Author Correction: Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease in Chinese Han population

AbstractMaple syrup urine disease (MSUD) is a rare autosomal recessive disorder that affects the degradation of branched chain amino acids (BCAAs). Only a few cases of MSUD have been documented in Mainland China. In this report, 8 patients (4 females and 4 males) with MSUD from 8 unrelated Chinese Han families were diagnosed at the age of 6 days to 4 months. All the coding regions and exon/intron boundaries of BCKDHA, BCDKHB, DBT and DLD genes were analyzed by targeted NGS in the 8 MSUD pedigrees. Targeted NGS revealed 2 pedigrees with MSUD Ia, 5 pedigrees with Ib, 1 pedigree with MSUD II. Totally, 13 variants were detected, including 2 variants (p.Ala216Val and p.Gly281Arg) in BCKDHA gene, 10 variants (p.Gly95Ala, p.Ser171Pro, p.Phe175Leu, p.Arg183Trp, p.Lys222Thr, p.Arg285Ter, p.Arg111Ter, p.S184Pfs*46, p.Arg170Cys, p.I160Ffs*25) in BCKDHB gene, 1 variant (p.Arg431Ter) in DBT gene. In addition, 4 previously unidentified variants (p.Gly281Arg in BCKDHA gene, p.Ser171Pro, p.Gly95Ala and p.Lys222Thr in BCKDHB gene) were identified. NGS plus Sanger sequencing detection is effective and accurate for gene diagnosis. Computational structural modeling indicated that these novel variations probably affect structural stability and considered as likely pathogenic variants.

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Compound Heterozygous Mutations in TMC1 and MYO15A Are Associated with Autosomal Recessive Nonsyndromic Hearing Loss in Two Chinese Han Families

Neural Plasticity ◽

10.1155/2020/8872185 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7

Author(s):

Pengcheng Xu ◽

Jun Xu ◽

Hu Peng ◽

Tao Yang

Keyword(s):

Hearing Loss ◽

Next Generation Sequencing ◽

Genetic Diagnosis ◽

Compound Heterozygous ◽

Next Generation ◽

Chinese Han ◽

Targeted Next Generation Sequencing ◽

Recessive Mutations ◽

Compound Heterozygous Mutations ◽

Generation Sequencing

Genetic hearing loss is a common sensory disorder, and its cause is highly heterogeneous. In this study, by targeted next-generation sequencing of 414 known deafness genes, we identified compound heterozygous mutations p.R34X/p.M413T in TMC1 and p.S3417del/p.R1407T in MYO15A in two recessive Chinese Han deaf families. Intrafamilial cosegregation of the mutations with the hearing phenotype was confirmed in both families by the Sanger sequencing. Auditory features of the affected individuals are consistent with that previously reported for recessive mutations in TMC1 and MYO15A. The two novel mutations identified in this study, p.M413T in TMC1 and p.R1407T in MYO15A, are classified as likely pathogenic according to the guidelines of ACMG. Our study expanded the mutation spectrums of TMC1 and MYO15A and illustrated that genotype-phenotype correlation in combination with next-generation sequencing may improve the accuracy for genetic diagnosis of deafness.

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Targeted Next-Generation Sequencing Identified Compound Heterozygous Mutations in MYO15A as the Probable Cause of Nonsyndromic Deafness in a Chinese Han Family

Neural Plasticity ◽

10.1155/2020/6350479 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Longhao Wang ◽

Lin Zhao ◽

Hu Peng ◽

Jun Xu ◽

Yun Lin ◽

...

Keyword(s):

Hearing Loss ◽

Next Generation Sequencing ◽

Cochlear Implantation ◽

Compound Heterozygous ◽

Next Generation ◽

Chinese Han ◽

Targeted Next Generation Sequencing ◽

Before And After ◽

Compound Heterozygous Mutations ◽

Generation Sequencing

Hearing loss is a highly heterogeneous disorder, with more than 60% of congenital cases caused by genetic factors. This study is aimed at identifying the genetic cause of congenital hearing loss in a Chinese Han family. Auditory evaluation before and after cochlear implantation and targeted next-generation sequencing of 140 deafness-related genes were performed for the deaf proband. Compound heterozygous mutations c.3658_3662del (p. E1221Wfs∗23) and c.6177+1G>T were identified in MYO15A as the only candidate pathogenic mutations cosegregated with the hearing loss in this family. These two variants were absent in 200 normal-hearing Chinese Hans and were classified as likely pathogenic and pathogenic, respectively, based on the ACMG guideline. Our study further expanded the mutation spectrum of MYO15A as the c.3658_3662del mutation is novel and confirmed that deaf patients with recessive MYO15A mutations have a good outcome for cochlear implantation.

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Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease

10.21203/rs.3.rs-221149/v1 ◽

2021 ◽

Author(s):

Xiaohua Fang ◽

Xiaofan Zhu ◽

Yin Feng ◽

Ying Bai ◽

Xuechao Zhao ◽

...

