scholarly journals Genetic and Phenotypic Variability in Chinese Patients With Branchio-Oto-Renal or Branchio-Oto Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Haifeng Feng ◽  
Hongen Xu ◽  
Bei Chen ◽  
Shuping Sun ◽  
Rongqun Zhai ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Phenotypic Variability ◽  
Bone Conduction ◽  
Missense Variant ◽  
Chinese Patients ◽  
Renal Anomalies ◽  
Auditory Rehabilitation ◽  
Whole Exome ◽  
Splicing Variants ◽  
Feasible Option

Background: Branchio-oto-renal syndrome (BOR) and branchio-oto syndrome (BOS) are rare autosomal dominant disorders defined by varying combinations of branchial, otic, and renal anomalies. Here, we characterized the clinical features and genetic etiology of BOR/BOS in several Chinese families and then explored the genotypes and phenotypes of BOR/BOS-related genes, as well as the outcomes of auditory rehabilitation in different modalities.Materials and Methods: Probands and all affected family members underwent detailed clinical examinations. Their DNA was subjected to whole-exome sequencing to explore the underlying molecular etiology of BOR/BOS; candidate variants were validated using Sanger sequencing and interpreted in accordance with the American College of Medical Genetics guidelines. In addition, a literature review concerning EYA1 and SIX1 alterations was performed to explore the genotypes and phenotypes of BOR/BOS-related genes.Results: Genetic testing identified the novel deletion (c.1425delC, p(Asp476Thrfs*4); NM_000,503.6), a nonsense variant (c.889C > T, p(Arg297*)), and two splicing variants in the EYA1 gene (c.1050+1G > T and c.1140+1G > A); it also identified one novel missense variant in the SIX1 gene (c.316G > A, p(Val106Met); NM_005,982.4). All cases exhibited a degree of phenotypic variability between or within families. Middle ear surgeries for improving bone-conduction component hearing loss had unsuccessful outcomes; cochlear implantation (CI) contributed to hearing gains.Conclusion: This is the first report of BOR/BOS caused by the SIX1 variant in China. Our findings increase the numbers of known EYA1 and SIX1 variants. They also emphasize the usefulness of genetic testing in the diagnosis and prevention of BOR/BOS while demonstrating that CI for auditory rehabilitation is a feasible option in some BOR/BOS patients.

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>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.

scholarly journals Initial whole-genome sequencing and analysis of the host genetic contribution to COVID-19 severity and susceptibility

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Fang Wang ◽  
Shujia Huang ◽  
Rongsui Gao ◽  
Yuwen Zhou ◽  
Changxiang Lai ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Phenotypic Variability ◽  
Missense Variant ◽  
Pedigree Analysis ◽  
Chinese Patients ◽  
Genetic Contribution ◽  
Loss Of Function ◽  
Genomic Study ◽  
Significant Gene ◽  
Host Genetic

Abstract The COVID-19 pandemic has accounted for millions of infections and hundreds of thousand deaths worldwide in a short-time period. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed interindividual phenotypic variability. Here, we report the first host genetic study in the Chinese population by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe, and critical ill patients after the correction of potential confounding factors. Pedigree analysis suggested a potential monogenic effect of loss of function variants in GOLGA3 and DPP7 for critically ill and asymptomatic disease demonstration. Genome-wide association study suggests the most significant gene locus associated with severity were located in TMEM189–UBE2V1 that involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We identified that the HLA-A*11:01, B*51:01, and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial genomic study of Chinese patients provides genetic insights into the phenotypic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host–pathogen interaction for COVID-19 and other infectious and complex diseases.

scholarly journals Molecular and clinical characteristics of monogenic diabetes mellitus in southern Chinese children with onset before 3 years of age

2020 ◽  
Vol 8 (1) ◽  
pp. e001345
Author(s):  
Yunting Lin ◽  
Huiying Sheng ◽  
Tzer Hwu Ting ◽  
Aijing Xu ◽  
Xi Yin ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Genetic Testing ◽  
Age Of Onset ◽  
Neonatal Diabetes ◽  
Monogenic Diabetes ◽  
Chinese Patients ◽  
Combination Strategy ◽  
Southern Chinese ◽  
Whole Exome ◽  
Design And Methods

