Identification of novel variants in a large cohort of children with Tay–Sachs disease

An initiative of a multicentric task force on lysosomal storage disorders by Government of India

Mehul Mistri, Sanjeev Mehta, Dhaval Solanki, Mahesh Kamate, Neerja Gupta, Madhulika Kabra, Ratna Puri, Katta Girisha, Sankar Hariharan, Sheela Nampoothiri, Frenny Sheth, Jayesh Sheth

Research output: Contribution to journalArticle

Abstract

Tay–Sachs disease (TSD) (OMIM) is a neurodegenerative lysosomal storage disorder caused due to mutations in the HEXA gene. To date, nearly 190 mutations have been reported in HEXA gene. Here, we have characterized 34 enzymatically confirmed TSD families to investigate the presence of novel as well as known variants in HEXA gene. Overall study detected 25 variants belonging to 31 affected TSD patients and 3 carrier couples confirmed by enzyme study. Of these 17 patients harbors 15 novel variants, including seven missense variants [p.V206L, p.Y213H, p.R252C, p.F257S, p.C328G, p.G454R, and p.P475R], four nonsense variant [p.S9X, p.E91X, p.W420X, and p.W482X], two splice site variants [c.347–1G>A and c.460–1G>A], and two small deletion [c.1349delC (p.A450VfsX3) and c.52delG (p.G18Dfs*82)]. While remaining 17 patients harbors 10 previously reported variants that includes six missense variants [p.M1T, p.R170Q, p.D322Y, p.D322N, p.E462V, and p.R499C], one nonsense variant [p.Q106X], two splice site variants [c.1073+1G>A and c.459+4A>G] and one 4 bp insertion [c.1278insTATC (p.Y427IfsX5)]. In conclusion, Indian infantile TSD patients provide newer insight into the molecular heterogeneity of the TSD. Combining present study and our earlier studies, we have observed that 67% genotypes found in Indian TSD patients are novel, which are associated with severe infantile phenotypes, while rest 33% genotypes found in our cohort were previously reported in various populations. In addition, higher frequency of the p.E462V and c.1278insTATC mutations in the present study further support and suggest the prevalence of p.E462V mutation in the Indian population.

Original languageEnglish
Pages (from-to)985-994
Number of pages10
JournalJournal of Human Genetics
Volume64
Issue number10
DOIs
Publication statusPublished - 01-10-2019

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India
Mutation
Genotype
Genes
Genetic Databases
Population
Phenotype
Enzymes

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Mistri, Mehul ; Mehta, Sanjeev ; Solanki, Dhaval ; Kamate, Mahesh ; Gupta, Neerja ; Kabra, Madhulika ; Puri, Ratna ; Girisha, Katta ; Hariharan, Sankar ; Nampoothiri, Sheela ; Sheth, Frenny ; Sheth, Jayesh. / Identification of novel variants in a large cohort of children with Tay–Sachs disease : An initiative of a multicentric task force on lysosomal storage disorders by Government of India. In: Journal of Human Genetics. 2019 ; Vol. 64, No. 10. pp. 985-994.
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abstract = "Tay–Sachs disease (TSD) (OMIM) is a neurodegenerative lysosomal storage disorder caused due to mutations in the HEXA gene. To date, nearly 190 mutations have been reported in HEXA gene. Here, we have characterized 34 enzymatically confirmed TSD families to investigate the presence of novel as well as known variants in HEXA gene. Overall study detected 25 variants belonging to 31 affected TSD patients and 3 carrier couples confirmed by enzyme study. Of these 17 patients harbors 15 novel variants, including seven missense variants [p.V206L, p.Y213H, p.R252C, p.F257S, p.C328G, p.G454R, and p.P475R], four nonsense variant [p.S9X, p.E91X, p.W420X, and p.W482X], two splice site variants [c.347–1G>A and c.460–1G>A], and two small deletion [c.1349delC (p.A450VfsX3) and c.52delG (p.G18Dfs*82)]. While remaining 17 patients harbors 10 previously reported variants that includes six missense variants [p.M1T, p.R170Q, p.D322Y, p.D322N, p.E462V, and p.R499C], one nonsense variant [p.Q106X], two splice site variants [c.1073+1G>A and c.459+4A>G] and one 4 bp insertion [c.1278insTATC (p.Y427IfsX5)]. In conclusion, Indian infantile TSD patients provide newer insight into the molecular heterogeneity of the TSD. Combining present study and our earlier studies, we have observed that 67{\%} genotypes found in Indian TSD patients are novel, which are associated with severe infantile phenotypes, while rest 33{\%} genotypes found in our cohort were previously reported in various populations. In addition, higher frequency of the p.E462V and c.1278insTATC mutations in the present study further support and suggest the prevalence of p.E462V mutation in the Indian population.",
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Identification of novel variants in a large cohort of children with Tay–Sachs disease : An initiative of a multicentric task force on lysosomal storage disorders by Government of India. / Mistri, Mehul; Mehta, Sanjeev; Solanki, Dhaval; Kamate, Mahesh; Gupta, Neerja; Kabra, Madhulika; Puri, Ratna; Girisha, Katta; Hariharan, Sankar; Nampoothiri, Sheela; Sheth, Frenny; Sheth, Jayesh.