Keyword(s):

Maple Syrup Urine Disease ◽

Mainland China ◽

Autosomal Recessive Disorder ◽

Maple Syrup ◽

Targeted Next Generation Sequencing ◽

Coding Regions ◽

Targeted Ngs ◽

Urine Disease ◽

Bckdhb Gene ◽

Branched Chain

Abstract Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder that affects the degradation of branched chain amino acids (BCAAs). Only a few cases of MSUD have been documented in Mainland China. In this report, 8 patients (4 girls and 4 boys) with MSUD from 8 unrelated Chinese families were diagnosed at the age of 9 days to 1 year and 8 months. All the coding regions and exon/intron boundaries of BCKDHA, BCDKHB, DBT, DLD genes were analyzed by targeted NGS in the 8 MSUD pedigrees. Targeted NGS revealed 2 pedigrees with MSUD Ia, 5 pedigrees with Ib, 1 pedigree with MSUD II. Totally, 13 variants were detected, including 2 variants (p.Ala216Val and p.Gly281Arg) in BCKDHA gene，10 variants (p.Gly95Ala, p.Ser171Pro, p.Phe175Leu, p.Arg183Trp, p.Lys222Thr, p.Arg285Ter，p.Arg111Ter，p.S184Pfs*46, p.Arg170Cys, p.I160Ffs*25) in BCKDHB gene, 1 variants (p.Arg431Ter) in DBT gene. In addition, 4 previously unidentified variants (p.Gly281Arg in BCKDHA gene, p.Ser171Pro, p.Gly95Ala and p.Lys222Thr in BCKDHB gene) were found. NGS plus Sanger sequencing detection is effective and accurate for making gene diagnosis. Computational structural modeling indicated that these novel variations might affect structural stability.

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Clinical and genetic study of twelve Chinese Han families with non-syndromic deafness

10.21203/rs.2.17760/v1 ◽

2019 ◽

Author(s):

Di Wu ◽

Weiyuan Huang ◽

Shuo Li ◽

Jie Zhang ◽

Xiaohua Chen ◽

...

Keyword(s):

Hearing Loss ◽

Next Generation Sequencing ◽

Accurate Diagnosis ◽

Next Generation ◽

Phenotype Correlation ◽

Chinese Han ◽

Targeted Next Generation Sequencing ◽

Whole Exome ◽

Syndromic Hearing Loss ◽

Generation Sequencing

Abstract BACKGROUND: Non-syndromic hearing loss is clinically and genetically heterogeneous. In this study, we characterized the clinical features of twelve Chinese Han deaf families in which mutations in common deafness genes GJB2 , SLC26A4 and MT-RNR1 were excluded. RESULTS: Targeted next-generation sequencing of 147 known deafness genes was performed in probands of ten families, while whole-exome sequencing was applied in those of the rest two. Pathogenic mutations in a total of 11 rare deafness genes, OTOF , CDH23 , PCDH15 , PDZD7 , ADGRV1 , KARS , OTOG , GRXCR2 , MYO6 , GRHL2 , and POU3F4 , were identified in all 12 probands, with 17 mutations being novel. Intrafamilial co-segregation of the mutations and the deafness phenotype were confirmed by Sanger sequencing. CONCLUSIONS: Our results expanded the mutation spectrum and genotype-phenotype correlation of non-syndromic hearing loss in Chinese Hans and also emphasized the importance of combining both next-generation sequencing and detailed auditory evaluation to achieve a more accurate diagnosis for non-syndromic hearing loss.

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Novel mutations identified in the Chinese Han population with keratoconus by next-generation sequencing

10.21203/rs.3.rs-121907/v1 ◽

2020 ◽

Author(s):

Binbin Chen ◽

Xiaoning Yu ◽

Xin Zhang ◽

Hao Yang ◽

Yilei Cui ◽

...

Keyword(s):

Next Generation Sequencing ◽

Chinese Han Population ◽

Chinese Patients ◽

Genome Wide Association Studies ◽

Next Generation ◽

Sequencing Technology ◽

Novel Mutations ◽

Chinese Han ◽

Han Population ◽

Generation Sequencing

Abstract BACKGROUND Keratoconus (KC) is characterized by bilateral progressive corneal thinning and ectasia. The prevalence of KC is approximately 8.8 to 54.4 per 100,000 individuals across the globe. Genetic factors have been shown to contribute to the pathogenesis of KC. This study will identify new mutations in the susceptibility gene of keratoconus (KC) in the Chinese Han population. METHODS A total of fifty-two patients with primary KC were recruited. Blood samples were collected, and genomic DNA was isolated from peripheral blood leukocytes. The entire coding region, intron–exon junctions, and promoter regions of sixteen known KC susceptibility genes were screened with next-generation sequencing technology, and all identified variants were further confirmed using the Sanger sequencing technology. The Sorting Intolerant from Tolerant (SIFT), Mutation Taster and PolyPhen 2 programs were used to predict the effect of amino acid substitution on protein. RESULTS After removing twelve known SNPs (single nucleotide polymorphisms) and three variants predicted to be harmless, nine novel mutations were identified in eight of the fifty-two patients, including c.455C > T:p.P152L in FNDC3B, c.3636_3637del:p.R1212fs in COL4A4, c.5015G > T:p.R1672L, c.3798dupA:p.P1267fs and c.28G > A:p.A10T in MPDZ, c.1940C > T:p.P647L in DOCK9, c.127_128insGGC:p.Q43delinsRQ in POLG, c.3019G > A:p.V1007I in IPO5, and c.624 + 7->A in TGFBI. All nine mutations in the patients with KC were heterozygote. CONCLUSION This study enlarged the gene profile of KC and should be further confirmed by well-powered, genome-wide association studies (GWAS) of Han Chinese patients.

