Lysosomal storage disorders: Novel and frequent pathogenic variants in a large cohort of Indian patients of Pompe, Fabry, Gaucher and Hurler disease

Thomas, Divya C.; Sharma, Sandeepika; Puri, Ratna Dua; Verma, Ishwar C.; Verma, Jyotsna

doi:10.1016/j.clinbiochem.2020.12.002

Cited by 9 publications

(11 citation statements)

References 35 publications

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“…A549 cells carrying a homozygous p.Ser164Arg KI displayed a marked decrease in both GCase levels and activity, effectively phenocopying gene KO cells. This result, the first functional evidence for p.Ser164Arg presented to date, is in line with the homozygous occurrence of this variant in Gaucher disease (GD) patients 55–57 , whose GCase levels and/or activity are severely reduced. Data from gnomAD 58 and a recent comprehensive investigation of GBA1 variant frequencies 59 only report occurrence of p.Ser164Arg in South Asians.…”

Section: Discussionsupporting

confidence: 83%

The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India

Andrews

Kukkle

Menon

et al. 2023

Preprint

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ImportanceRecent studies have advanced our understanding of the genetic drivers of Parkinson’s Disease (PD). Rare variants in more than 20 genes are generally accepted to be causal for PD, and the latest PD GWAS study identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused.ObjectiveTo identify genetic risk factors for PD in a South Asian population and therefore increase understanding of PD genetics more broadly.DesignThis study included common variant (minor allele frequency, MAF > 5%) genome-wide association studies (GWAS) for PD diagnosis (case-control analysis) and age of onset of motor symptoms (case-only analysis). In addition, rare variant (MAF < 1%) analyses delimiting the presence of pathogenic or likely pathogenic variants in previously known PD genes (case-only) and evaluating differential burden of predicted deleterious variants at the gene level (case-control) were performed. Finally, rare and common variants were combined to examine the distribution of a PD polygenic risk score within groups defined by presence of a PD gene mutation.Setting10 specialty movement disorder centers across India.Participants674 PD subjects predominantly with age of onset ≤ 50 years (encompassing juvenile, young, or early-onset PD) were recruited from the contributing centers over a 2-year period. 1,376 control subjects were selected from the reference population GenomeAsia, Phase 2.Main Outcomes & MeasuresDiagnosis of PD, age of onset of motor symptoms.ResultsCommon variant GWAS of PD diagnosis yielded a genome-wide significant signal (lead SNP p-value = 4.11E-11) in theSNCAregion, strongly colocalized (posterior probability = 1) withSNCAregion signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. The top-ranked gene from gene burden studies of rare predicted loss-of-function and deleterious variants wasBSN, which encodes Bassoon, a presynaptic protein previously associated with neurodegenerative disease.Conclusions & RelevanceThis study constitutes the largest genetic investigation of PD and first demonstration ofSNCAassociation with PD in an Indian population to date. Ongoing work seeks to expand this cohort, enabling improved statistical power to detect PD genes in this understudied group.

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Section: Discussionsupporting

confidence: 83%

The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India

Andrews

Kukkle

Menon

et al. 2023

Preprint

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“…A549 cells carrying a homozygous p.Ser164Arg KI exhibited a marked decrease in both GCase levels and activity, effectively phenocopying gene KO cells. This result, the first functional evidence for p.Ser164Arg presented to date, is in line with the homozygous occurrence of this variant in Gaucher disease (GD) patients, 55–57 whose GCase levels and/or activity are severely reduced. Data from gnomAD 58 and a recent comprehensive investigation of GBA1 variant frequencies 59 only report the occurrence of p.Ser164Arg in South Asians.…”

Section: Discussionsupporting

confidence: 82%

The Genetic Drivers of Juvenile, Young, and Early‐Onset Parkinson's Disease in India

