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Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts

Niemann–Pick type C (NPC, ORPHA: 646) is a neuro-visceral, psychiatric disease caused predominantly by pathogenic variants in the NPC1 gene or seldom in NPC2. The rarity of the disease, and its wide range of clinical phenotypes and ages of onset, turn the diagnosis into a significant challenge. Othe...

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Autores principales: Encarnação, Marisa, Ribeiro, Isaura, David, Hugo, Coutinho, Maria Francisca, Quelhas, Dulce, Alves, Sandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671040/
https://www.ncbi.nlm.nih.gov/pubmed/38002933
http://dx.doi.org/10.3390/genes14111990
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author Encarnação, Marisa
Ribeiro, Isaura
David, Hugo
Coutinho, Maria Francisca
Quelhas, Dulce
Alves, Sandra
author_facet Encarnação, Marisa
Ribeiro, Isaura
David, Hugo
Coutinho, Maria Francisca
Quelhas, Dulce
Alves, Sandra
author_sort Encarnação, Marisa
collection PubMed
description Niemann–Pick type C (NPC, ORPHA: 646) is a neuro-visceral, psychiatric disease caused predominantly by pathogenic variants in the NPC1 gene or seldom in NPC2. The rarity of the disease, and its wide range of clinical phenotypes and ages of onset, turn the diagnosis into a significant challenge. Other than the detailed clinical history, the typical diagnostic work-up for NPC includes the quantification of pathognomonic metabolites. However, the molecular basis diagnosis is still of utmost importance to fully characterize the disorder. Here, the authors provide an overview of splicing variants in the NPC1 and NPC2 genes and propose a new workflow for NPC diagnosis. Splicing variants cover a significant part of the disease-causing variants in NPC. The authors used cDNA analysis to study the impact of such variants, including the collection of data to classify them as leaky or non-leaky pathogenic variants. However, the presence of naturally occurring spliced transcripts can misdiagnose or mask a pathogenic variant and make the analysis even more difficult. Analysis of the NPC1 cDNA in NPC patients in parallel with controls is vital to assess and detect alternatively spliced forms. Moreover, nonsense-mediated mRNA decay (NMD) analysis plays an essential role in evaluating the naturally occurring transcripts during cDNA analysis and distinguishing them from other pathogenic variants’ associated transcripts.
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spelling pubmed-106710402023-10-25 Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts Encarnação, Marisa Ribeiro, Isaura David, Hugo Coutinho, Maria Francisca Quelhas, Dulce Alves, Sandra Genes (Basel) Review Niemann–Pick type C (NPC, ORPHA: 646) is a neuro-visceral, psychiatric disease caused predominantly by pathogenic variants in the NPC1 gene or seldom in NPC2. The rarity of the disease, and its wide range of clinical phenotypes and ages of onset, turn the diagnosis into a significant challenge. Other than the detailed clinical history, the typical diagnostic work-up for NPC includes the quantification of pathognomonic metabolites. However, the molecular basis diagnosis is still of utmost importance to fully characterize the disorder. Here, the authors provide an overview of splicing variants in the NPC1 and NPC2 genes and propose a new workflow for NPC diagnosis. Splicing variants cover a significant part of the disease-causing variants in NPC. The authors used cDNA analysis to study the impact of such variants, including the collection of data to classify them as leaky or non-leaky pathogenic variants. However, the presence of naturally occurring spliced transcripts can misdiagnose or mask a pathogenic variant and make the analysis even more difficult. Analysis of the NPC1 cDNA in NPC patients in parallel with controls is vital to assess and detect alternatively spliced forms. Moreover, nonsense-mediated mRNA decay (NMD) analysis plays an essential role in evaluating the naturally occurring transcripts during cDNA analysis and distinguishing them from other pathogenic variants’ associated transcripts. MDPI 2023-10-25 /pmc/articles/PMC10671040/ /pubmed/38002933 http://dx.doi.org/10.3390/genes14111990 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Encarnação, Marisa
Ribeiro, Isaura
David, Hugo
Coutinho, Maria Francisca
Quelhas, Dulce
Alves, Sandra
Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts
title Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts
title_full Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts
title_fullStr Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts
title_full_unstemmed Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts
title_short Challenges in the Definitive Diagnosis of Niemann–Pick Type C—Leaky Variants and Alternative Transcripts
title_sort challenges in the definitive diagnosis of niemann–pick type c—leaky variants and alternative transcripts
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10671040/
https://www.ncbi.nlm.nih.gov/pubmed/38002933
http://dx.doi.org/10.3390/genes14111990
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