دورية أكاديمية
أعرض في EDS

Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype.

التفاصيل البيبلوغرافية
العنوان: Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype.
المؤلفون: Harkness JR; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health Sciences, University of Manchester, Manchester, UK., Thomas HB; Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health Sciences, University of Manchester, Manchester, UK., Urquhart JE; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health Sciences, University of Manchester, Manchester, UK., Jamieson P; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK., O'Keefe RT; Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health Sciences, University of Manchester, Manchester, UK., Kingston HM; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK., Deshpande C; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK., Newman WG; Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, Faculty of Biology, Medicine and Health Sciences, University of Manchester, Manchester, UK. Electronic address: william.newman@manchester.ac.uk.
مؤلفون مشاركون: Genomics England Research Consortium
المصدر: European journal of medical genetics [Eur J Med Genet] 2024 Feb; Vol. 67, pp. 104907. Date of Electronic Publication: 2023 Dec 21.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101247089 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-0849 (Electronic) Linking ISSN: 17697212 NLM ISO Abbreviation: Eur J Med Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Amsterdam : Elsevier, c2005-
مواضيع طبية MeSH: Cutis Laxa*/genetics , Ehlers-Danlos Syndrome*/genetics, Humans ; Male ; Copper-Transporting ATPases/genetics ; Mutation ; Peptide Fragments/genetics ; Phenotype
مستخلص: Genetic variants in ATP7A are associated with a spectrum of X-linked disorders. In descending order of severity, these are Menkes disease, occipital horn syndrome, and X-linked distal spinal muscular atrophy. After 30 years of diagnostic investigation, we identified a deep intronic ATP7A variant in four males from a family affected to variable degrees by a predominantly skeletal phenotype, featuring bowing of long bones, elbow joints with restricted mobility which dislocate frequently, coarse curly hair, chronic diarrhoea, and motor coordination difficulties. Analysis of whole genome sequencing data from the Genomics England 100,000 Genomes Project following clinical re-evaluation identified a deep intronic ATP7A variant, which was predicted by SpliceAI to have a modest splicing effect. Using a mini-gene splicing assay, we determined that the intronic variant results in aberrant splicing. Sanger sequencing of patient cDNA revealed ATP7A transcripts with exon 5 skipping, or inclusion of a novel intron 4 pseudoexon. In both instances, frameshift leading to premature termination are predicted. Quantification of ATP7A mRNA transcripts using a qPCR assay indicated that the majority of transcripts (86.1 %) have non-canonical splicing, with 68.0 % featuring exon 5 skipping, and 18.1 % featuring the novel pseudoexon. We suggest that the variability of the phenotypes within the affected males results from the stochastic effects of splicing. This deep intronic variant, resulting in aberrant ATP7A splicing, expands the understanding of intronic variation on the ATP7A-related disease spectrum.
(Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
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فهرسة مساهمة: Keywords: ATP7A; Deep intronic variant; Genome; Menkes disease; Non-coding; Occipital horn syndrome; Rare disease; Splicing
المشرفين على المادة: EC 7.2.2.8 (ATP7A protein, human)
EC 7.2.2.8 (Copper-Transporting ATPases)
0 (Peptide Fragments)
SCR Disease Name: Occipital horn syndrome
تواريخ الأحداث: Date Created: 20231223 Date Completed: 20240201 Latest Revision: 20240309
رمز التحديث: 20240309
مُعرف محوري في PubMed: PMC10918460
DOI: 10.1016/j.ejmg.2023.104907
PMID: 38141875
قاعدة البيانات: MEDLINE
الوصف
تدمد:1878-0849
DOI:10.1016/j.ejmg.2023.104907