Thipwimol Tim-Aroon1, Khunton Wichajarn2, Kamornwan Katanyuwong3, Pranoot Tanpaiboon4, Nithiwat Vatanavicharn5, Kullasate Sakpichaisakul6,7, Arthaporn Kongkrapan1, Jakris Eu-Ahsunthornwattana8, Supranee Thongpradit9, Kanya Moolsuwan10, Nusara Satproedprai11, Surakameth Mahasirimongkol11, Tassanee Lerksuthirat9, Bhoom Suktitipat12,13, Natini Jinawath10,13, Duangrurdee Wattanasirichaigoon14. 1. Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 2. Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand. 3. Department of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand. 4. Children's National Rare Disease Institute, Children's National Hospital, Washington, DC, USA. 5. Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 6. Division of Neurology, Department of Pediatrics, Queen Sirikit National Institute of Child Health, Ministry of Public Health, Bangkok, Thailand. 7. College of Medicine, Rangsit University, Bangkok, Thailand. 8. Department of Community Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 9. Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 10. Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. 11. Department of Medical Science, Ministry of Public Health, Nonthaburi, Thailand. 12. Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. 13. Integrative Computational Bioscience Center, Mahidol University, Salaya, Nakhon Pathom, Thailand. 14. Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. duangrurdee.wat@mahidol.ac.th.
Abstract
BACKGROUND: Sandhoff disease (SD) is an autosomal recessive lysosomal storage disorder, resulting in accumulation of GM2 ganglioside, particular in neuronal cells. The disorder is caused by deficiency of β-hexosaminidase B (HEX-B), due to pathogenic variant of human HEXB gene. METHOD: This study describes clinical features, biochemical, and genetic defects among Thai patients with infantile SD during 2008-2019. RESULTS: Five unrelated Thai patients presenting with developmental regression, axial hypotonia, seizures, exaggerated startle response to noise, and macular cherry red spot were confirmed to have infantile SD based on deficient HEX enzyme activities and biallelic variants of the HEXB gene. In addition, an uncommon presenting feature, cardiac defect, was observed in one patient. All the patients died in their early childhood. Plasma total HEX and HEX-B activities were severely deficient. Sequencing analysis of HEXB gene identified two variants including c.1652G>A (p.Cys551Tyr) and a novel variant of c.761T>C (p.Leu254Ser), in 90 and 10% of the mutant alleles found, respectively. The results from in silico analysis using multiple bioinformatics tools were in agreement that the p.Cys551Tyr and the p.Leu254Ser are likely pathogenic variants. Molecular modelling suggested that the Cys551Tyr disrupt disulfide bond, leading to protein destabilization while the Leu254Ser resulted in change of secondary structure from helix to coil and disturbing conformation of the active site of the enzyme. Genome-wide SNP array analysis showed no significant relatedness between the five affected individuals. These two variants were not present in control individuals. The prevalence of infantile SD in Thai population is estimated 1 in 1,458,521 and carrier frequency at 1 in 604. CONCLUSION: The study suggests that SD likely represents the most common subtype of rare infantile GM2 gangliosidosis identified among Thai patients. We firstly described a potential common variant in HEXB in Thai patients with infantile onset SD. The data can aid a rapid molecular confirmation of infantile SD starting with the hotspot variant and the use of expanded carrier testing.
BACKGROUND: Sandhoff disease (SD) is an autosomal recessive lysosomal storage disorder, resulting in accumulation of GM2 ganglioside, particular in neuronal cells. The disorder is caused by deficiency of β-hexosaminidase B (HEX-B), due to pathogenic variant of human HEXB gene. METHOD: This study describes clinical features, biochemical, and genetic defects among Thai patients with infantile SD during 2008-2019. RESULTS: Five unrelated Thai patients presenting with developmental regression, axial hypotonia, seizures, exaggerated startle response to noise, and macular cherry red spot were confirmed to have infantile SD based on deficient HEX enzyme activities and biallelic variants of the HEXB gene. In addition, an uncommon presenting feature, cardiac defect, was observed in one patient. All the patients died in their early childhood. Plasma total HEX and HEX-B activities were severely deficient. Sequencing analysis of HEXB gene identified two variants including c.1652G>A (p.Cys551Tyr) and a novel variant of c.761T>C (p.Leu254Ser), in 90 and 10% of the mutant alleles found, respectively. The results from in silico analysis using multiple bioinformatics tools were in agreement that the p.Cys551Tyr and the p.Leu254Ser are likely pathogenic variants. Molecular modelling suggested that the Cys551Tyr disrupt disulfide bond, leading to protein destabilization while the Leu254Ser resulted in change of secondary structure from helix to coil and disturbing conformation of the active site of the enzyme. Genome-wide SNP array analysis showed no significant relatedness between the five affected individuals. These two variants were not present in control individuals. The prevalence of infantile SD in Thai population is estimated 1 in 1,458,521 and carrier frequency at 1 in 604. CONCLUSION: The study suggests that SD likely represents the most common subtype of rare infantile GM2 gangliosidosis identified among Thai patients. We firstly described a potential common variant in HEXB in Thai patients with infantile onset SD. The data can aid a rapid molecular confirmation of infantile SD starting with the hotspot variant and the use of expanded carrier testing.
