Homozygous deletion of exons 2 and 3 of NPC2 associated with Niemann–Pick disease type C

Hebbar, Malavika; L, Harsha Prasada; Bhowmik, Aneek Das; Trujillano, Daniel; Shukla, Anju; Chakraborti, Shrijeet; Kandaswamy, Krishna Kumar; Rolfs, Arndt; Kamath, Nutan; Dalal, Ashwin; Bielas, Stephanie; Girisha, Katta M.

doi:10.1002/ajmg.a.37794

Cited by 6 publications

(3 citation statements)

References 14 publications

(16 reference statements)

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“…The underlying biochemical defect in type C is abnormal cholesterol transport which leads to sphingomyelin and cholesterol accumulation in the lysosomes and a secondary partial reduction in acid sphingomyelinase activity. NPC1 and NPC2 are the genes underlying NPD type C. Few cases of NPC are reported compared to NPD [15–17]. In present study, we found one case with NPC1 , with a likely deleterious variant in homozygous state.…”

Section: Discussionsupporting

confidence: 51%

Niemann-Pick Disease: An Underdiagnosed Lysosomal Storage Disorder

Panigrahi

Dhanorkar

Suthar

et al. 2019

Case Reports in Genetics

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Lysosomal storage disorders (LSDs) collectively constitute a significant public health burden in developing countries. Commoner LSDs include Gaucher, Fabry, and Niemann-Pick disease (NPD), but many cases remain undiagnosed. With the high incidence of consanguineous marriages, South East Asian countries are expected to have high prevalence of these LSDs. Here we report 4 cases of NPD type A/B in 3 families presenting with hepatosplenomegaly and cytopenias including one family with two sibs having hypertension and mitral valve prolapse. The diagnosis of NPD was proven by mutation analysis with identification of novel mutations, including a novel 4 bp insertion mutation (C>CCTGG) in exon 2 of the SMPD1 gene. We also had two cases of NPD type C, confirmed on mutation analysis.

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Section: Discussionsupporting

confidence: 51%

Niemann-Pick Disease: An Underdiagnosed Lysosomal Storage Disorder

Panigrahi

Dhanorkar

Suthar

et al. 2019

Case Reports in Genetics

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“…Although very rare, SVs have been documented in research literature, providing insights into missing NPC1/2 mutant alleles. In particular, NPC1 whole-gene deletion has been characterized in Niemann–Pick type C patients [ 101 , 102 ], as well as two different larger structural variants encompassing NPC1 and flanking genes ( RMC1 and part of ANKRD29 in the first one, ANKRD29 and LAMA3 in the second one) [ 100 ], and a homozygous deletion of exons 2 and 3 of NPC2 [ 103 ].…”

Section: Svs In Lsdsmentioning

confidence: 99%

Detection of Structural Variants by NGS: Revealing Missing Alleles in Lysosomal Storage Diseases

Cognata¹,

Cavallaro²

2022

Biomedicines

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Lysosomal storage diseases (LSDs) are a heterogeneous group of rare multisystem metabolic disorders occurring mostly in infancy and childhood, characterized by a gradual accumulation of non-degraded substrates inside the cells. Although biochemical enzymatic assays are considered the gold standard for diagnosis of symptomatic patients, genotyping is a requirement for inclusion in enzyme replacement programs and is a prerequisite for carrier tests in relatives and DNA-based prenatal diagnosis. The emerging next-generation sequencing (NGS) technologies are now offering a powerful diagnostic tool for genotyping LSDs patients by providing faster, cheaper, and higher-resolution testing options, and are allowing to unravel, in a single integrated workflow SNVs, small insertions and deletions (indels), as well as major structural variations (SVs) responsible for the pathology. Here, we summarize the current knowledge about the most recurrent and private SVs involving LSDs-related genes, review advantages and drawbacks related to the use of the NGS in the SVs detection, and discuss the challenges to bring this type of analysis in clinical diagnostics.

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“…The overlapping phenotypes and involvement of multiple genes in lysosomal disorders, and the need for intervention in the form of enzyme replacement therapy at the earliest, call for use of NGS approaches for faster diagnosis. In Niemann–Pick disease type C, an LSD with a wide clinical spectrum, a novel mutation was identified by whole exome sequencing in a proband of Asian origin, which was a deletion spanning two exons of Niemann–Pick disease type C2 (NPC2) gene [173].…”

Section: Main Textmentioning

confidence: 99%

Genomics of rare genetic diseases—experiences from India

Sivasubbu

Scaria

2019

Hum Genomics

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Home to a culturally heterogeneous population, India is also a melting pot of genetic diversity. The population architecture characterized by multiple endogamous groups with specific marriage patterns, including the widely prevalent practice of consanguinity, not only makes the Indian population distinct from rest of the world but also provides a unique advantage and niche to understand genetic diseases. Centuries of genetic isolation of population groups have amplified the founder effects, contributing to high prevalence of recessive alleles, which translates into genetic diseases, including rare genetic diseases in India. Rare genetic diseases are becoming a public health concern in India because a large population size of close to a billion people would essentially translate to a huge disease burden for even the rarest of the rare diseases. Genomics-based approaches have been demonstrated to accelerate the diagnosis of rare genetic diseases and reduce the socio-economic burden. The Genomics for Understanding Rare Diseases: India Alliance Network (GUaRDIAN) stands for providing genomic solutions for rare diseases in India. The consortium aims to establish a unique collaborative framework in health care planning, implementation, and delivery in the specific area of rare genetic diseases. It is a nation-wide collaborative research initiative catering to rare diseases across multiple cohorts, with over 240 clinician/scientist collaborators across 70 major medical/research centers. Within the GUaRDIAN framework, clinicians refer rare disease patients, generate whole genome or exome datasets followed by computational analysis of the data for identifying the causal pathogenic variations. The outcomes of GUaRDIAN are being translated as community services through a suitable platform providing low-cost diagnostic assays in India. In addition to GUaRDIAN, several genomic investigations for diseased and healthy population are being undertaken in the country to solve the rare disease dilemma. In summary, rare diseases contribute to a significant disease burden in India. Genomics-based solutions can enable accelerated diagnosis and management of rare diseases. We discuss how a collaborative research initiative such as GUaRDIAN can provide a nation-wide framework to cater to the rare disease community of India.

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Homozygous deletion of exons 2 and 3 of NPC2 associated with Niemann–Pick disease type C

Cited by 6 publications

References 14 publications

Niemann-Pick Disease: An Underdiagnosed Lysosomal Storage Disorder

Niemann-Pick Disease: An Underdiagnosed Lysosomal Storage Disorder

Detection of Structural Variants by NGS: Revealing Missing Alleles in Lysosomal Storage Diseases

Genomics of rare genetic diseases—experiences from India

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