IntroductionA specific molecular diagnosis of monogenic diabetes mellitus (MDM) will help to predict the clinical course and guide management. This study aims to identify the causative genes implicated in Chinese patients with MDM with onset before 3 years of age.Research design and methods71 children with diabetes mellitus (43 diagnosed before 6 months of age, and 28 diagnosed between 6 months and 3 years of age who were negative for diabetes-associated autoantibodies) underwent genetic testing with a combination strategy of Sanger sequencing, chromosome microarray analysis and whole exome sequencing. They were categorized into four groups according to the age of onset of diabetes (at or less than 6 months, 6 to 12 months, 1 to 2 years, 2 to 3 years) to investigate the correlation between genotype and phenotype.ResultsGenetic abnormalities were identified in 39 of 71 patients (54.93%), namely KCNJ11 (22), ABCC8 (3), GCK (3), INS (3), BSCL2 (1) and chromosome abnormalities (7). The majority (81.40%, 35/43) of neonatal diabetes diagnosed less than 6 months of age and 33.33% (3/9) of infantile cases diagnosed between 6 and 12 months of age had a genetic cause identified. Only 11.11% (1/9) of cases diagnosed between 2 and 3 years of age were found to have a genetic cause, and none of the 10 patients diagnosed between 1 and 2 years had a positive result in the genetic analysis. Vast majority or 90.48% (19/21) of patients with KCNJ11 (19) or ABCC8 (2) variants had successful switch trial from insulin to oral sulfonylurea.ConclusionsThis study suggests that genetic testing should be given priority in diabetes cases diagnosed before 6 months of age, as well as those diagnosed between 6 and 12 months of age who were negative for diabetes-associated autoantibodies. This study also indicates significant impact on therapy with genetic cause confirmation.

scholarly journals Clinical impact of low coverage in whole-exome genetic testing in the assessment of familial arrhythmogenic right ventricular cardiomyopathy: a case report

2021 ◽  
Vol 5 (6) ◽  
Author(s):  
Sarah Costa ◽  
Elisa Pons ◽  
Argelia Medeiros-Domingo ◽  
Ardan M Saguner
Keyword(s):  
Genetic Testing ◽  
Right Ventricular ◽  
Genetic Screening ◽  
Arrhythmogenic Right Ventricular Cardiomyopathy ◽  
Screening Method ◽  
Missense Variant ◽  
Ventricular Cardiomyopathy ◽  
Cascade Screening ◽  
Good Tool ◽  
Whole Exome

Abstract Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited condition, with approximately 60% of patients carrying a possibly disease-causing genetic variant. Known desmosomal genes account for about 50% of those variants. We herein report a family with ARVC in which a pathogenic desmosomal variant was missed because of the initial genetic testing method. Case summary A 54-year-old man diagnosed with ARVC underwent genetic cascade screening for a heterozygous titin variant (TTN: c.26542C>T), detected in his phenotypically affected sister. He did not harbour this TTN variant. Moreover, reclassification of this variant based on the American College of Medical Genetics (ACMG) 2015 criteria showed it to be likely benign. Upon genetic re-screening with a dedicated cardiomyopathy panel a heterozygous missense variant in desmoglein-2 (DSG2: c.152G>C) was found. His sister’s DNA was re-analysed and the same DSG2 variant was detected, and classified as LP (likely pathogenic) by current literature. Discussion The initial genetic screening tool used in the patient’s sister (whole-exome sequencing, WES) failed to detect the likely causative desmosomal variant in our family. While WES represents a good tool in searching for novel genes in Trio Analysis, it has a low DNA coverage in important regions (mean 10×) of known ARVC-associated genes. We therefore propose using smaller panels with better coverage in the clinical setting, such as Trusight-cardio (mean DNA coverage 100–300×) as an initial genetic screening method.

