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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.
J Hum Genet. 2019 Oct; 64(10):985-994.JH

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.

Authors+Show Affiliations

FRIGE's Institute of Human Genetics, Ahmedabad, Gujarat, India.Usha Deep Hospital, Naranpura, Ahmedabad, Gujarat, India.Mantra Child Neurology & Epilepsy Clinic, Bhavnagar, Gujarat, India.KLES Prabhakar Kore Hospital, Belgaum, Karnataka, India.All India Institute of Medical Sciences (AIIMS), New Delhi, India.All India Institute of Medical Sciences (AIIMS), New Delhi, India.Sir Ganga Ram Hospital, New Delhi, India.Kasturba Medical College, Manipal, Karnataka, India.SAT Hospital, Thiruvanathapuram, Trivandrum, India.Amrita Institute of Medical Science & Research Centre, Kochi, Kerala, India.FRIGE's Institute of Human Genetics, Ahmedabad, Gujarat, India.FRIGE's Institute of Human Genetics, Ahmedabad, Gujarat, India. jshethad1@gmail.com.

Pub Type(s)

Journal Article
Multicenter Study

Language

eng

PubMed ID

31388111

Citation

Mistri, Mehul, et al. "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." Journal of Human Genetics, vol. 64, no. 10, 2019, pp. 985-994.
Mistri M, Mehta S, Solanki D, et al. 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. J Hum Genet. 2019;64(10):985-994.
Mistri, M., Mehta, S., Solanki, D., Kamate, M., Gupta, N., Kabra, M., Puri, R., Girisha, K., Hariharan, S., Nampoothiri, S., Sheth, F., & Sheth, J. (2019). 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. Journal of Human Genetics, 64(10), 985-994. https://doi.org/10.1038/s10038-019-0647-8
Mistri M, et al. 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. J Hum Genet. 2019;64(10):985-994. PubMed PMID: 31388111.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. 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, Y1 - 2019/08/06/ PY - 2018/10/15/received PY - 2019/07/16/accepted PY - 2019/06/26/revised PY - 2019/8/8/pubmed PY - 2020/5/15/medline PY - 2019/8/8/entrez SP - 985 EP - 994 JF - Journal of human genetics JO - J. Hum. Genet. VL - 64 IS - 10 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. SN - 1435-232X UR - https://www.unboundmedicine.com/medline/citation/31388111/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 L2 - http://www.diseaseinfosearch.org/result/7008 DB - PRIME DP - Unbound Medicine ER -