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Conference Paper: Diagnostic outcome of whole exome sequencing in Hong Kong familes with autism spectrum disorder

TitleDiagnostic outcome of whole exome sequencing in Hong Kong familes with autism spectrum disorder
Authors
Issue Date2019
PublisherThe Hong Kong Paediatric Society.
Citation
Joint Annual Scientific Meeting 2019 of The Hong Kong Paediatric Society, Hong Kong College of Paediatricians, Hong Kong Paediatric Nurses Association, & Hong Kong College of Paediatric Nursing. Hong Kong, 28 September 2019, p. 20 How to Cite?
AbstractBackground: Autism spectrum disorder (ASD) is characterized by deficit in social communication and restricted repetitive behaviour or interest. While it is known that common variants and copy number variations contribute significantly to the pathogenesis of ASD, rare de novo single nucleotide variants are known to cause ASD in some of the cases. Currently, the mutational spectrum of ASD in Southern Chinese is understudied. We aimed at studying the diagnostic outcome of whole exome sequencing (WES) in Hong Kong families with ASD. Methods: We recruited subjects diagnosed with ASD based on DSM IV-TR or DSM-V criteria and their asymptomatic parents at Duchess of Kent Children's Hospital Child Assessment Centre to this study. WES was performed at Icahn School of Medicine at Mount Sinai as a part of the Autism Sequencing Consortium international collaboration. We performed sample-level and variant-level quality control using GATK-VQSR, KGGSeq and PLINK. De novo variants were called using customised bioinformatics pipeline with triodenovo and confirmed by manual inspection using IGV. Variants were prioritized based on population frequency (gnomAD frequency ≤ 1%) and ASD gene list curated by literature search. Phenotype-based variant prioritization was performed using text-mining algorithm VarElect in cases with additional phenotype or dysmorphism. The pathogenicity of variants was determined using ACMG guideline. Pathogenic mutations were confirmed using Sanger Sequencing. Results: We recruited 329 subjects in this study, of which 100 probands originated from trio or multiplex families and 229 subjects were singleton. Nine pathogenic/ likely pathogenic variants were identified in 8 cases (one proband was found to harbour both NSD1 and CHD7 mutations). Disease-causing mutation were identified in overgrowth-related genes (NSD1, PPP2R5D, PTEN, EZH2), multiplecongenital- anomalies-related genes (CREBBP, CHD7), neurodevelopmental-disorder-related genes (DEAF1, GRIN2B) and hearing-loss-related gene (WFS1). 6/9 of the variants were de novo while the inheritance of the remaining cases cannot be determined due to the lack of parental samples. The overall diagnostic yield was 2.5% while the diagnostic yield of trio/multiplex cases was 5.3%. Conclusion: Despite having relatively low diagnostic yield, WES still identifies pathogenic mutations in a small but significant proportion of ASD families. Case-based analysis also highlights phenotype expansion of ASD as clinical genetics transit into the era of genotype-guided practice. Pathogenic variants identified in syndromic ASD genes were found to present as non-syndromic ASD.
DescriptionPaediatric Research Oral Presentation - no. PRO8
Persistent Identifierhttp://hdl.handle.net/10722/277848

 

