Mutation screening of the USH2A gene reveals two novel pathogenic variants in Chinese patients causing simplex usher syndrome 2

Background: Chordoma is a rare bone cancer with an unknown etiology. TBXT is the only chordoma susceptibility gene identified to date; germline single nucleotide variants and copy number variants in TBXT have been associated with chordoma susceptibility in familial and sporadic chordoma. However, the genetic susceptibility of chordoma remains largely unknown. In this study, we investigated rare germline genetic variants in genes involved in TBXT/chordoma-related signaling pathways and other biological processes in chordoma patients from North America and China. Methods: We identified variants that were very rare in general population and internal control datasets and showed evidence for pathogenicity in 265 genes in a whole exome sequencing (WES) dataset of 138 chordoma patients of European ancestry and in a whole genome sequencing (WGS) dataset of 80 Chinese patients with skull base chordoma. Results: Rare and likely pathogenic variants were identified in 32 of 138 European ancestry patients (23%), including genes that are part of notochord development, PI3K/AKT/mTOR, Sonic Hedgehog, SWI/SNF complex and mesoderm development pathways. Rare pathogenic variants in COL2A1, EXT1, PDK1, LRP2, TBXT and TSC2, among others, were also observed in Chinese patients. Conclusion: We identified several rare loss-of-function and predicted deleterious missense variants in germline DNA from patients with chordoma, which may influence chordoma predisposition and reflect a complex susceptibility, warranting further investigation in large studies.

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Prevalent Pathogenic Variants of ATP7B in Chinese Patients with Wilson’s Disease: Geographical Distribution and Founder Effect

Genes ◽

10.3390/genes12030336 ◽

2021 ◽

Vol 12 (3) ◽

pp. 336

Author(s):

Guo-Min Yang ◽

Rou-Min Wang ◽

Nan Xia ◽

Zi-Wei Zheng ◽

Yi Dong ◽

...

Keyword(s):

Geographical Distribution ◽

Founder Effect ◽

Wilson’S Disease ◽

Autosomal Recessive Disorder ◽

Wilson's Disease ◽

Chinese Patients ◽

Mainland Chinese ◽

Pathogenic Variants ◽

Specific Distribution ◽

The Common

Wilson’s disease (WD) is an autosomal recessive disorder caused by ATP7B pathogenic variants. This study aimed to show the geographical distribution and haplotype spectrum of three prevalent pathogenic variants (p.R778L, p.P992L, p.T935M) in mainland Chinese population and clarify whether the founder effect may account for their origins. We firstly summarized the frequency and geographical distribution of p.R778L, p.P992L and p.T935M in 715 WD patients. Then, to construct haplotypes associated with the three variants, Sanger sequencing and microsatellite typing at three dinucleotide-repeat markers (D13S314, D13S301, D13S316) flanking the ATP7B gene were performed in 102 WD families. An obvious regional-specific distribution feature was found in p.T935M. Linkage disequilibrium at the three markers was shown in all the three variants and we found the common haplotypes specific for p.R778L, p.P992L and p.T935M respectively, represented successively by 10-7-7, 10-9-5 and 12-4-8, which all exhibited great significance vs. the control chromosomes (p < 0.01). Meanwhile, haplotypes for the three variants differed from the studies in other regions to some extent. The common haplotypes we found indicate that three prevalent pathogenic variants emerge due to the founder effect. Furthermore, the study contributes to expand our knowledge of the genetic diversity of WD from a cross-regional perspective.

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Novel SCN5A and GPD1L Variants Identified in Two Unrelated Han-Chinese Patients With Clinically Suspected Brugada Syndrome

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.758903 ◽

2021 ◽

Vol 8 ◽

Author(s):

Meng Yuan ◽

Yi Guo ◽

Hong Xia ◽

Hongbo Xu ◽

Hao Deng ◽

...

