Pathogenic Mutations and Putative Phenotype-Affecting Variants in Polish Myofibrillar Myopathy Patients

Journal of Clinical Medicine

Monika Gos¹  Aleksandra Maruszak²  JakubP Fichna²  Cezary Zekanowski²  Anna Potulska-Chromik³  Biruta Kierdaszuk³  Andrzej Opuchlik³  Edyta Rosiak⁴  Maria Jędrzejowska⁵ 

[1] Department of Medical Genetics, Institute of Mother and Child, 17a Kasprzaka St, 01-211 Warsaw, Poland;Department of Neurodegenerative Disorders, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland;Department of Neurology, Medical University of Warsaw, 1a Banacha St., 02-097 Warsaw, Poland;II Department of Radiology, Medical University of Warsaw, 1a Banacha St., 02-097 Warsaw, Poland;Neuromuscular Unit, Mossakowski Medical Research Institute, Polish Academy of Sciences, 5 Pawinskiego St., 02-106 Warsaw, Poland;

关键词: skeletal muscle;    NGS;    WGS;    genomic data;    oligogenic inheritance;    variant load;   

DOI  :  10.3390/jcm10050914

来源: DOAJ

【 摘 要 】

Myofibrillar myopathies (MFM) are heterogeneous hereditary muscle diseases with characteristic myopathological features of Z-disk dissolution and aggregates of its degradation products. The onset and progression of the disease are variable, with an elusive genetic background, and around half of the cases lacking molecular diagnosis. Here, we attempted to establish possible genetic foundations of MFM by performing whole exome sequencing (WES) in eleven unrelated families of 13 patients clinically diagnosed as MFM spectrum. A filtering strategy aimed at identification of variants related to the disease was used and included integrative analysis of WES data and human phenotype ontology (HPO) terms, analysis of muscle-expressed genes, and analysis of the disease-associated interactome. Genetic diagnosis was possible in eight out of eleven cases. Putative causative mutations were found in the DES (two cases), CRYAB, TPM3, and SELENON (four cases) genes, the latter typically presenting with a rigid spine syndrome. Moreover, a variety of additional, possibly phenotype-affecting variants were found. These findings indicate a markedly heterogeneous genetic background of MFM and show the usefulness of next generation sequencing in the identification of disease-associated mutations. Finally, we discuss the emerging concept of variant load as the basis of phenotypic heterogeneity.

【 授权许可】

Unknown