Exome sequencing in undiagnosed congenital myopathy reveals new genes and refines genes-phenotypes correlations

Abstract

Background: Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end.

Methods: To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes.

Results: Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical-histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets.

Conclusions: Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments.

Keywords: Centronuclear myopathy; Congenital myopathy; Core myopathy; Exome sequencing; Genetic diagnosis; Genetic heterogeneity; Myopathy; Nemaline myopathy; Phenotypic heterogeneity; Tubular aggregate myopathy.

Fig. 1

Overview of patients enrolling the MYOCAPTURE cohort. A Geographic origin of genetic samples. Europe: European countries other than France. B Diagnosis ratio. Diagnosis: patients with confirmed pathogenic variant(s). Candidate: patients with suspected pathogenic variant(s) in one candidate gene

Fig. 2

Distribution of inheritance patterns and types of pathogenic variants linked to the different implicated genes in the MYOCAPTURE cohort. A Mode of inheritance of pathogenic variants in diagnosed patients. The bar chart indicates the ratio of patients with pathogenic variants in a given gene. The color code illustrates the mode of inheritance per gene (bars) and as a global overview (diagram). B Type of pathogenic variants. The bar chart shows the number of pathogenic variants per gene. Homozygous mutations count as two. For the patients with SRPK3/TTN digenism, the pathogenic variants in TTN and SRPK3 are depicted in separate bars. The respective gene is underlined. The overall distribution of pathogenic variant types is illustrated in the upper diagram. CNV copy number variants

Fig. 3

Distribution of known and novel myopathy genes. In the bar chart, the percentages indicate the ratio of families carrying pathogenic variant(s) in a given gene. New genes identified within the MYOCAPTURE project are shown in orange. For known genes, percentages of patients with classical phenotype (blue) or with new phenotype (yellow) are indicated. The global distribution of pathogenic variants is depicted in the upper diagram

Fig. 4

Congenital myopathy-causing genes. In total, pathogenic variants in 48 genes have been identified in the MYOCAPTURE cohort. The diagram depicts the distribution of these genes based on histological phenotypes and the intersections between phenotypes. The new genes not previously linked to a congenital myopathy are indicated in bold and underlined. CFTD congenital fiber type disorder, CNM centronuclear myopathy, TAM tubular aggregate myopathy