In: Journal of Human Genetics, Vol. 64, No. 10, 01.10.2019, p. 985-994.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of novel variants in a large cohort of children with Tay–Sachs disease

T2 - An initiative of a multicentric task force on lysosomal storage disorders by Government of India

AU - Mistri, Mehul

AU - Mehta, Sanjeev

AU - Solanki, Dhaval

AU - Kamate, Mahesh

AU - Gupta, Neerja

AU - Kabra, Madhulika

AU - Puri, Ratna

AU - Girisha, Katta

AU - Hariharan, Sankar

AU - Nampoothiri, Sheela

AU - Sheth, Frenny

AU - Sheth, Jayesh

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Tay–Sachs disease (TSD) (OMIM) is a neurodegenerative lysosomal storage disorder caused due to mutations in the HEXA gene. To date, nearly 190 mutations have been reported in HEXA gene. Here, we have characterized 34 enzymatically confirmed TSD families to investigate the presence of novel as well as known variants in HEXA gene. Overall study detected 25 variants belonging to 31 affected TSD patients and 3 carrier couples confirmed by enzyme study. Of these 17 patients harbors 15 novel variants, including seven missense variants [p.V206L, p.Y213H, p.R252C, p.F257S, p.C328G, p.G454R, and p.P475R], four nonsense variant [p.S9X, p.E91X, p.W420X, and p.W482X], two splice site variants [c.347–1G>A and c.460–1G>A], and two small deletion [c.1349delC (p.A450VfsX3) and c.52delG (p.G18Dfs*82)]. While remaining 17 patients harbors 10 previously reported variants that includes six missense variants [p.M1T, p.R170Q, p.D322Y, p.D322N, p.E462V, and p.R499C], one nonsense variant [p.Q106X], two splice site variants [c.1073+1G>A and c.459+4A>G] and one 4 bp insertion [c.1278insTATC (p.Y427IfsX5)]. In conclusion, Indian infantile TSD patients provide newer insight into the molecular heterogeneity of the TSD. Combining present study and our earlier studies, we have observed that 67% genotypes found in Indian TSD patients are novel, which are associated with severe infantile phenotypes, while rest 33% genotypes found in our cohort were previously reported in various populations. In addition, higher frequency of the p.E462V and c.1278insTATC mutations in the present study further support and suggest the prevalence of p.E462V mutation in the Indian population.

AB - Tay–Sachs disease (TSD) (OMIM) is a neurodegenerative lysosomal storage disorder caused due to mutations in the HEXA gene. To date, nearly 190 mutations have been reported in HEXA gene. Here, we have characterized 34 enzymatically confirmed TSD families to investigate the presence of novel as well as known variants in HEXA gene. Overall study detected 25 variants belonging to 31 affected TSD patients and 3 carrier couples confirmed by enzyme study. Of these 17 patients harbors 15 novel variants, including seven missense variants [p.V206L, p.Y213H, p.R252C, p.F257S, p.C328G, p.G454R, and p.P475R], four nonsense variant [p.S9X, p.E91X, p.W420X, and p.W482X], two splice site variants [c.347–1G>A and c.460–1G>A], and two small deletion [c.1349delC (p.A450VfsX3) and c.52delG (p.G18Dfs*82)]. While remaining 17 patients harbors 10 previously reported variants that includes six missense variants [p.M1T, p.R170Q, p.D322Y, p.D322N, p.E462V, and p.R499C], one nonsense variant [p.Q106X], two splice site variants [c.1073+1G>A and c.459+4A>G] and one 4 bp insertion [c.1278insTATC (p.Y427IfsX5)]. In conclusion, Indian infantile TSD patients provide newer insight into the molecular heterogeneity of the TSD. Combining present study and our earlier studies, we have observed that 67% genotypes found in Indian TSD patients are novel, which are associated with severe infantile phenotypes, while rest 33% genotypes found in our cohort were previously reported in various populations. In addition, higher frequency of the p.E462V and c.1278insTATC mutations in the present study further support and suggest the prevalence of p.E462V mutation in the Indian population.

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