1268A family with a novel variant in the SLC4A3 gene leading to short QT phenotype - the importance of whole-exome-sequencing and cascade screening

EP Europace ◽  
2020 ◽  
Vol 22 (Supplement_1) ◽  
Author(s):  
B Kovacs ◽  
U Graf ◽  
I Magyar ◽  
L Baehr ◽  
A Maspoli ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Variant ◽  
Missense Variant ◽  
Index Patient ◽  
Causative Mutation ◽  
Cascade Screening ◽  
Whole Exome ◽  
Work Up

Abstract Funding Acknowledgements none Introduction  Short QT syndrome (SQTS) is a rare, autosomal dominant disease causing ventricular fibrillation and sudden cardiac death. Genetic testing is recommended according to current guidelines. Mutations in KCNQ1, KCNH2, KCNJ2 and more recently SLC4A3 genes have been implicated in SQTS. These genes encode potassium channel subunits and a bicarbonate transporter regulating intracellular pH. A dominant mutation in this transporter can lead to increased intracellular pH and shortened action potential. Purpose  We present a family with a short QT phenotype and recurrent syncope in whom a novel genetic variant was detected by whole-exome sequencing (WES), confirmed by cascade screening. Methods  We performed a thorough work-up of the index patient including medical history, physical examination, 12-lead ECG, echocardiography, stress testing, coronary angiography, flecainide challenge, and genetic testing with NGS. QTc was determined using Bazett’s formula. CS of all 1° and two 2° relatives was performed. Results  The ECG of the index patient showed a QTc of 340ms and characteristics compatible with a SQTS (figure). Clinical work-up was unremarkable. A first genetic search with next generation sequencing focusing on genes that have been previously involved in the pathogenesis of channelopathies detected a rare known heterozygous missense variant in the KCNH2 gene (Arg328Cys, frequency 0.053%), which was predicted to be pathogenic according to various prediction algorithms (Polyphen, SIFT, Align GVGD, mutation taster). ECG screening of all asymptomatic first-degree family members identified a SQT phenotype in the mother (QTc 355ms), but not in the father (QTc 380ms) and sister (410ms). The KCNH2 variant was found in the father and sister but not the affected mother, which excludes this variant as the causative mutation in this family. Therefore, reanalysis of WES data was performed and revealed a novel heterozygous missense variant p.(Arg370Cys) in the SLC4A3 gene, recently associated with SQTS. A mutation in this gene at the same position has been previously reported in SQTS. The p.(Arg370Cys) mutation was found in the mother but not in the unaffected father or sister. Furthermore the mutation was present in two affected maternal uncles (QTc 319ms and 342ms) supporting the assumption that this was the causative mutation in this family. Conclusions  A novel genetic variant in the SLC4A3 gene leading to sQT phenotype could be detected using WES and cascade screening. Predictive bioinformatic algorithms to assess the pathogenicity of missense variants are of limited relevance, but genetic analysis of additional unaffected and affected family members may be instrumental to identify pathogenic DNA sequence variations. Abstract Figure. Pedigree and ECGs of the family

scholarly journals EXT1 and EXT2 Variants in 22 Chinese Families With Multiple Osteochondromas: Seven New Variants and Potentiation of Preimplantation Genetic Testing and Prenatal Diagnosis

2020 ◽  
Vol 11 ◽  
Author(s):  
Ye Wang ◽  
Liangying Zhong ◽  
Yan Xu ◽  
Lei Ding ◽  
Yuanjun Ji ◽  
...  
Keyword(s):  
Prenatal Diagnosis ◽  
Genetic Testing ◽  
Successful Implementation ◽  
Preimplantation Genetic Testing ◽  
Chinese Families ◽  
Pathogenic Variants ◽  
Multiple Osteochondromas ◽  
Whole Exome ◽  
Splicing Variants ◽  
Phenotypic And Genetic Characterization

