prenatal diagnosis and genetic counseling of families with NPD type A and B.