Novel pathogenic variants in the RECQL4 gene causing Rothmund‐Thomson syndrome in three Chinese patients

2021 ◽  
Author(s):  
Yingzi Zhang ◽  
Wen Qin ◽  
Huijun Wang ◽  
Zhimiao Lin ◽  
Zhanli Tang ◽  
...  
Keyword(s):  
Chinese Patients ◽  
Pathogenic Variants ◽  
Rothmund Thomson Syndrome

scholarly journals Rare Germline Variants in Chordoma-Related Genes and Chordoma Susceptibility

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2704
Author(s):  
Sally Yepes ◽  
Nirav N. Shah ◽  
Jiwei Bai ◽  
Hela Koka ◽  
Chuzhong Li ◽  
...  
Keyword(s):  
Internal Control ◽  
Susceptibility Gene ◽  
Copy Number Variants ◽  
Bone Cancer ◽  
Chinese Patients ◽  
European Ancestry ◽  
Unknown Etiology ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Pathogenic Variants

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.

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

Genes ◽  
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.

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

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&gt;C in the sodium voltage-gated channel alpha subunit 5 gene (SCN5A) and a novel heterozygous missense variant c.161A&gt;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.

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

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.

scholarly journals Mutational Spectrum Analysis of Seven Genes Associated with Thyroid Dyshormonogenesis

2018 ◽  
Vol 2018 ◽  
pp. 1-14 ◽  
Author(s):  
Xi Chen ◽  
Xiaohong Kong ◽  
Jie Zhu ◽  
Tingting Zhang ◽  
Yanwei Li ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Genetic Alterations ◽  
Chinese Patients ◽  
Study Cohort ◽  
Chinese Han ◽  
Hormone Synthesis ◽  
Functional Studies ◽  
Pathogenic Variants ◽  
Thyroid Dyshormonogenesis ◽  
Generation Sequencing

Objective. Thyroid dyshormonogenesis (DH) is a genetically heterogeneous inherited disorder caused by thyroid hormone synthesis abnormalities. This study aims at comprehensively characterizing the mutation spectrum in Chinese patients with DH. Subjects and Methods. We utilized next-generation sequencing to screen for mutations in seven DH-associated genes (TPO, DUOX2, TG, DUOXA2, SLC26A4, SLC5A5, and IYD) in 21 Chinese Han patients with DH from Xinjiang Province. Results. Twenty-eight rare nonpolymorphic variants were found in 19 patients (90.5%), including 19, 5, 3, and 1 variants in DUOX2, TG, DUOXA2, and SLC26A4, respectively. Thirteen (62%) patients carried monogenic mutations, and six (28.5%) carried oligogenic mutations. Fifteen (71%) patients carried 2 or more DUOX2 (14) or DUOXA2 (1) variants. The genetic basis of DH in nine (43%) patients harboring biallelic or triallelic pathogenic variants was resolved. Seventeen patients (81%) carried DUOX2 mutations, most commonly p.R1110Q or p.K530X. No correlations were found between DUOX2 mutation types or numbers and clinical phenotypes. Conclusions. DUOX2 mutations were the most predominant genetic alterations of DH in the study cohort. Oligogenicity may explain the genetic basis of disease in many DH patients. Functional studies and further clinical studies with larger DH patient cohorts are needed to validate the roles of the mutations identified in this study.

scholarly journals Analysis of the UGT1A1 Genotype in Hyperbilirubinemia Patients: Differences in Allele Frequency and Distribution

2019 ◽  
Vol 2019 ◽  
pp. 1-9
Author(s):  
Xiao-xiao Mi ◽  
Jian Yan ◽  
Xiao-jie Ma ◽  
Ge-li Zhu ◽  
Yi-dan Gao ◽  
...  
Keyword(s):  
Promoter Region ◽  
Direct Sequencing ◽  
Chinese Patients ◽  
Southeastern China ◽  
Unconjugated Hyperbilirubinemia ◽  
Gilbert Syndrome ◽  
Pathogenic Variants ◽  
Ethnic Populations ◽  
Age Range ◽  
Frequent Allele