Multiple osteochondromas (MO), the most common type of benign bone tumor, is an autosomal dominant skeletal disorder characterized by multiple cartilage-capped bony protuberances. In most cases, EXT1 and EXT2, which encode glycosyltransferases involved in the biosynthesis of heparan sulfate, are the genes responsible. Here we describe the clinical, phenotypic and genetic characterization of MO in 22 unrelated Chinese families involving a total of 60 patients. Variant detection was performed by means of a battery of different techniques including Sanger sequencing and whole-exome sequencing (WES). The pathogenicity of the missense and splicing variants was explored by means of in silico prediction algorithms. Sixteen unique pathogenic variants, including 10 in the EXT1 gene and 6 in the EXT2 gene, were identified in 18 (82%) of the 22 families. Fourteen (88%) of the 16 variants were predicted to give rise to truncated proteins whereas the remaining two were missense. Seven variants were newly described here, further expanding the spectrum of MO-causing variants in the EXT1 and EXT2 genes. More importantly, the identification of causative variants allowed us to provide genetic counseling to 8 MO patients in terms either of preimplantation genetic testing (PGT) or prenatal diagnosis, thereby preventing the reoccurrence of MO in the corresponding families. This study is the first to report the successful implementation of PGT in MO families and describes the largest number of subjects undergoing prenatal diagnosis to date.

scholarly journals Initial Whole Genome Sequencing and Analysis of the Host Genetic Contribution to COVID-19 Severity and Susceptibility

2020 ◽  
Author(s):  
Fang Wang ◽  
Shujia Huang ◽  
Rongsui Gao ◽  
Yuwen Zhou ◽  
Changxiang Lai ◽  
...  
Keyword(s):  
Genetic Difference ◽  
Phenotypic Variability ◽  
Missense Variant ◽  
Initial Study ◽  
Chinese Patients ◽  
Genetic Contribution ◽  
Significant Gene ◽  
Patient Groups ◽  
Host Genetic ◽  
The Stability

AbstractThe COVID-19 pandemic has accounted for more than five million infections and hundreds of thousand deaths worldwide in the past six months. The patients demonstrate a great diversity in clinical and laboratory manifestations and disease severity. Nonetheless, little is known about the host genetic contribution to the observed inter-individual phenotypic variability. Here, we report the first host genetic study in China by deeply sequencing and analyzing 332 COVID-19 patients categorized by varying levels of severity from the Shenzhen Third People’s Hospital. Upon a total of 22.2 million genetic variants, we conducted both single-variant and gene-based association tests among five severity groups including asymptomatic, mild, moderate, severe and critical ill patients after the correction of potential confounding factors. The most significant gene locus associated with severity is located in TMEM189-UBE2V1 involved in the IL-1 signaling pathway. The p.Val197Met missense variant that affects the stability of the TMPRSS2 protein displays a decreasing allele frequency among the severe patients compared to the mild and the general population. We also identified that the HLA-A*11:01, B*51:01 and C*14:02 alleles significantly predispose the worst outcome of the patients. This initial study of Chinese patients provides a comprehensive view of the genetic difference among the COVID-19 patient groups and highlighted genes and variants that may help guide targeted efforts in containing the outbreak. Limitations and advantages of the study were also reviewed to guide future international efforts on elucidating the genetic architecture of host-pathogen interaction for COVID-19 and other infectious and complex diseases.

Whole exome sequencing identifies FOXL2, FOXA2 and FOXA3 as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract

2021 ◽  
Author(s):  
Bixia Zheng ◽  
Steve Seltzsam ◽  
Chunyan Wang ◽  
Luca Schierbaum ◽  
Sophia Schneider ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Whole Exome Sequencing ◽  
Congenital Anomalies ◽  
De Novo ◽  
Horseshoe Kidney ◽  
Missense Variant ◽  
Whole Exome ◽  
Fox Genes