Authors: Eric F Pettersen; Thomas D Goddard; Conrad C Huang; Gregory S Couch; Daniel M Greenblatt; Elaine C Meng; Thomas E Ferrin Journal: J Comput Chem Date: 2004-10 Impact factor: 3.376
Authors: Sayantan Das; Lukas Forer; Sebastian Schönherr; Carlo Sidore; Adam E Locke; Alan Kwong; Scott I Vrieze; Emily Y Chew; Shawn Levy; Matt McGue; David Schlessinger; Dwight Stambolian; Po-Ru Loh; William G Iacono; Anand Swaroop; Laura J Scott; Francesco Cucca; Florian Kronenberg; Michael Boehnke; Gonçalo R Abecasis; Christian Fuchsberger Journal: Nat Genet Date: 2016-08-29 Impact factor: 38.330
Authors: Shane McCarthy; Sayantan Das; Warren Kretzschmar; Olivier Delaneau; Andrew R Wood; Alexander Teumer; Hyun Min Kang; Christian Fuchsberger; Petr Danecek; Kevin Sharp; Yang Luo; Carlo Sidore; Alan Kwong; Nicholas Timpson; Seppo Koskinen; Scott Vrieze; Laura J Scott; He Zhang; Anubha Mahajan; Jan Veldink; Ulrike Peters; Carlos Pato; Cornelia M van Duijn; Christopher E Gillies; Ilaria Gandin; Massimo Mezzavilla; Arthur Gilly; Massimiliano Cocca; Michela Traglia; Andrea Angius; Jeffrey C Barrett; Dorrett Boomsma; Kari Branham; Gerome Breen; Chad M Brummett; Fabio Busonero; Harry Campbell; Andrew Chan; Sai Chen; Emily Chew; Francis S Collins; Laura J Corbin; George Davey Smith; George Dedoussis; Marcus Dorr; Aliki-Eleni Farmaki; Luigi Ferrucci; Lukas Forer; Ross M Fraser; Stacey Gabriel; Shawn Levy; Leif Groop; Tabitha Harrison; Andrew Hattersley; Oddgeir L Holmen; Kristian Hveem; Matthias Kretzler; James C Lee; Matt McGue; Thomas Meitinger; David Melzer; Josine L Min; Karen L Mohlke; John B Vincent; Matthias Nauck; Deborah Nickerson; Aarno Palotie; Michele Pato; Nicola Pirastu; Melvin McInnis; J Brent Richards; Cinzia Sala; Veikko Salomaa; David Schlessinger; Sebastian Schoenherr; P Eline Slagboom; Kerrin Small; Timothy Spector; Dwight Stambolian; Marcus Tuke; Jaakko Tuomilehto; Leonard H Van den Berg; Wouter Van Rheenen; Uwe Volker; Cisca Wijmenga; Daniela Toniolo; Eleftheria Zeggini; Paolo Gasparini; Matthew G Sampson; James F Wilson; Timothy Frayling; Paul I W de Bakker; Morris A Swertz; Steven McCarroll; Charles Kooperberg; Annelot Dekker; David Altshuler; Cristen Willer; William Iacono; Samuli Ripatti; Nicole Soranzo; Klaudia Walter; Anand Swaroop; Francesco Cucca; Carl A Anderson; Richard M Myers; Michael Boehnke; Mark I McCarthy; Richard Durbin Journal: Nat Genet Date: 2016-08-22 Impact factor: 38.330