Keyword(s):

Brugada Syndrome ◽

Missense Variant ◽

Han Chinese ◽

Chinese Patients ◽

Splicing Variant ◽

Pathogenic Variants ◽

Whole Exome ◽

Gated Channel ◽

Life Threatening ◽

Glycerol 3 Phosphate Dehydrogenase

Brugada syndrome (BrS) is a complexly genetically patterned, rare, malignant, life-threatening arrhythmia disorder. It is autosomal dominant in most cases and characterized by identifiable electrocardiographic patterns, recurrent syncope, nocturnal agonal respiration, and other symptoms, including sudden cardiac death. Over the last 2 decades, a great number of variants have been identified in more than 36 pathogenic or susceptibility genes associated with BrS. The present study used the combined method of whole exome sequencing and Sanger sequencing to identify pathogenic variants in two unrelated Han-Chinese patients with clinically suspected BrS. Minigene splicing assay was used to evaluate the effects of the splicing variant. A novel heterozygous splicing variant c.2437-2A>C in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) and a novel heterozygous missense variant c.161A>T [p.(Asp54Val)] in the glycerol-3-phosphate dehydrogenase 1 like gene (GPD1L) were identified in these two patients with BrS-1 and possible BrS-2, respectively. Minigene splicing assay indicated the deletion of 15 and 141 nucleotides in exon 16, resulting in critical amino acid deletions. These findings expand the variant spectrum of SCN5A and GPD1L, which can be beneficial to genetic counseling and prenatal diagnosis.

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The Frequency of Familial Mediterranean Fever Gene Mutations and the Correlations between Phenotype and Genotype in Turkish Children

Asian Journal of Pediatric Research ◽

10.9734/ajpr/2020/v4i230145 ◽

2020 ◽

pp. 20-26

Author(s):

Hakan Erdogan ◽

Ayse Cavidan Sonkur ◽

Orhan Görükmez ◽

Ayse Erdogan ◽

Dilek Damla Saymazlar ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Mutation Screening ◽

Mefv Gene ◽

Gene Mutations ◽

Retrospective Case ◽

Turkish Children ◽

Pathogenic Variants ◽

Frequent Mutations ◽

Training And Research ◽

Mediterranean Fever

Aim: Familial Mediterranian Fever is an autosomal recessive disease characterized by recurrent inflammatory attacks of serosal membranes. The aim of the current study was to determine the frequency of the Mediterranean fever (MEFV) gene pathogenic variants in 158 children (78 male, 80 female) diagnosed with Familial Mediterranean Fever (FMF) and to compare the phenotype-genotype correlation. Methods: In our retrospective case-control study, 158 FMF patients (78 males, 80 females) who were diagnosed with MEFV gene mutation in Bursa Yuksek Ihtisas Training and Research Hospital, Department of Pediatrics between January 2018 and June 2019 were included in the study. Mutation screening of the MEFV gene was performed for 12 mutations and the 8 most common mutations were taken into the study. Results: Abdominal pain (77.8%), fever (74%) and arthralgia (46.2%) were the most prevalent clinical features in our patients. The most frequent mutations were M694V, E148Q, V726A, M680I and P369S. In cases with M694 mutation, it was noted that the incidence of arthritis was 2.5 times, appendectomy frequency 3.1 times higher, and early diagnosis probability 3.2 times higher. The frequency of chest pain was 2.9 times higher in the M680I mutation, and the frequency of arthralgia was 2.2 times higher in the P369S mutation. Conclusion: Patient’s mutations in FMF patients are important for clinical expectations, and some mutations such as P369S are not as innocent as expected. However, reevaluation of phenotypes of mutations that are rare with more patients will be significant.

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Phenotype Analysis and Genetic Study of Chinese Patients With Treacher Collins Syndrome

The Cleft Palate-Craniofacial Journal ◽

10.1177/10556656211037509 ◽

2021 ◽

pp. 105566562110375

Author(s):

Meng Lu ◽

Bin Yang ◽

Zixiang Chen ◽

Haiyue Jiang ◽

Bo Pan

Keyword(s):

