Clinical Presentation and Genetic Heterogeneity Including Two Novel Variants in Sri Lankan Patients With Infantile Sandhoff Disease.

Infantile Sandhoff Disease (iSD) is a subtype of GM2 gangliosidosis, which is never been reported in Sri Lanka. Data of eight children, who were diagnosed with iSD during the period of 2017 to 2021, were analyzed retrospectively. The aim of this study was to analyze genotypic and phenotypic variations of native iSDs. Café-au-lait spots, mitral regurgitation and atrial septal defect were found in our patients but never reported in the literature. We found c.1417 + 5G>A and c.1303_1304insCT p.(Arg435Thrfs*10) novel variants of HEXB gene among the nine different gene mutations that were identified. The commonest HEXB gene variant identified in India was c.850 C4T (p.R284X) but was not noticed among Sri Lankan patients. In contrast to other studies, all our patients died within the age of two years. This is the first Sri Lankan study that expands the clinical and molecular basis of iSD with its novel findings.

A heterozygous variant in the SLC22A12 gene in a Sri Lanka family associated with mild renal hypouricemia.

BACKGROUND: Renal hypouricemia is a rare heterogeneous inherited disorder characterized by impaired tubular uric acid transport, reabsorption insufficiency and /or acceleration of secretion. The affected individuals are predisposed to nephrolithiasis and recurrent episodes of exercise-induced acute kidney injury. Type 1 is caused by dysfunctional variants in the SLC22A12 gene (URAT1), while type 2 is caused by defects in the SLC2A9 gene (GLUT9). To date, more than 150 patients with the loss-of-function mutations for the SLC22A12 gene have been found (compound heterozygotes and/or homozygotes), most of whom are Japanese and Koreans. CASE PRESENTATION: Herein, we report a nine year old Sri Lankan boy with renal hypouricemia (serum uric acid 97 µmol/L, fractional excretion of uric acid 33%).The sequencing analysis of SLC22A12 revealed a potentially deleterious missense variant c.1400C > T (p.T467 M, rs200104135) in heterozygous state. This variant has been previously identified in homozygous and/or compound heterozygous state with other causative SLC22A12 variant c.1245_1253del (p.L415_G417del) in Roma population. CONCLUSIONS: This is the first identification of a family with mild renal hypouricemia1 associated to the p.T467 M variant. Detailed investigations of urate blood and urine concentrations in patients with unexplained hypouricemia are needed and renal hypouricemia should also be considered in patients other than those from Japan and/or Korea. Our finding confirms an uneven geographical and ethnic distribution of Romany prevalent SLC22A12 variant that need to be considered in Asian patients (population data Genome Aggregation Database: allele frequency in South Asia 0.007055, in East Asia 0.001330).