DC FieldValueLanguage
dc.contributor.authorChan, MCY-
dc.contributor.authorMak, CCY-
dc.contributor.authorTsang, HY-
dc.contributor.authorYeung, KS-
dc.contributor.authorFung, JLF-
dc.contributor.authorYu, MHC-
dc.contributor.authorLee, MMY-
dc.contributor.authorChung, CCY-
dc.contributor.authorLee, SL-
dc.contributor.authorChung, BHY-
dc.date.accessioned2019-10-04T08:02:34Z-
dc.date.available2019-10-04T08:02:34Z-
dc.date.issued2019-
dc.identifier.citationJoint Annual Scientific Meeting 2019 of The Hong Kong Paediatric Society, Hong Kong College of Paediatricians, Hong Kong Paediatric Nurses Association, & Hong Kong College of Paediatric Nursing. Hong Kong, 28 September 2019, p. 20-
dc.identifier.urihttp://hdl.handle.net/10722/277848-
dc.descriptionPaediatric Research Oral Presentation - no. PRO8-
dc.description.abstractBackground: Autism spectrum disorder (ASD) is characterized by deficit in social communication and restricted repetitive behaviour or interest. While it is known that common variants and copy number variations contribute significantly to the pathogenesis of ASD, rare de novo single nucleotide variants are known to cause ASD in some of the cases. Currently, the mutational spectrum of ASD in Southern Chinese is understudied. We aimed at studying the diagnostic outcome of whole exome sequencing (WES) in Hong Kong families with ASD. Methods: We recruited subjects diagnosed with ASD based on DSM IV-TR or DSM-V criteria and their asymptomatic parents at Duchess of Kent Children's Hospital Child Assessment Centre to this study. WES was performed at Icahn School of Medicine at Mount Sinai as a part of the Autism Sequencing Consortium international collaboration. We performed sample-level and variant-level quality control using GATK-VQSR, KGGSeq and PLINK. De novo variants were called using customised bioinformatics pipeline with triodenovo and confirmed by manual inspection using IGV. Variants were prioritized based on population frequency (gnomAD frequency ≤ 1%) and ASD gene list curated by literature search. Phenotype-based variant prioritization was performed using text-mining algorithm VarElect in cases with additional phenotype or dysmorphism. The pathogenicity of variants was determined using ACMG guideline. Pathogenic mutations were confirmed using Sanger Sequencing. Results: We recruited 329 subjects in this study, of which 100 probands originated from trio or multiplex families and 229 subjects were singleton. Nine pathogenic/ likely pathogenic variants were identified in 8 cases (one proband was found to harbour both NSD1 and CHD7 mutations). Disease-causing mutation were identified in overgrowth-related genes (NSD1, PPP2R5D, PTEN, EZH2), multiplecongenital- anomalies-related genes (CREBBP, CHD7), neurodevelopmental-disorder-related genes (DEAF1, GRIN2B) and hearing-loss-related gene (WFS1). 6/9 of the variants were de novo while the inheritance of the remaining cases cannot be determined due to the lack of parental samples. The overall diagnostic yield was 2.5% while the diagnostic yield of trio/multiplex cases was 5.3%. Conclusion: Despite having relatively low diagnostic yield, WES still identifies pathogenic mutations in a small but significant proportion of ASD families. Case-based analysis also highlights phenotype expansion of ASD as clinical genetics transit into the era of genotype-guided practice. Pathogenic variants identified in syndromic ASD genes were found to present as non-syndromic ASD.-
dc.languageeng-
dc.publisherThe Hong Kong Paediatric Society. -
dc.relation.ispartofJoint Annual Scientific Meeting 2019 of The Hong Kong Paediatric Society, Hong Kong College of Paediatricians, Hong Kong Paediatric Nurses Association, & Hong Kong College of Paediatric Nursing-
dc.titleDiagnostic outcome of whole exome sequencing in Hong Kong familes with autism spectrum disorder-
dc.typeConference_Paper-
dc.identifier.emailMak, CCY: cmakl@HKUCC-COM.hku.hk-
dc.identifier.emailYeung, KS: ksyyeung@HKUCC-COM.hku.hk-
dc.identifier.emailFung, JLF: jasflfs@HKUCC-COM.hku.hk-
dc.identifier.emailLee, MMY: mianne@hku.hk-
dc.identifier.emailLee, SL: slleem@hku.hk-
dc.identifier.emailChung, BHY: bhychung@hku.hk-
dc.identifier.authorityChung, BHY=rp00473-
dc.identifier.hkuros306977-
dc.identifier.spage20-
dc.identifier.epage20-
dc.publisher.placeHong Kong-

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