Rare Variants ◽

Clinical Care ◽

Treacher Collins Syndrome ◽

Chinese Patients ◽

Pathogenic Variants ◽

Premature Termination Codons ◽

Whole Exome ◽

Exome Aggregation Consortium ◽

Phenotype Analysis ◽

Sporadic Cases

Objective The aim of this study was to confirm the pathogenic variants, explore the genotype–phenotype correlation and characteristics of Chinese patients with Treacher Collins syndrome (TCS). Design Clinical details of 3 TCS family cases and 2 sporadic cases were collected and analyzed. Whole-exome sequencing and Sanger sequencing were conducted to detect causative variants. Setting Tertiary clinical care. Patients This study included 8 patients clinically diagnosed with TCS who were from 3 familial cases and 2 sporadic cases. Main Outcome Measures When filtering the database, variants were saved as rare variants if their frequency were less than 0.005 in the 1000 Genomes Project Database, the Exome Aggregation Consortium (ExAC) browser, and the Novogene database, or they would be removed as common ones. The pathogenic variants identified were verified by polymerase chain reaction. The sequencing results were analyzed by Chromas 2.1 software. Results Two novel pathogenic variants (NM_000356.3: c.537del and NM_000356.3: c.1965_1966dupGG) and 2 known pathogenic variants (NM_000356.3: c.1535del, NM_000356.3: c.4131_4135del) were identified within TCOF1 which are predicted to lead to premature termination codons resulting in a truncated protein. There was a known missense SNP (NM_015972.3: c.139G>A) within POLR1D. No phenotype–genotype correlation was observed. Instead, these 8 patients demonstrated the high genotypic and phenotypic heterogeneity of TCS. Conclusions This study expands on the pathogenic gene pool of Chinese patients with TCS. Besides the great variation among patients which is similar to international reports, Chinese patients have their own characteristics in clinical phenotype and pathogenesis mutations.

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Mutation screening and burden analysis of GLT8D1 in Chinese patients with ALS

10.21203/rs.3.rs-26967/v1 ◽

2020 ◽

Author(s):

Bei Cao ◽

Xiaojing Gu ◽

Qianqian Wei ◽

Chunyu Li ◽

Yongping Chen ◽

...

Keyword(s):

Rare Variants ◽

Mutation Screening ◽

Large Cohort ◽

Chinese Patients ◽

Causative Gene ◽

Variant Of Uncertain Significance ◽

Sporadic Als ◽

Gene Level ◽

Exon 4

Abstract Objective Glycosyltransfersase 8 domain containing 1 ( GLT8D1 ) gene was identified to be an amyotrophic lateral sclerosis (ALS) causative gene via pedigree co-segregation and burden analysis. However, validations based on large cohort of ALS among different ethnic population are essential. We aimed to systematically screen all exons of GLT8D1 in a large cohort of Chinese ALS patients, study the genotype-phenotype correlation and explore the role of rare variants of GLT8D1 in ALS.Methods A total of 977 sporadic ALS (sALS) and 47 familial ALS (fALS) cases underwent whole exome sequencing. Rare variants with MAF<0.1% in GLT8D1 were analyzed. Moreover, by using the controls from gnomAD database, rare variants were included in the burden analysis via 5 different algorithms.Results We identified 1 likely pathogenic variant in the exon 4 of GLT8D1 in a fALS case and validated within the pedigree. Moreover, 3 variant of uncertain significance (VUS) in 4 patients among the 977 sALS cases 1 VUS in 1 case among the 47 fALS cases were also identified. Furthermore, in the burden analysis, there were no significant enrichment of rare variants of GLT8D1 in the whole gene level or exon 4 exclusively among Chinese patients with sALS.Conclusion Cosegregation findings in our study further supported the pathogenic role of GLT8D1 in fALS. However, no pathogenic mutation was identified in the sALS patients, and rare variants were not enriched in the whole gene level or exon 4 of GLT8D1 among sALS patients, both of which suggested that the GLT8D1 may not play a role in Chinese patients with sALS.

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Novel Usher syndrome pathogenic variants identified in cases with hearing and vision loss

BMC Medical Genetics ◽

10.1186/s12881-019-0777-z ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 4

Author(s):

Justin A. Pater ◽

Jane Green ◽

Darren D. O’Rielly ◽

Anne Griffin ◽

Jessica Squires ◽

...

Keyword(s):

Vision Loss ◽

Usher Syndrome ◽

Pathogenic Variants

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Genotypic characteristics of Chinese patients with BHD syndrome and functional analysis of FLCN variants

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1198-y ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 2

Author(s):

Keqiang Liu ◽

Wenshuai Xu ◽

Xinlun Tian ◽

Meng Xiao ◽

Xinyue Zhao ◽

...