Andrews,

Kukkle,

Menon

et al. 2023

Movement Disorders

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BackgroundRecent studies have advanced our understanding of the genetic drivers of Parkinson's disease (PD). Rare variants in more than 20 genes are considered causal for PD, and the latest PD genome‐wide association study (GWAS) identified 90 independent risk loci. However, there remains a gap in our understanding of PD genetics outside of the European populations in which the vast majority of these studies were focused.ObjectiveThe aim was to identify genetic risk factors for PD in a South Asian population.MethodsA total of 674 PD subjects predominantly with age of onset (AoO) ≤50 years (encompassing juvenile, young, or early‐onset PD) were recruited from 10 specialty movement disorder centers across India over a 2‐year period; 1376 control subjects were selected from the reference population GenomeAsia, Phase 2. We performed various case‐only and case–control genetic analyses for PD diagnosis and AoO.ResultsA genome‐wide significant signal for PD diagnosis was identified in the SNCA region, strongly colocalizing with SNCA region signal from European PD GWAS. PD cases with pathogenic mutations in PD genes exhibited, on average, lower PD polygenic risk scores than PD cases lacking any PD gene mutations. Gene burden studies of rare, predicted deleterious variants identified BSN, encoding the presynaptic protein Bassoon that has been previously associated with neurodegenerative disease.ConclusionsThis study constitutes the largest genetic investigation of PD in a South Asian population to date. Future work should seek to expand sample numbers in this population to enable improved statistical power to detect PD genes in this understudied group. © 2023 Denali Therapeutics and The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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“…Eight out of ten patients in this study underwent GBA analysis, five of which were homozygous for c.1226A>G (p.Asn409Ser) and three were homozygous for c.1448T>C (p.Leu483Pro). These two mutations have been the most commonly reported in previous studies from Egypt (6,(30)(31) and India (4,11,25,32) . P.Leu483Pro is a pan-ethnic mutation and the most commonly reported mutation in patients with Gaucher disease type I worldwide (25,32) .…”

Section: Discussionmentioning

confidence: 67%

“…These two mutations have been the most commonly reported in previous studies from Egypt (6,(30)(31) and India (4,11,25,32) . P.Leu483Pro is a pan-ethnic mutation and the most commonly reported mutation in patients with Gaucher disease type I worldwide (25,32) . It has been thought that p.Leu483Pro mutation is associated with neuronopathic GD (types II and III) (33,34) .…”

Section: Discussionmentioning

confidence: 67%

Characterization of 42 Egyptian Children with Lysosomal Storage Disorders

Fahmy¹,

Abdelkreem²,

Mohamed³

et al. 2022

The Egyptian Journal of Hospital Medicine

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Background: Lysosomal storage disorders (LSDs) are a heterogeneous family of genetic diseases with a broad phenotypic spectrum. There is a paucity of data on LSDs from developing countries. Objective: We aimed to study the pattern, relative frequency, and phenotypic spectrum of LSDs in children at an Egyptian medical center. Patients and Methods: This study included children < 18 years with LSDs diagnosed and followed up at an Egyptian medical center from January 2018 to December 2021. Data were collected on patients' demographics, clinical features, characteristic metabolites, specific enzyme assay, and genetic testing. Results: Forty-two children (62% males, 74% parental consanguinity and 26% positive family history) were diagnosed with 10 different LSDs, representing 14% of all cases with inborn errors of metabolism (IEMs). The most frequent LSDs groups were mucopolysaccharidosis (MPS) (52.4%) and sphingolipidosis (40.8%). The most common individual diseases were MPS I (26.2%), Gaucher disease (23.8), MPS III (16.7%), and acid sphingomyelinase deficiency (11.9%). The median age at presentation was two years with a median diagnostic delay of 12 months. The most common clinical manifestations were delayed development, intellectual disability, visceromegaly, coarse facial features, and skeletal abnormalities. Finally, genetic data were available for only 12 patients (8 Gaucher disease, 3 MPS-III, and 1 MPS-VI). Conclusion: LSDs (most commonly MPS and Gaucher disease) represent an important part of IEMs at our medical center, and the diagnosis seems challenging and often delayed.

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Lysosomal storage disorders: Novel and frequent pathogenic variants in a large cohort of Indian patients of Pompe, Fabry, Gaucher and Hurler disease

Cited by 9 publications

References 35 publications

The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India

The genetic drivers of juvenile, young, and early-onset Parkinson’s Disease in India

The Genetic Drivers of Juvenile, Young, and Early‐Onset Parkinson's Disease in India

Characterization of 42 Egyptian Children with Lysosomal Storage Disorders

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