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Morales-Romero, B.* ; Muñoz-Pujol, G.* ; Artuch, R.* ; García-Cazorla, A.* ; O'Callaghan, M.* ; Sykut-Cegielska, J.* ; Campistol, J.M.* ; Moreno-Lozano, P.J.* ; Oud, M.M.* ; Wevers, R.A.* ; Lefeber, D.J.* ; Esteve-Codina, A.* ; Yépez, V.A.* ; Gagneur, J.* ; Wortmann, S.B.* ; Prokisch, H. ; Ribes, A.* ; García-Villoria, J.* ; Tort, F.*

Genome and RNA sequencing were essential to reveal cryptic intronic variants associated to defective ATP6AP1 mRNA processing.

Mol. Genet. Metab. 142:108511 (2024)
Postprint DOI PMC
Open Access Green
The diagnosis of Mendelian disorders has notably advanced with integration of whole exome and genome sequencing (WES and WGS) in clinical practice. However, challenges in variant interpretation and uncovered variants by WES still leave a substantial percentage of patients undiagnosed. In this context, integrating RNA sequencing (RNA-seq) improves diagnostic workflows, particularly for WES inconclusive cases. Additionally, functional studies are often necessary to elucidate the impact of prioritized variants on gene expression and protein function. Our study focused on three unrelated male patients (P1-P3) with ATP6AP1-CDG (congenital disorder of glycosylation), presenting with intellectual disability and varying degrees of hepatopathy, glycosylation defects, and an initially inconclusive diagnosis through WES. Subsequent RNA-seq was pivotal in identifying the underlying genetic causes in P1 and P2, detecting ATP6AP1 underexpression and aberrant splicing. Molecular studies in fibroblasts confirmed these findings and identified the rare intronic variants c.289-233C > T and c.289-289G > A in P1 and P2, respectively. Trio-WGS also revealed the variant c.289-289G > A in P3, which was a de novo change in both patients. Functional assays expressing the mutant alleles in HAP1 cells demonstrated the pathogenic impact of these variants by reproducing the splicing alterations observed in patients. Our study underscores the role of RNA-seq and WGS in enhancing diagnostic rates for genetic diseases such as CDG, providing new insights into ATP6AP1-CDG molecular bases by identifying the first two deep intronic variants in this X-linked gene. Additionally, our study highlights the need to integrate RNA-seq and WGS, followed by functional validation, in routine diagnostics for a comprehensive evaluation of patients with an unidentified molecular etiology.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Atp6ap1-cdg ; Congenital Disorders Of Glycosylation ; Intronic Variant ; Rna-seq ; Whole Exome Sequencing ; Whole Genome Sequencing
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 1096-7192
e-ISSN 1096-7192
Journal Molecular Genetics and Metabolism
Quellenangaben Volume: 142, Issue: 3, Pages: , Article Number: 108511 Supplement: ,
Publisher Elsevier
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503292-001
DOI 10.1016/j.ymgme.2024.108511
Scopus ID 85195858949
PubMed ID 38878498
Erfassungsdatum 2024-07-19
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