Identification of deletion-duplication in HEXA gene in five children with Tay-Sachs disease from India

Abstract

BackgroundTay-Sachs disease (TSD) is a sphingolipid storage disorder caused by mutations in the HEXA gene. To date, nearly 170 mutations of HEXA have been described, including only one 7.6 kb large deletion.MethodsMultiplex Ligation-dependent Probe Amplification (MLPA) study was carried out in 5 unrelated patients for copy number changes where heterozygous and/or homozygous disease causing mutation/s could not be identified in the coding region by sequencing of HEXA gene.ResultsThe study has identified the presence of a homozygous deletion of exon-2 and exon-3 in two patients, two patient showed compound heterozygosity with exon 1 deletion combined with missense mutation p.E462V and one patient was identified with duplication of exon-1 with novel variants c.1527-2A > T as a second allele.ConclusionThis is the first report of deletion/duplication in HEXA gene providing a new insight into the molecular basis of TSD and use of MLPA assay for detecting large copy number changes in the HEXA gene.

Tay-Sachs Disease: Two Novel Rare HEXA Mutations from Pakistan and Morocco

“…It represents the first well characterized lysosomal storage disease and is considered the prototype of GM2 gangliosidoses, which are caused by deficiency of either of 2 isoenzymes of β hexosaminidase namely β hexosaminidase A and B. TSD is caused by pathogenic variants in the HEXA gene leading to deficiency of β hexosaminidase A (HEXA) isoenzyme activity. The human HEXA gene is located on chromosome 15 (15q23-q24) with 35.56 kb spans and contains 14 exons [1]. The encodedHEXA is an important lysosomal hydrolytic enzyme.…”

Thirty two novel nsSNPs May effect onHEXAprotein Leading to Tay-Sachs disease (TSD) Using a Computational Approach

“…Patients with HexA deficiency suffer from GM2 ganglioside accumulates inside neural's lysosomes. Therefore, HexA deficiency primarily affects the nervous system [1,2,4,[6][7][8][9][10][11][12][13][14].According to the disease onset age, TSD is differentiated into three types which are: acute infantile, juvenile, and late-onset. Acute infantile TSD is the most common type.…”

“…In addition, the infected infant progressively suffers from diminished attentiveness and an exaggerated startle response. As TSD continues to destroy the brain infant suffers from seizures, blindness, and death which usually occurs before four years of age [8,9,11,[13][14][15].The human HEXA gene [OMIM *606869] encodes the alpha subunit of the lysosomal hexosaminidase A isozyme (HexA) which is located on chromosome 15 q23-q24 and contains 14 exons. More than two hundred mutations have been reported in the HEXA gene to cause TSD and its variants.…”

“…More than two hundred mutations have been reported in the HEXA gene to cause TSD and its variants. These mutations include single base substitutions, small deletion, duplications, insertions splicing alterations, complex gene rearrangement, partial large duplications, partial deletion, splicing mutations, nonsense mutations and missense mutations that lead to the disruption of transcription, translation, folding, dimerization of monomers and catalytic dysfunction of HexA protein [4,8,11,15,16].…”

“…In addition, the infected infant progressively suffers from diminished attentiveness and an exaggerated startle response. As TSD continues to destroy the brain infant suffers from seizures, blindness, and death which usually occurs before four years of age [8,9,11,[13][14][15].…”