F001 A genetic evaluation of HD phenocopies from India

<h3>Background</h3> Huntington’s disease patients who have a pathogenic CAG repeat expansion in the Huntingtin gene usually present with chorea, behaviour and memory problems. A finite subset of patients with clinical symptoms of chorea do not have an HTT mutation (HD phenocopies). Junctophilin 3 gene with pathogenic CTG expansions have been found in HDL2 patients of African origin.¹ Mutations at other loci may also contribute to HD phenocopies.² <h3>Aim</h3> To evaluate the JPH3 gene for CTG repeat expansions in patients who tested negative for CAG mutations in HTT gene. To identify other pathogenic variants that might contribute to the HD like phenotype. <h3>Methods</h3> PCR was done using primers for the CTG repeat expansions in JPH3 gene followed by capillary gel electrophoresis. A few samples underwent sequencing for a more detailed analysis. <h3>Results</h3> Two hundred HD negative samples (111 male, 89 female), forty four of whom had family history of chorea were genotyped at the JPH3 locus. The samples displayed a range of repeat sizes from 6 to 19 CTG with no sample having a pathogenic expansion. The most common alleles were 13 and 15 CTG repeats. A novel heterozygous frame shift mutation p.Met219fs in exon 5 of TBP (NM_003194.5) causing loss of both DNA binding domains maybe pathogenic in patient(64Y Male) with chorea and psychiatric symptoms. <h3>Conclusion</h3> There were no HDL2 cases with pathogenic CTG expansions. The differences in prevalence of HDL2 in different world populations is intriguing and needs further study. Pathogenic CAG expansions in TBP gene that cause SCA17 has been referred to as Huntington disease-like 4.³ We report a frameshift mutation resulting in loss of both functional domains in the TBP gene. Whole genome sequencing can detect novel deleterious variants which might explain HD phenocopies. <h3>References</h3> Krause A, Anderson DG, Ferreira-Correia A, <i>et al. Nat Rev Neurol</i> 2024;<b>20</b>:36–49. Nguyen R, Ortigoza-Escobar JD, Burgunder JM, <i>et al. Frontiers in Neurology</i> 2022;<b>13</b>. Rossi M, Hamed M, <i>et al. Movement Disorders</i> 2023;<b>38</b>:368–377.