The impact of exome sequencing on the diagnostic yield of muscular dystrophies in consanguineous families

Dardas, Zain; Swedan, Samer; Qassem, Ahmad Al-Sheikh; Azab, Belal

doi:10.1016/j.ejmg.2020.103845

Cited by 5 publications

(4 citation statements)

References 32 publications

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“…Differences in the extent of genetic prescreening and the application of gene panels and exome sequencing covering different numbers of genes have been proposed to contribute to divergent detection rates of causative variants [6,8,14]. The association of founder mutations with specific ethnicities [17] and higher rates of consanguinity in some study populations are additional factors potentially resulting in higher rates of molecular diagnoses [15,18]. In accordance with these data, the vast majority of solved cases (77.3%) in our study could also be diagnosed by NGS-based approaches.…”

Section: Discussionmentioning

confidence: 99%

Clinico‐genetic spectrum of limb‐girdle muscular weakness in Austria: A multicentre cohort study

Krenn

Tomschik

Wagner

et al. 2022

Euro J of Neurology

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Background and purpose Hereditary myopathies with limb‐girdle muscular weakness (LGW) are a genetically heterogeneous group of disorders, in which molecular diagnosis remains challenging. Our aim was to present a detailed clinical and genetic characterization of a large cohort of patients with LGW. Methods This nationwide cohort study included patients with LGW suspected to be associated with hereditary myopathies. Parameters associated with specific genetic aetiologies were evaluated, and we further assessed how they predicted the detection of causative variants by conducting genetic analyses. Results Molecular diagnoses were identified in 62.0% (75/121) of the cohort, with a higher proportion of patients diagnosed by next‐generation sequencing (NGS) than by single‐gene testing (77.3% vs. 22.7% of solved cases). The median (interquartile range) time from onset to genetic diagnosis was 8.9 (3.7–19.9) and 17.8 (7.9–27.8) years for single‐gene testing and NGS, respectively. The most common diagnoses were myopathies associated with variants in CAPN3 (n = 9), FKRP (n = 9), ANO5 (n = 8), DYSF (n = 8) and SGCA (n = 5), which together accounted for 32.2% of the cohort. Younger age at disease onset (p = 0.043), >10× elevated creatine kinase activity levels (p = 0.024) and myopathic electromyography findings (p = 0.007) were significantly associated with the detection of causative variants. Conclusions Our findings suggest that an earlier use of NGS in patients with LGW is needed to avoid long diagnostic delays. We further present parameters predictive of a molecular diagnosis that may help to select patients for genetic analyses, especially in centres with limited access to sequencing.

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Section: Discussionmentioning

confidence: 99%

Clinico‐genetic spectrum of limb‐girdle muscular weakness in Austria: A multicentre cohort study

Krenn

Tomschik

Wagner

et al. 2022

Euro J of Neurology

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“…Across the five consanguineous families, four variations in the RP1 and RLBP1 genes were identified as disease-causing variants in patients with retinitis pigmentosa [ 141 ]. Two novel pathogenic variants in the DYSF gene were identified in the patients with muscular dystrophies from consanguineous Jordanian families [ 142 ]. Eight Jordanian consanguineous families with multiple keratoconic individuals were analyzed using WES, which revealed two variants in the genes MYOF and STX2 , and one variant in the genes COL6A5 , ZNF676 and ZNF765 [ 143 ] .…”

Section: Other Genetic Diseasesmentioning

confidence: 99%

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

Borgio

2021

Arch Med Sci

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More than 25 million DNA variations were discovered as novel including major alleles from Arab population. Exome studies on Arabs discovered >3000 novel nucleotide variants associated with >1200 rare genetic disorders. Reclassification of many pathogenic variant into benign through the Arab database enhance building a detailed and comprehensive map of Arab morbid genome. Intellectual disability stands first with the combined and observed carrier frequency. Genome studies and advanced computational biology discovered interesting novel candidate disease marker variations in many genes from consanguineous families with intellectual disability, neurogenetic disorders, blood and bleeding disorder and rare genetic diseases. Pathogenic variants in C12orf57 gene are prominently associated with the etiology of developmental delay/intellectual impairment. Arab mitogenome exposed hundreds of variations in mtDNA genome and its association with obesity. Further study is needed in genomics to fully comprehend the molecular abnormalities and associated pathogenesis that cause inherited disorders in Arab ancestries.

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“…Indeed, next-generation sequencing has been applied in the investigation of the genetics of unidentified MDs and achieved valuable results [ 7 , 32 , 33 , 34 ]. For example, Dardas et al [ 32 ] applied whole exome sequencing (WES) and obtained diagnosis in seven out of eight unrelated consanguineous Jordanian families with MDs. WES is also a powerful diagnostic tool for limb-girdle muscular dystrophy [ 35 , 36 ].…”

Section: Introductionmentioning

confidence: 99%

“…Next-generation sequencing is merging as a promising tool for diagnosis of MDs and CMDs. Indeed, next-generation sequencing has been applied in the investigation of the genetics of unidentified MDs and achieved valuable results [7,[32][33][34]. For example, Dardas et al [32] applied whole exome sequencing (WES) and obtained diagnosis in seven out of eight unrelated consanguineous Jordanian families with MDs.…”

Section: Introductionmentioning

confidence: 99%

Whole Exome Sequencing as a Diagnostic Tool for Unidentified Muscular Dystrophy in a Vietnamese Family

Nguyen

Ngọc

et al. 2020

Diagnostics

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Muscular dystrophies are a group of heterogeneous clinical and genetic disorders. Two siblings presented with characteristics like muscular dystrophy, abnormal white matter, and elevated serum creatine kinase level. The high throughput of whole exome sequencing (WES) makes it an efficient tool for obtaining a precise diagnosis without the need for immunohistochemistry. WES was performed in the two siblings and their parents, followed by prioritization of variants and validation by Sanger sequencing. Very rare variants with moderate to high predicted impact in genes associated with neuromuscular disorders were selected. We identified two pathogenic missense variants, c.778C>T (p.H260Y) and c.2987G>A (p.C996Y), in the LAMA2 gene (NM_000426.3), in the homozygous state in two siblings, and in the heterozygous state in their unaffected parents, which were confirmed by Sanger sequencing. Variant c.2987G>A has not been reported previously. These variants may lead to a change in the structure and function of laminin-α2, a member of the family of laminin-211, which is an extracellular matrix protein that functions to stabilize the basement membrane of muscle fibers during contractions. Overall, WES enabled an accurate diagnosis of both patients with LAMA2-related muscular dystrophy and expanded the spectrum of missense variants in LAMA2.

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The impact of exome sequencing on the diagnostic yield of muscular dystrophies in consanguineous families

Cited by 5 publications

References 32 publications

Clinico‐genetic spectrum of limb‐girdle muscular weakness in Austria: A multicentre cohort study

Clinico‐genetic spectrum of limb‐girdle muscular weakness in Austria: A multicentre cohort study

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

Whole Exome Sequencing as a Diagnostic Tool for Unidentified Muscular Dystrophy in a Vietnamese Family

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