A KLHL40 3’ UTR splice-altering variant causes milder NEM8, an under-appreciated disease mechanism
A KLHL40 3’ UTR splice-altering variant causes milder NEM8, an under-appreciated disease mechanism
Abstract Nemaline myopathy 8 (NEM8) is typically a severe autosomal recessive disorder associated with variants in the kelch-like family member 40 gene (KLHL40). Common features include fetal akinesia, fractures, contractures, dysphagia, respiratory failure, and neonatal death. Here, we describe a man in his 20s with relatively mild NEM8. He presented with hypotonia and bilateral femur fractures at birth, later developing bilateral Achilles’ contractures, scoliosis, and elbow and knee contractures. He had walking difficulties throughout childhood and became wheelchair bound during adolescence after prolonged immobilisation. Muscle MRI during adolescence indicated prominent fat replacement in his pelvic girdle, posterior compartments of thighs, and vastus intermedius. Muscle biopsy revealed nemaline bodies and intranuclear rods. RNA sequencing and western blotting of patient skeletal muscle indicated significant reduction in KLHL40 mRNA and protein respectively. Using gene panel screening, exome sequencing and RNA sequencing, we identified compound heterozygous variants in KLHL40; a truncating 10.9 kb deletion in trans with a likely pathogenic variant (c.*152G>T) in the 3’ untranslated region (UTR). Computational tools SpliceAI and Introme predicted the c.*152G>T variant created a cryptic donor splice site. RNA-seq and in vitro analyses indicated that the c.*152G>T variant induces multiple de novo splicing events that likely provoke nonsense mediated decay of KLHL40 mRNA explaining the loss of mRNA expression and protein abundance in the patient. Analysis of 3’ UTR variants in ClinVar suggests SNPs that introduce aberrant 3’ UTR splicing may be underrecognised in Mendelian disease. We encourage consideration of this mechanism during variant curation.
Faiz Fathimath、Sullivan Patricia、Oates Emily、Beilharz Traude、Cabrera-Serrano Macarena、Ravenscroft Gianina、Dofash Lein N.H.、Monahan Gavin、Servi¨￠n-Morilla Emilia、Rivas Eloy、Taylor Rhonda L.、Davis Mark R.、Clayton Joshua、Laing Nigel G.
Diagnostic GenomicsChildren?ˉs Cancer Institute, Lowy Cancer Centre, UNSW SydneySchool of Biotechnology & Biomolecular Sciences, The University of New South WalesDevelopment and Stem Cells Program, Department of Biochemistry & Molecular Biology, Biomedicine Discovery Institute, Monash UniversityDepartment of Neurology, Neuromuscular Unit and Instituto de Biomedicina de Sevilla/CSIC, Hospital Universitario Virgen del Roc¨aoHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia||School of Biomedical Sciences, University of Western AustraliaHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia||School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin UniversityHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western AustraliaInstituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Roc¨ao/Consejo Superior de Investigaciones Cient¨aficas/Universidad de SevillaDepartment of Pathology, Hospital Universitario Virgen del Roc¨ao SevillaHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western AustraliaDiagnostic GenomicsHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western AustraliaHarry Perkins Institute of Medical Research, Centre for Medical Research, University of Western Australia
基础医学临床医学遗传学
Faiz Fathimath,Sullivan Patricia,Oates Emily,Beilharz Traude,Cabrera-Serrano Macarena,Ravenscroft Gianina,Dofash Lein N.H.,Monahan Gavin,Servi¨￠n-Morilla Emilia,Rivas Eloy,Taylor Rhonda L.,Davis Mark R.,Clayton Joshua,Laing Nigel G..A KLHL40 3’ UTR splice-altering variant causes milder NEM8, an under-appreciated disease mechanism[EB/OL].(2025-03-28)[2025-05-02].https://www.medrxiv.org/content/10.1101/2022.08.08.22278402.点此复制
评论