Background: Over 400 genes contribute to the development of congenital heart disease (CHD). Additionally,multisystemic manifestations accompanying syndromic CHD pose a higher risk of genetic diseases. This studyinvest...Background: Over 400 genes contribute to the development of congenital heart disease (CHD). Additionally,multisystemic manifestations accompanying syndromic CHD pose a higher risk of genetic diseases. This studyinvestigated the diagnostic yield of whole-exome sequencing (WES) in patients with sporadic syndromic CHDand the phenotypic factors affecting the genetic diagnostic rate. Methods: Sixty-four patients with sporadic syndromicCHD aged <18 years underwent WES between May 2018 and December 2020 in a single tertiary center,and the association between genetic testing data and extracardiac phenotypes was analyzed. Results: Extracardiacphenotypes were measured as 3.66 ± 3.05 (standard deviation, interquartile range: 2–5) items per patient. WESdetected diagnostic variants in 19 (29.7%) patients: seven (36.8%), seven (36.8%), and five (26.3%) with pathogenicvariants, likely pathogenic variants, and variants of unknown significance, respectively. Post-diagnosis surveillanceidentified the extracardiac phenotype in 54.5% (6/11) of patients. De novo variants accounted for 76.2%(15/19) of variants and autosomal dominant inheritance for 94.7% (18/19). Most diseases were ultra-rare. No significantdifferences were noted in cardiac and extracardiac phenotypes, single or combined (all P > 0.05), betweenthe groups with and without a diagnostic variant. However, patients with ≥3 extracardiac phenotypes had a significantlyhigher likelihood of having a diagnostic variant than those with ≤2 (38.3% vs. 5.9%, odds ratio = 9.93,95% confidence interval = 1.21–81.44, P = 0.013). Conclusions: The number of extracardiac phenotypes is importantin predicting the possibility of genetic diagnosis. Physicians will be able to select patients with a high probabilityof genetic diagnosis and provide appropriate genetic counseling based on the results of this study.展开更多
Background and Method:The genetic cause of infantile-onset cardiomyopathy is rarely investigated.Here,we conducted whole exome sequencing(WES)and mitochondrial DNA(mtDNA)sequencing in eight patients with infantile-ons...Background and Method:The genetic cause of infantile-onset cardiomyopathy is rarely investigated.Here,we conducted whole exome sequencing(WES)and mitochondrial DNA(mtDNA)sequencing in eight patients with infantile-onset cardiomyopathy to identify genetic variations.Result:Among these patients,two(25%)had dilated cardiomyopathy(DCMP),two(25%)had left ventricular non-compaction(LVNC),and four(50%)had hypertrophic cardiomyopathy(HCMP).Except four patients identified prenatally,the remaining patients presented at a median age of 85.5 days.WES identified genetic variants in a total of seven(87.5%)patients and mtDNA sequencing in the other case.TPM1 and MYH7 variants were identified in the two patients with DCMP;MYH11 and MYLK2 variants in the two patients with LVNC;HRAS,BRAF,and MYH7 variants in three patients with HCMP;and MT-ND1 variant in one patient with HCMP having high blood lactic acid levels.Among the eight variants,four were classified as pathogenic or likely-pathogenic according to the American College of Medical Genetics(ACMG)guidelines,and the remaining were identified as variants of unknown significance(VUSs).Three pathogenic mutations were de novo,whereas four(likely-pathogenic or VUSs)were inherited from a respective parent,excluding one variant where parental testing was unavailable,questioning whether these inherited variants are disease-causing.Three patients died before 3 months of age.Conclusion:Genomic studies,such as WES with additional mtDNA sequencing,can identify a genetic variant in high proportions of patients with infantile-onset cardiomyopathy.The clinical implication of the parentally inherited variant needs to be assessed in a larger patient and family cohort with a longitudinal follow-up.展开更多
Otoancorin(OTOA)is a glycosylphosphatidylinositol(GPI)-anchored protein mediating the attachment of the tectorial membrane(TM)to the spiral limbus(SL)in the inner ear.Homozygous or compound heterozygous mutations in O...Otoancorin(OTOA)is a glycosylphosphatidylinositol(GPI)-anchored protein mediating the attachment of the tectorial membrane(TM)to the spiral limbus(SL)in the inner ear.Homozygous or compound heterozygous mutations in OTOA cause autosomal recessive deafness(DFNB22).We performed short-read exome sequencing(SRS)in a 10-monthold boy with sensorineural hearing loss,identifying a potential p.Glu787*variant in OTOA.Interestingly,this variant is common among normal-hearing individuals,leading us to question its pathogenic potential.展开更多
基金This work was supported by an Institute for Information and CommunicationsTechnology Promotion (IITP) grant funded by the Korean Government (MSIT) (2018-0-00861,Intelligent SW Technology Development for Medical Data Analysis).