Objective. The spectrum of UDP-glucuronyl transferase A1 (UGT1A1) variants in hereditary unconjugated hyperbilirubinemia varies markedly between different ethnic populations. This study evaluated the UGT1A1 genotypes in hyperbilirubinemia patients from southeastern China. Methods. We enrolled 60 patients from southeastern China (44 men and 16 women; age range: 3–76 years) with unconjugated hyperbilirubinemia and performed genetic analysis of the UGT1A1 gene by direct sequencing. Results. For patients with Gilbert syndrome, 85% (47/55) harbored pathogenic variants of UGT1A1⁎60. Both UGT1A1⁎28 and UGT1A1⁎81 were detected in the promoter region of UGT1A1. Additionally, 83% (20/24) of patients with Gilbert syndrome heterozygous for UGT1A1⁎60 had an association with heterozygous variation of UGT1A1⁎28 or UGT1A1⁎81, while 91% (21/23) of Gilbert syndrome patients homozygous for UGT1A1⁎60 had biallelic variations of UGT1A1⁎28 and UGT1A1⁎81. We detected 213 UGT1A1 allelic variants, including six novel variations, with the most frequent allele being the UGT1A1⁎60, followed by UGT1A1⁎28 and UGT1A1⁎6. All of the patients showed multiple sites of variants in UGT1A1; however, variation number was not associated with bilirubin levels (P>0.05). Conclusions. The spectrum of UGT1A1 variants in southeastern Chinese patients was distinct from other ethnic populations. Our findings broaden the knowledge concerning traits associated with UGT1A1 variants and help profile genotype–phenotype correlations in hyperbilirubinemia patients.

scholarly journals Report of Two Novel Mutations in Indian Patients with Rothmund–Thomson Syndrome

2019 ◽  
Vol 08 (03) ◽  
pp. 163-167
Author(s):  
Sakshi Yadav ◽  
Seema Thakur ◽  
Juergen Kohlhase ◽  
Neetu Bhari ◽  
Madhulika Kabra ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Supportive Therapy ◽  
Failure To Thrive ◽  
Autosomal Recessive Disorder ◽  
Skin Lesions ◽  
Poor Growth ◽  
Pathogenic Variants ◽  
Specific Distribution ◽  
Novel Variants ◽  
Rothmund Thomson Syndrome

AbstractRothmund–Thomson syndrome (RTS) is a rare autosomal recessive disorder caused by mutations in RECQL4 and has characteristic clinical features. We report two unrelated phenotypically diverse patients (cases 1 and 2) with RTS having novel variants in RECQL4 gene. Case-1 was evaluated for poor growth and recurrent fractures and skin lesions. Case-2 presented at 4 months with failure to thrive and radial ray defect and developed poikilodermatous skin lesions after infancy. Both cases were confirmed to have homozygous pathogenic variants in RECQL4. Both patients have normal intellect and are on supportive therapy. The presence of characteristic poikiloderma lesions with specific distribution and skeletal anomalies in a patient with proportionate short stature is a clue toward the diagnosis of RTS.

scholarly journals Characteristics and genetic testing outcomes of patients with clinically suspected paraganglioma/pheochromocytoma (PGL/PCC) syndrome in Singapore

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Kay Reen Ting ◽  
Pei Yi Ong ◽  
Samuel Ow Guan Wei ◽  
Rajeev Parameswaran ◽  
Chin Meng Khoo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Cancer Genetics ◽  
Chinese Patients ◽  
Hereditary Cancer Syndrome ◽  
Limited Data ◽  
Cancer Syndrome ◽  
Causative Gene ◽  
Asian Patients ◽  
Pathogenic Variants ◽  
History Of

Abstract Background Hereditary paraganglioma (PGL) and pheochromocytoma (PCC) syndromes are rare conditions, with limited data on spectrum of causative gene variants of these syndromes in Asian patients. Methods We describe the clinical characteristics and genetic testing outcomes of patients with suspected hereditary PGL/PCC who were referred to a tertiary cancer genetics clinic in Singapore. Results Among 2196 patients with suspected hereditary cancer syndrome evaluated at the cancer genetics clinic from 2000 to 2019, 13/2196 (0.6%) patients fulfilled clinical suspicion for hereditary PGL/PCC syndrome. After genetic counselling, 10 patients underwent multi-gene next generation sequencing and deletion/duplication analysis, including SDHAF2, SDHA, SDHB, SDHC, SDHD, VHL, NF1, RET, MAX, and TMEM127. Seven of 10 patients (70%) were identified to carry pathogenic variants, including 3 unrelated Chinese patients with head and neck PGL who carried the same SDHD: c.3G > C (p.Met1Ile) variant that was previously reported to be a possible founder variant in Chinese, and 3 patients with urogenital PGL and 1 patient with retroperitoneal PGL who carried different SDHB variants. Variant carriers were younger, more likely to present with multiple tumours, or have family history of paraganglioma or pheochromocytoma, than non- variant carriers. Conclusion Hereditary PGL/PCC accounts for only 0.6% of patients seen in an adult cancer genetics clinic in Asia. SDHD and SDHB genes remain the most important causative genes of hereditary PGL/PCC in Asia even when patients are tested with multi-gene NGS panel.

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