Keyword(s):

Clinical Features ◽

Spontaneous Pneumothorax ◽

Mutation Screening ◽

Skin Lesions ◽

Mrna Splicing ◽

Mutation Spectrum ◽

Chinese Patients ◽

Renal Tumors ◽

Lung Cysts ◽

Splicing Pattern

Abstract Background Birt-Hogg-Dubé syndrome (BHDS) is an autosomal dominant disease featured by lung cysts, spontaneous pneumothorax, fibrofolliculomas and renal tumors. The causative gene for BHDS is the folliculin (FLCN) gene and more than 200 mutations have been reported in FLCN, mostly truncating mutations. The aim of this study is to better characterize the clinical features and mutation spectrum of Chinese BHDS patients and to systematically evaluate the effects of non-truncating mutations on mRNA splicing pattern. Methods We enrolled 47 patients from 39 unrelated families with symptoms highly suggestive of BHDS after informed consent and detailed clinical data were collected. Exon sequencing followed by multiplex ligation-dependent probe amplification testing were applied for mutation screening. The effects of non-truncating mutations, including 15 missense mutations and 6 in-frame deletions, on mRNA splicing were investigated by minigene assays. Results A total of 24 FLCN germline variants were found in 39 patients from 31 distinct families. Out of these patients, 100% (36/36) presented with lung cysts and 58.3% (21/36) had experienced spontaneous pneumothorax. Seventeen mutation carriers had skin lesions (47.2%, 17/36) and 9 (30%, 9/30) had kidney lesions including 8 with renal cysts and 1 with renal hamartoma. Among all detected variants 14 (58.3%, 14/24) were novel, including 11 variants classified to be pathogenic and 3 variants of uncertain significance. None of 21 non-truncating mutations changed the mRNA splicing pattern of minigenes. Conclusions We found different clinical features of Chinese BHDS patients compared with Caucasians, with more lung cysts and pneumothorax but fewer skin lesions and malignant renal cancer. Chinese patients with BHDS also have a different mutation spectrum from other races. Non-truncating mutations in FLCN did not disrupt mRNA splicing pattern, in turn supporting the hypothesis that these mutations impair folliculin function by disrupting the stability of the FLCN gene product.

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Next Generation Sequencing Identifies Five Novel Mutations in Lebanese Patients with Bardet–Biedl and Usher Syndromes

Genes ◽

10.3390/genes10121047 ◽

2019 ◽

Vol 10 (12) ◽

pp. 1047 ◽

Cited By ~ 1

Author(s):

Lama Jaffal ◽

Wissam H Joumaa ◽

Alexandre Assi ◽

Charles Helou ◽

George Cherfan ◽

...

Keyword(s):

Next Generation Sequencing ◽

Usher Syndrome ◽

Bioinformatic Analysis ◽

Next Generation ◽

Novel Mutations ◽

Pathogenic Variants ◽

Whole Exome ◽

Targeted Ngs ◽

Next Generation Sequencing Ngs ◽

Generation Sequencing

Aim: To identify disease-causing mutations in four Lebanese families: three families with Bardet–Biedl and one family with Usher syndrome (BBS and USH respectively), using next generation sequencing (NGS). Methods: We applied targeted NGS in two families and whole exome sequencing (WES) in two other families. Pathogenicity of candidate mutations was evaluated according to frequency, conservation, in silico prediction tools, segregation with disease, and compatibility with inheritance pattern. The presence of pathogenic variants was confirmed via Sanger sequencing followed by segregation analysis. Results: Most likely disease-causing mutations were identified in all included patients. In BBS patients, we found (M1): c.2258A > T, p. (Glu753Val) in BBS9, (M2): c.68T > C; p. (Leu23Pro) in ARL6, (M3): c.265_266delTT; p. (Leu89Valfs*11) and (M4): c.880T > G; p. (Tyr294Asp) in BBS12. A previously known variant (M5): c.551A > G; p. (Asp184Ser) was also detected in BBS5. In the USH patient, we found (M6): c.188A > C, p. (Tyr63Ser) in CLRN1. M2, M3, M4, and M6 were novel. All of the candidate mutations were shown to be likely disease-causing through our bioinformatic analysis. They also segregated with the corresponding phenotype in available family members. Conclusion: This study expanded the mutational spectrum and showed the genetic diversity of BBS and USH. It also spotlighted the efficiency of NGS techniques in revealing mutations underlying clinically and genetically heterogeneous disorders.

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