文摘Background: Over 400 genes contribute to the development of congenital heart disease (CHD). Additionally,multisystemic manifestations accompanying syndromic CHD pose a higher risk of genetic diseases. This studyinvestigated the diagnostic yield of whole-exome sequencing (WES) in patients with sporadic syndromic CHDand the phenotypic factors affecting the genetic diagnostic rate. Methods: Sixty-four patients with sporadic syndromicCHD aged <18 years underwent WES between May 2018 and December 2020 in a single tertiary center,and the association between genetic testing data and extracardiac phenotypes was analyzed. Results: Extracardiacphenotypes were measured as 3.66 ± 3.05 (standard deviation, interquartile range: 2–5) items per patient. WESdetected diagnostic variants in 19 (29.7%) patients: seven (36.8%), seven (36.8%), and five (26.3%) with pathogenicvariants, likely pathogenic variants, and variants of unknown significance, respectively. Post-diagnosis surveillanceidentified the extracardiac phenotype in 54.5% (6/11) of patients. De novo variants accounted for 76.2%(15/19) of variants and autosomal dominant inheritance for 94.7% (18/19). Most diseases were ultra-rare. No significantdifferences were noted in cardiac and extracardiac phenotypes, single or combined (all P > 0.05), betweenthe groups with and without a diagnostic variant. However, patients with ≥3 extracardiac phenotypes had a significantlyhigher likelihood of having a diagnostic variant than those with ≤2 (38.3% vs. 5.9%, odds ratio = 9.93,95% confidence interval = 1.21–81.44, P = 0.013). Conclusions: The number of extracardiac phenotypes is importantin predicting the possibility of genetic diagnosis. Physicians will be able to select patients with a high probabilityof genetic diagnosis and provide appropriate genetic counseling based on the results of this study.
基金This work was supported by an Institute for Information and Communications Technology Promotion(IITP)grant funded by the Korean government(MSIT)(2018-0-00861,Intelligent SW Technology Development for Medical Data Analysis).
文摘Background and Method:The genetic cause of infantile-onset cardiomyopathy is rarely investigated.Here,we conducted whole exome sequencing(WES)and mitochondrial DNA(mtDNA)sequencing in eight patients with infantile-onset cardiomyopathy to identify genetic variations.Result:Among these patients,two(25%)had dilated cardiomyopathy(DCMP),two(25%)had left ventricular non-compaction(LVNC),and four(50%)had hypertrophic cardiomyopathy(HCMP).Except four patients identified prenatally,the remaining patients presented at a median age of 85.5 days.WES identified genetic variants in a total of seven(87.5%)patients and mtDNA sequencing in the other case.TPM1 and MYH7 variants were identified in the two patients with DCMP;MYH11 and MYLK2 variants in the two patients with LVNC;HRAS,BRAF,and MYH7 variants in three patients with HCMP;and MT-ND1 variant in one patient with HCMP having high blood lactic acid levels.Among the eight variants,four were classified as pathogenic or likely-pathogenic according to the American College of Medical Genetics(ACMG)guidelines,and the remaining were identified as variants of unknown significance(VUSs).Three pathogenic mutations were de novo,whereas four(likely-pathogenic or VUSs)were inherited from a respective parent,excluding one variant where parental testing was unavailable,questioning whether these inherited variants are disease-causing.Three patients died before 3 months of age.Conclusion:Genomic studies,such as WES with additional mtDNA sequencing,can identify a genetic variant in high proportions of patients with infantile-onset cardiomyopathy.The clinical implication of the parentally inherited variant needs to be assessed in a larger patient and family cohort with a longitudinal follow-up.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korean government(MSIT)(No.2021R1C1C1007980 to B.J.K.)Chungnam National University Sejong Hospital Research Fund,2022,and Chungnam National University(to B.J.K.)+6 种基金supported by the Basic Science Research Program through the NRF,funded by the Ministry of Education(No.2021R1A2C2092038 to B.Y.C.)Bio Core Facility Center program(No.NRF-2022M3A9G1014007 to B.Y.C.)the Basic Research Laboratory program through the NRF,funded by the Ministry of Education(No.RS-2023-0021971031482092640001 to B.Y.C.)the Technology Innovation Program(No.K_G012002572001 to B.Y.C.)funded By the Ministry of Trade,Industry&Energy(MOTIE,Korea)funded by SNUBH(Seoul National University Bundang Hospital)intramural research fund(No.13-2022-0010,02-2017-0060,16-2023-0002,13-2023-0002,16-2022-0005,13-2024-0004,and 13-2017-0013 to B.Y.C.)supported by the National Institute on Deafness and Other Communication Disorders(NIDCD)part of the US National Institutes of Health(No.R01DC018814 to S.P.).
文摘Otoancorin(OTOA)is a glycosylphosphatidylinositol(GPI)-anchored protein mediating the attachment of the tectorial membrane(TM)to the spiral limbus(SL)in the inner ear.Homozygous or compound heterozygous mutations in OTOA cause autosomal recessive deafness(DFNB22).We performed short-read exome sequencing(SRS)in a 10-monthold boy with sensorineural hearing loss,identifying a potential p.Glu787*variant in OTOA.Interestingly,this variant is common among normal-hearing individuals,leading us to question its pathogenic potential.
