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Tay-Sachs disease is an autosomal recessive neurodegenerative disorder occurring due to impaired activity of β-hexosaminidase-A (EC 3.2.1.52), resulting from the mutation in HEXA gene. Very little is known about the molecular pathology of TSD in Indian children except for a few mutations identified by us. The present study is aimed to determine additional mutations leading to Tay-Sachs disease in nine patients confirmed by the deficiency of β-hexosaminidase-A (&lt; 2% of total hexosaminidase activity for infantile patients) in leucocytes. The enzyme activity was assessed by using substrates 4-methylumbelliferyl-N-acetyl-β-d-glucosamine and 4-methylumbelliferyl-N-acetyl-β-d-glucosamine-6-sulfate for total-hexosaminidase and hexosaminidase-A respectively, and heat inactivation method for carrier detection. The exons and exon-intron boundaries of the HEXA gene were bi-directionally sequenced on an automated sequencer. 'In silico' analyses for novel mutations were carried out using SIFT, Polyphen2 and MutationT@ster software programs. The structural study was carried out by UCSF Chimera software using the crystallographic structure of β-hexosaminidase-A (PDB-ID: 2GJX) as the template. Our study identified four novel mutations in three cases. These include a compound heterozygous missense mutation c.524A&gt;C (D175A) and c.805G&gt;C (p.G269R) in one case; and one small 1 bp deletion c.426delT (p.F142LfsX57) and one splice site mutation c.459+4A&gt;C in the other two cases respectively. None of these mutations were detected in 100 chromosomes from healthy individuals of the same ethnic group. Three previously reported missense mutations, (i) c.532C&gt;T (p.R178C), (ii) c.964G&gt;T (p.D322Y), and (iii) c.1385A&gt;T (p.E462V); two nonsense mutations (i) c.709C&gt;T (p.Q237X) and (ii) c.1528C&gt;T (p.R510X), one 4 bp insertion c.1277_1278insTATC (p.Y427IfsX5) and one splice site mutation c.459+5G&gt;A were also identified in six cases. We observe from this study that novel mutations are more frequently observed in Indian patients with Tay-Sachs disease with clustering of ~ 73% of disease causing mutations in exons 5 to 12. This database can be used for a carrier rate screening in the larger population of the country.

Expanding the spectrum of HEXA mutations in Indian patients with Tay–Sachs disease