Identification and characterization of 30 novel pathogenic variations in 69 unrelated Indian patients with Mucolipidosis Type II and Type III

Pasumarthi, Divya; Gupta, Neerja; Sheth, Jayesh; Jain, Sakshi; Rungsung, Ikrormi; Kabra, Madhulika; Ranganath, Prajnya; Aggarwal, Shagun; Phadke, Shubha R.; Girisha, Katta M.; Shukla, Anju; Datar, Chaitanya; Verma, I. C.; Puri, Ratna Dua; Bhavsar, Riddhi; Mistry, Mehul; Sankar, V.H.; Gowrishankar, Kalpana; Agrawal, Divya; Nair, Mohandas; Danda, Sumita; Soni, Jai Prakash; Dalal, Ashwin

doi:10.1038/s10038-020-0797-8

Cited by 5 publications

(6 citation statements)

References 17 publications

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“…54% variants were novel in our cohort. Previous studies on pediatric cohorts with lysosomal storage disorders from our population have showed 45%–68% disease causing variants as being novel 41,42 . This indicates under‐representation of our population genotypes in the available disease databases.…”

Section: Discussionmentioning

confidence: 85%

“…Previous studies on pediatric cohorts with lysosomal storage disorders from our population have showed 45%-68% disease causing variants as being novel. 41,42 This indicates under-representation of our population genotypes in the available disease databases. It also shows that a genotype first approach 14 is not feasible for under-represented ethnicities at present and there is a need to expand representation from diverse populations in literature.…”

Section: T a B L E 1 Cases With Variants In Same Molecular Pathways O...mentioning

confidence: 99%

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Fetal phenotypes of Mendelian disorders: A descriptive study from India

et al. 2022

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Objective: Exome sequencing (ES)-based diagnosis of Mendelian diseases in the fetus is limited by paucity of phenotypic information. This study reports the comprehensive phenotypes of some fetuses with Mendelian disorders. Methods: Next generation technology-based sequencing of all coding regions of the genome (Exome sequencing) or targeted gene sequencing using Sanger or next generation platforms was performed in a cohort of deeply phenotyped, cytogenetically normal fetuses with morphological defects. Prenatal ultrasonographic phenotypes and postmortem details including dysmorphology, histopathology, and radiography were ascertained. Novel candidate genes, novel/unusual findings, and unusual genotypes in cases with confirmed Mendelian disorders are described. Results: Of the 102 fetuses sequenced, 45 (44%) achieved definitive diagnosis of aMendelian disorder with 50 pathogenic/likely pathogenic variants. The majority (87%) were autosomal recessive, 69% families were consanguineous, and 54% variants were novel. Dysmorphic syndromes, skeletal dysplasias, and metabolic disorders were the commonest disease categories, ciliopathies and dystroglycanopathies, commonest molecular categories. We describe the first fetal description of six monogenic diseases, and nine cases with novel histological findings. Nineteen cases had novel/unusual findings. Conclusion:This cohort demonstrates how deep fetal phenotypes of some Mendelian disorders can show novel/unusual findings, which have important implications for prenatal diagnosis of these conditions. Key pointsWhat's already known about this topic � Exome sequencing improves the genetic diagnostic yield in fetuses with abnormal perinatal phenotypes.� Knowledge of perinatal phenotypes of Mendelian disorders is limited and this compromises use of exome sequencing in prenatal period.� Dysmorphology plays an important role in recognition of Mendelian disorders.Neelam Saini and Vijaya Sree Venkatapuram have contributed equally

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Section: Discussionmentioning

confidence: 85%

Section: T a B L E 1 Cases With Variants In Same Molecular Pathways O...mentioning

confidence: 99%

Fetal phenotypes of Mendelian disorders: A descriptive study from India

et al. 2022

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“…The GNPTG gene is responsible for encoding the alpha and beta subunits, as well as the gamma subunit of the UDPGlcNAc-1phosphotransferase enzyme, which is crucial for the correct transportation of lysosomal acid hydrolases (Leroy et al, 2014). Mucolipidosis types II and III are severe forms of autosomal recessive lysosomal storage diseases that can be caused by mutations in the GNPTG gene (Chen et al, 2015;Pasumarthi et al, 2020). A study of individuals with stuttering from Pakistan and North America revealed multiple mutations in the GNPTG gene associated with lysosomal enzyme targeting pathways (Kang et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatic analysis reveals lysosome-related biomarkers and molecular subtypes in preeclampsia: novel insights into the pathogenesis of preeclampsia

2023

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Background: The process of lysosomal biogenesis and exocytosis in preeclamptic placentae plays a role in causing maternal endothelial dysfunction. However, the specific lysosome-associated markers relevant to preeclampsia (PE) are not well-defined. Our objective is to discover new biomarkers and molecular subtypes associated with lysosomes that could improve the diagnosis and treatment of PE.Methods: We obtained four microarray datasets related to PE from the Gene Expression Omnibus (GEO) database. The limma package was utilized to identify genes that were differentially expressed between individuals with the disease and healthy controls. The logistic regression analysis was used to identify core diagnostic biomarkers, which were subsequently validated by independent datasets and clinical samples. Additionally, a consensus clustering method was utilized to distinguish between different subtypes of PE. Following this, functional enrichment analysis, GSEA, GSVA, and immune cell infiltration were conducted to compare the two subtypes and identify any differences in their functional characteristics and immune cell composition.Results: We identified 16 PE-specific lysosome-related genes. Through regression analysis, two genes, GNPTG and CTSC, were identified and subsequently validated in the external validation cohort GSE60438 and through qRT-PCR experiment. A nomogram model for the diagnosis of PE was developed and evaluated using these two genes. The model had a remarkably high predictive power (AUC values of the training set, validation set, and clinical samples were 0.897, 0.788, and 0.979, respectively). Additionally, two different molecular subtypes (C1 and C2) were identified, and we found notable variations in the levels of immune cells present in the two subtypes.Conclusion: Our results not only offered a classification system but also identified novel diagnostic biomarkers for PE patients. Our findings offered an additional understanding of how to categorize PE patients and also highlighted potential avenues for creating treatments for individuals with PE.

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“…2 B), Batten disease, Niemann-Pick disease, Morquio-A disease ( Fig. 2 C), Mucolipidosis III alpha, beta and gamma, 12 , 13 and MPS II. 14 The first attempt to treat this group of disorders using enzyme replacement therapy (ERT) was made in 1990.…”

Section: Introductionmentioning

confidence: 98%