Dataset Information

Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing.

ABSTRACT: This study aimed to study the diagnostic value of targeted next-generation sequencing (NGS) in limb-girdle muscular dystrophies (LGMDs), and investigate the mutational spectrum of Chinese LGMD patients. We performed targeted NGS covering 420 genes in 180 patients who were consecutively suspected of LGMDs and underwent muscle biopsies from January 2013 to May 2015. The association between genotype and myopathological profiles was analyzed in the genetically confirmed LGMD patients. With targeted NGS, one or more rare variants were detected in 138 patients, of whom 113 had causative mutations, 10 sporadic patients had one pathogenic heterozygous mutation related to a recessive pattern of LGMDs, and 15 had variants of uncertain significance. No disease-causing mutation was found in the remaining 42 patients. Combined with the myopathological findings, we achieved a positive genetic diagnostic rate as 68.3% (123/180). Totally 105 patients were diagnosed as LGMDs with genetic basis. Among these 105 patients, the most common subtypes were LGMD2B in 52 (49.5%), LGMD2A in 26 (24.8%) and LGMD 2D in eight (7.6%), followed by LGMD1B in seven (6.7%), LGMD1E in four (3.8%), LGMD2I in three (2.9%), and LGMD2E, 2F, 2H, 2K, 2L in one patient (1.0%), respectively. Although some characteristic pathological changes may suggest certain LGMD subtypes, both heterogeneous findings in a certain subtype and overlapping presentations among different subtypes were not uncommon. The application of NGS, together with thorough clinical and myopathological evaluation, can substantially improve the molecular diagnostic rate in LGMDs. Confirming the genetic diagnosis in LGMD patients can help improve our understanding of their myopathological changes.

SUBMITTER: Yu M

PROVIDER: S-EPMC5389788 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing.

Yu Meng M Zheng Yiming Y Jin Suqin S Gang Qiang Q Wang Qingqing Q Yu Peng P Lv He H Zhang Wei W Yuan Yun Y Wang Zhaoxia Z

PloS one 20170412 4

This study aimed to study the diagnostic value of targeted next-generation sequencing (NGS) in limb-girdle muscular dystrophies (LGMDs), and investigate the mutational spectrum of Chinese LGMD patients. We performed targeted NGS covering 420 genes in 180 patients who were consecutively suspected of LGMDs and underwent muscle biopsies from January 2013 to May 2015. The association between genotype and myopathological profiles was analyzed in the genetically confirmed LGMD patients. With targeted ...[more]

PMID: 28403181

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Project description:PurposeRetinoblastoma (RB) is a pediatric ocular malignancy due to biallelic inactivation of the RB1 gene. Genetic testing is critically important for treatment decisions for this disease. Targeted next-generation sequencing (NGS) has been demonstrated to be an effective strategy for discovering all types of mutations in the RB1 gene. The aim of this study is the application of targeted NGS in a cohort of Chinese patients with retinoblastoma to identify germline mutations in the RB1 gene.MethodsBlood samples were collected from 149 unrelated probands with retinoblastoma (62 bilaterally and 87 unilaterally) and their parent(s). Genomic DNA was analyzed with custom panel-based targeted NGS, and the panel was designed to include exons 1-27 of the RB1 gene with flanking intronic sequences. Single nucleotide variations (SNVs) and small insertions/deletions (InDels) identified were confirmed with Sanger sequencing. If the Sanger sequencing of a low-frequency variant (LFV) detected with targeted NGS was negative, PCR-based deep NGS was conducted for added confirmation. Copy number variations (CNVs) detected with targeted NGS were confirmed with multiplex ligation-dependent probe amplification (MLPA).ResultsOverall, 74 germline mutations were detected in 48.3% of the probands (72/149, 56 bilateral and 16 unilateral cases). The total detection rate in the bilateral cases was 90.3% (56/62). These mutations included 64 SNVs and InDels (25 nonsense, 20 splicing, ten frameshift, eight missense, and one synonymous variants) and ten CNVs. All CNVs were confirmed with MLPA. Twenty-four (32.4%, 24/74) variants detected were novel, including nine splicing, six frameshift, five missense, and four nonsense variants. Eight LFVs (10.8%, 8/74) were found with targeted NGS; six of which were identified with Sanger sequencing, and two were identified with PCR-based deep NGS (13.16% and 3.000% mutant rates, respectively).ConclusionsThis study expanded the spectrum of germline mutations in RB1 using targeted NGS technology, which is a cost-saving and efficient method for genetic sequencing of retinoblastoma and may improve the molecular diagnosis of retinoblastoma.

Dataset Information

Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing.

Publications

Mutational spectrum of Chinese LGMD patients by targeted next-generation sequencing.

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