Abstract Background Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidney, may also represent monogenic causes of CAKUT. Methods We here performed whole exome sequencing (WES) in 541 families with CAKUT and generated 4 lists of CAKUT candidate genes: A) 36 FOX genes showing high expression during renal development, B) 4 FOX genes known to cause CAKUT to validate list A; C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families, and D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes. Results To prioritize potential novel CAKUT candidates in FOX gene family, we overlapped 36 FOX genes (list A) with list C and D of WES-derived CAKUT candidates. Intersection with list C, identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D, identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals. Conclusion We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

Novel Recurrent Altered Genes in Chinese Patients With Anaplastic Thyroid Cancer

2021 ◽  
Author(s):  
Lingyun Zhang ◽  
Zhixiang Ren ◽  
Zhengzheng Su ◽  
Yang Liu ◽  
Tian Yang ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Copy Number ◽  
Treatment Strategies ◽  
Gene Mutations ◽  
Anaplastic Thyroid Cancer ◽  
Chinese Patients ◽  
Driver Gene ◽  
Phosphatidylinositol 3 Kinase ◽  
Entire Cohort ◽  
Whole Exome

Abstract Background Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy, and few systematic investigations on genomic profiles of ATC have been performed in Chinese patients. Methods Fifty-four ATC patients in West China Hospital between 2010 to 2020 were retrospectively analyzed, while 29 patients with available samples were sequenced by whole-exome sequencing (WES). The associations between genomic alterations and clinical characteristics were statistically evaluated. Results The median overall survival was 3.0 months in the entire cohort, which was impacted by multiple clinical features, including age, tumor size, and different treatment strategies. In the WES cohort, totally 797 nonsilent mutations were detected; the most frequently altered genes were TP53 (48%), BRAF (24%), PIK3CA (24%), and TERT promoter (21%). Although these mutations have been well-reported in previous studies, ethnic specificity was exhibited in terms of mutation frequency. Moreover, several novel significantly mutated genes were identified including RBM15 (17%), NOTCH2NL (14%), CTNNA3 (10%), and KATNAL2 (10%). WES-based copy number alteration analysis also revealed a high frequent gain of NOTCH2NL (41%), which induced its increased expression. Gene mutations and copy number alterations were enriched in phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin (mTOR), NOTCH, and WNT pathways. Conclusions This study reveals shared and ethnicity-specific genomic profiles of ATC in Chinese patients and suggests NOTCH2NL may act as a novel candidate driver gene for ATC tumorigenesis.

scholarly journals A homozygous mutation of GNRHR in a familial case diagnosed with polycystic ovary syndrome

2017 ◽  
Vol 176 (5) ◽  
pp. K9-K14 ◽  
Author(s):  
Sandrine Caburet ◽  
Ronit Beck Fruchter ◽  
Bérangère Legois ◽  
Marc Fellous ◽  
Stavit Shalev ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Sanger Sequencing ◽  
Polycystic Ovary ◽  
Missense Variant ◽  
Genetic Alterations ◽  
Homozygous Mutation ◽  
Gonadotropin Secretion ◽  
Whole Exome ◽  
A Genome

Context PCOS is a heterogeneous condition characterized by hyperandrogenism and chronic anovulation and affects about 10% of women. Its etiology is poorly known, but a dysregulation of gonadotropin secretion is one of its hallmarks. Objective As the etiology of PCOS is unclear, we have performed a genome-wide analysis of a consanguineous family with three sisters diagnosed with PCOS. Methods Whole-exome sequencing and Sanger sequencing confirmation. Results Whole-exome sequencing allowed the detection of the missense variant rs104893836 located in the first coding exon of the GNRHR gene and leading to the p.Gln106Arg (p.Q106R) substitution. Sanger sequencing of all available individuals of the family confirmed that the variant was homozygous in the three affected sisters and heterozygous in both parents. Conclusions This is the first description of a GNRHR gene mutation in patients diagnosed with PCOS. Although we do not exclude a possible interaction of the identified variant with the genetic background and/or the environment, our result suggests that genetic alterations in the hypothalamo–pituitary axis may play role in the pathogenesis of PCOS.

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