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Targeted next-generation sequencing in papillary thyroid carcinoma of Chinese Han population.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17574 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17574-e17574

Author(s):

Jie Liu ◽

Huizheng Li ◽

Rong Du ◽

Nan Fang ◽

Jingbo Zhang ◽

...

Keyword(s):

Thyroid Cancer ◽

Next Generation Sequencing ◽

Papillary Thyroid Carcinoma ◽

Gene Mutations ◽

Braf V600e Mutation ◽

Braf V600e ◽

Papillary Thyroid ◽

Chinese Han ◽

Han Population ◽

Generation Sequencing

e17574 Background: Papillary Thyroid Carcinoma (PTC) is the most common type of thyroid cancer. Developments in next-generation sequencing (NGS) technology can help to disclose the genotype of PTC in the Chinese Han population. Methods: A total of 50 patients with PTC who underwent thyroidectomy in 2015-2018 at the Affiliated Dalian Friendship Hospital of Medical University were enrolled. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 57 thyroid cancer-associated genes were amplified, barcoded and sequenced using an Illumina MiSeq 500 platform. Results: A total of 591 mutations were detected in 50 samples, including 514 missense mutations (87%), 39 frameshift mutations (6.6%), 22 stop-gain (3.7%) and 16 indel (2.7%) variants. Among them, only 64 mutations have been studied with cancer clinical relevance. The BRAF V600E mutation was present in 42 of 50 (84%) patients, and was the most common mutation. The CHEK2 mutation was present in 27 of 50 (54%) patients. The 10 most important genes with mutations included AKT1 (34%), EIF1AX( 30%), ATM (20%) , MED12 (18%) , NF1 (18%), RET (18%), RBM10 (16%) and TERT (12%). Among them, the CHEK2, AKT1 and EIF1AX mutations were always concomitant with the BRAF V600E mutation, which is controversial to previous studies. Only two samples had no mutation tested. The medium mutation is 11 muts/sample. Six samples had more than 10 occurrences of gene mutations. However, the mutation burden has no relevance to lymph node metastasis or other pathological prognostic factors. Conclusions: BRAF V600E is the most common and important mutation in PTC, but there are also many other genes that mutate in this disease. The gene mutation in PTC varies in different patients, but no relevance between pathological factors and gene mutations have been founded . However, the discovery of the gene mutation spectrum in the Han Chinese population with PTC could enhance the understanding of this disease’s clinical behavior.

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Targeted Next-Generation Sequencing Identifies Separate Causes of Hearing Loss in One Deaf Family and Variable Clinical Manifestations for the p.R161C Mutation in SOX10

Neural Plasticity ◽

10.1155/2020/8860837 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Xiaoyu Yu ◽

Yun Lin ◽

Hao Wu

Keyword(s):

Hearing Loss ◽

Next Generation Sequencing ◽

Hypogonadotropic Hypogonadism ◽

Family Members ◽

Clinical Manifestations ◽

Next Generation ◽

Chinese Han ◽

Targeted Next Generation Sequencing ◽

Wide Range ◽

Generation Sequencing

Hearing loss is the most common sensory deficit in humans. Identifying the genetic cause and genotype-phenotype correlation of hearing loss is sometimes challenging due to extensive clinical and genetic heterogeneity. In this study, we applied targeted next-generation sequencing (NGS) to resolve the genetic etiology of hearing loss in a Chinese Han family with multiple affected family members. Targeted sequencing of 415 deafness-related genes identified the heterozygous c.481C>T (p.R161C) mutation in SOX10 and the homozygous c.235delC (p.L79Cfs∗3) mutation in GJB2 as separate pathogenic mutations in distinct affected family members. The SOX10 c.481C>T (p.R161C) mutation has been previously reported in a Caucasian patient with Kallmann syndrome that features congenital hypogonadotropic hypogonadism with anosmia. In contrast, family members carrying the same p.R161C mutation in this study had variable Waardenburg syndrome-associated phenotypes (hearing loss and/or hair hypopigmentation) without olfactory or reproductive anomalies. Our results highlight the importance of applying comprehensive diagnostic approaches such as NGS in molecular diagnosis of hearing loss and show that the p.R161C mutation in SOX10 may be associated with a wide range of variable clinical manifestations.

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