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Utilisation of exome sequencing for muscular disorders in Thai paediatric patients: diagnostic yield and mutational spectrum.

ABSTRACT: Muscular dystrophies and congenital myopathies are heterogeneous groups of inherited muscular disorders. An accurate diagnosis is challenging due to their complex clinical presentations and genetic heterogeneity. This study aimed to determine the utilisation of exome sequencing (ES) for Thai paediatric patients with muscular disorders. Of 176 paediatric patients suspected of genetic/inherited myopathies, 133 patients received a molecular diagnosis after performing conventional investigations, single gene testing, and gene panels. The remaining 43 patients from 42 families could be classified into three groups: Group 1, MLPA-negative Duchenne muscular dystrophy (DMD) with 9 patients (9/43; 21%), Group 2, other muscular dystrophies (MD) with 18 patients (18/43; 42%) and Group 3, congenital myopathies (CM) with 16 patients (16/43; 37%). All underwent exome sequencing which could identify pathogenic variants in 8/9 (89%), 14/18 (78%), and 8/16 (50%), for each Group, respectively. Overall, the diagnostic yield of ES was 70% (30/43) and 36 pathogenic/likely pathogenic variants in 14 genes were identified. 18 variants have never been previously reported. Molecular diagnoses provided by ES changed management in 22/30 (73%) of the patients. Our study demonstrates the clinical utility and implications of ES in inherited myopathies.

SUBMITTER: Summa S

PROVIDER: S-EPMC9876991 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Utilisation of exome sequencing for muscular disorders in Thai paediatric patients: diagnostic yield and mutational spectrum.

Summa Sarinya S Ittiwut Chupong C Kulsirichawaroj Pimchanok P Paprad Tanitnun T Likasitwattanakul Surachai S Sanmaneechai Oranee O Boonsimma Ponghatai P Suphapeetiporn Kanya K Shotelersuk Vorasuk V

Scientific reports 20230125 1

Muscular dystrophies and congenital myopathies are heterogeneous groups of inherited muscular disorders. An accurate diagnosis is challenging due to their complex clinical presentations and genetic heterogeneity. This study aimed to determine the utilisation of exome sequencing (ES) for Thai paediatric patients with muscular disorders. Of 176 paediatric patients suspected of genetic/inherited myopathies, 133 patients received a molecular diagnosis after performing conventional investigations, si ...[more]

PMID: 36697461

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Project description:BackgroundGaucher disease (GD) is a rare lysosomal storage disorder, characterized by hepatosplenomegaly and pancytopenia, with or without neurologic involvement. The disorder is categorized into three phenotypes: GD type 1 or nonneuronopathic GD; GD type 2 or acute neuronopathic GD; and GD type 3 or chronic neuronopathic GD. The purposes of this study were to describe clinical characteristics of Thai GD in patients diagnosed and/or followed up during 2010-2018 and to perform re-genotyping including analysis of GBA recombinant alleles which had not been investigated in Thai patients before.ResultsThere were 27 patients from seven medical centers, enrolled in the study. All the cases had pediatric onset. GD3 (44.5%) was the most common phenotype, followed by GD2 (40.7%) and GD1 (14.8%), with one case of neonatal GD. The median age of onset for GD1, GD2, and GD3 was 72, 4 and 12 months, respectively, suggesting relatively earlier onset of GD1 and GD3 in Thai patients. All patients with GD1 and most patients with GD3 received ERT. Four patients with GD3 had ERT followed by HSCT. Patients with GD3 who received no or late ERT showed unfavorable outcomes. We identified 14 variants including two novel (p.S384F and p.W533*) and 12 reported pathogenic variants: p.L483P, p.N409S, p.R159W, p.P305A, p.A175G, p.D448H, p.V414L, IVS2+1G>A, IVS6-1G>C, IVS7+1G>C, IVS9-3C>G, and Rec1a. The p.L483P was the most prevalent allele found in this study, at 66% (33/50 alleles), followed by IVS2+1G>A, Rec1a, and IVS6-1G>C. Twenty-four percent of patients were reassigned with validated genotypes, most of whom (4 of 6) were patients with GD2. The [p.S384F + p.W533*] being compounded with p.L483P, was found in the patient with neonatal GD, suggesting that the p.S384F could potentiate the deleterious effect of the p.W533*, and/or vice versa.ConclusionsNeuronopathic GD was strikingly prevalent among Thai affected population. Homozygous p.L483P was the most common genotype identified in Thai patients. Recombinant allele Rec1a and splicing mutations were associated with GD2 and severe cases of GD3. Mutation spectrum could be useful for designing stepwise molecular analysis, genetic screenings in population, and new therapeutic research for neuronopathic GD.

Project description:BackgroundAbout 80% of the roughly 7,000 known rare diseases are single gene disorders, about 85% of which are ultra-rare, affecting less than one in one million individuals. NGS technologies, in particular whole genome sequencing (WGS) in paediatric patients suffering from severe disorders of likely genetic origin improve the diagnostic yield allowing targeted, effective care and management. The aim of this study is to perform a systematic review and meta-analysis to assess the effectiveness of WGS, with respect to whole exome sequencing (WES) and/or usual care, for the diagnosis of suspected genetic disorders among the paediatric population.MethodsA systematic review of the literature was conducted querying relevant electronic databases, including MEDLINE, EMBASE, ISI Web of Science, and Scopus from January 2010 to June 2022. A random-effect meta-analysis was run to inspect the diagnostic yield of different techniques. A network meta-analysis was also performed to directly assess the comparison between WGS and WES.ResultsOf the 4,927 initially retrieved articles, thirty-nine met the inclusion criteria. Overall results highlighted a significantly higher pooled diagnostic yield for WGS, 38.6% (95% CI: [32.6 - 45.0]), in respect to WES, 37.8% (95% CI: [32.9 - 42.9]) and usual care, 7.8% (95% CI: [4.4 - 13.2]). The meta-regression output suggested a higher diagnostic yield of the WGS compared to WES after controlling for the type of disease (monogenic vs non-monogenic), with a tendency to better diagnostic performances for Mendelian diseases. The network meta-analysis showed a higher diagnostic yield for WGS compared to WES (OR = 1.54, 95%CI: [1.11 - 2.12]).ConclusionsAlthough whole genome sequencing for the paediatric population with suspected genetic disorders provided an accurate and early genetic diagnosis in a high proportion of cases, further research is needed for evaluating costs, effectiveness, and cost-effectiveness of WGS and achieving an informed decision-making process.Trial registrationThis systematic review has not been registered.

Dataset Information

Utilisation of exome sequencing for muscular disorders in Thai paediatric patients: diagnostic yield and mutational spectrum.

Publications

Utilisation of exome sequencing for muscular disorders in Thai paediatric patients: diagnostic yield and mutational spectrum.

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