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Conference Paper: NSD1+/- DNA methylation (DNAm) signature: A novel functional diagnostic tool for Sotos syndrome

TitleNSD1+/- DNA methylation (DNAm) signature: A novel functional diagnostic tool for Sotos syndrome
Authors
KeywordsClinical Genetics and Dysmorphology
KW042 - diagnostics
KW008 - bioinformatics
KW107 - intellectual and developmental disability
KW110 - methylation
KW040 - development
Issue Date2014
PublisherAmerican Society of Human Genetics.
Citation
The 64th Annual Meeting of the American Society of Human Genetics (ASHG 2014), San Diego, CA., 18-22 October 2014. How to Cite?
AbstractSotos syndrome (SS) is characterized by somatic overgrowth and intellectual disability. Most SS cases have mutations in NSD1 (nuclear receptor-binding SET domain protein 1), a histone lysine methyltransferase. To determine if NSD1 mutations impact stable epigenetic marks such as DNAm, we compared DNAm in peripheral blood from SS cases with NSD1 mutations (NSD1+/-; n=20) to controls (n=53) using the Illumina Infinium450methylation BeadChip (450k array). Differential DNAm analysis using non-parametric statistics (with correction for multiple testing) identified a surprisingly high number of differentially methylated (DM) CG sites between SS and controls. The majority (99.3%) of these sites demonstrated loss of DNAm and were distributed across the genome. Using unsupervised hierarchical clustering of the significant DM sites, all SS cases with loss of function mutations in NSD1 clustered as a distinct group. The specificity of this signature was 100%; in comparison to DNAm profiles of 450k data from the GEO database for blood samples (n= 1200). The sensitivity of the NSD1+/- signature was tested in an independent replication cohort of 19 SS cases from Hong Kong with NSD1 loss of function mutations. The NSD1+/- signature demonstrated a sensitivity of 100%; highlighting its exceptional power in defining pathogenicity for mutations in NSD1. The classification of single nucleotide substitutions into benign or disease causing (damaging) variants represents an ongoing challenge in clinical diagnostics. To test the hypothesis that the NSD1+/- DNAm signature will inform the functional classification of NSD1 variants into benign or disease causing, we analyzed 16 cases with reported missense variants in NSD1. Using hierarchical clustering we classified these variants as pathogenic (n=9) or benign (n=7). Clinical re-assessment of 11/16 of these cases, for whom photos and adequate clinical information were available, was conducted by two experienced dysmorphologists (RW and DC) who were blinded to the methylation results. There was 100%; concordance between clinical impression and DNAm data. In comparison, 4/5 algorithms (SIFT, Polyphen-2, etc) were inconsistent in their prediction of pathogenicity. Our data suggest that the NSD1+/- DNAm signature reflects the functional effect of NSD1 variants on the methylome and can be used as a more robust predictor than existing algorithms for the functional classification of NSD1 variants in overgrowth disorders.
DescriptionSession - 32. Molecular Insights into Mendelian Disorders: no. 130
The Conference abstracts' website is located at http://www.ashg.org/meetings/meetings_futurepast.shtml
Persistent Identifierhttp://hdl.handle.net/10722/206855

 

DC FieldValueLanguage
dc.contributor.authorChonufani, Sen_US
dc.contributor.authorCytrynbaum, Cen_US
dc.contributor.authorChung, BHYen_US
dc.contributor.authorTurinsky, ALen_US
dc.contributor.authorGrafodatskaya, Den_US
dc.contributor.authorChen, YAen_US
dc.contributor.authorLuk, HMen_US
dc.contributor.authorLo, IFMen_US
dc.contributor.authorLam, STSen_US
dc.contributor.authorStavropoulos, DJen_US
dc.contributor.authorGibson, Ben_US
dc.contributor.authorReardon, Men_US
dc.contributor.authorBrudno, Men_US
dc.contributor.authorMendoza-Londono, Ren_US
dc.contributor.authorChitayat, Den_US
dc.contributor.authorWeksberg, Ren_US
dc.date.accessioned2014-12-02T10:37:55Z-
dc.date.available2014-12-02T10:37:55Z-
dc.date.issued2014en_US
dc.identifier.citationThe 64th Annual Meeting of the American Society of Human Genetics (ASHG 2014), San Diego, CA., 18-22 October 2014.en_US
dc.identifier.urihttp://hdl.handle.net/10722/206855-
dc.descriptionSession - 32. Molecular Insights into Mendelian Disorders: no. 130-
dc.descriptionThe Conference abstracts' website is located at http://www.ashg.org/meetings/meetings_futurepast.shtml-
dc.description.abstractSotos syndrome (SS) is characterized by somatic overgrowth and intellectual disability. Most SS cases have mutations in NSD1 (nuclear receptor-binding SET domain protein 1), a histone lysine methyltransferase. To determine if NSD1 mutations impact stable epigenetic marks such as DNAm, we compared DNAm in peripheral blood from SS cases with NSD1 mutations (NSD1+/-; n=20) to controls (n=53) using the Illumina Infinium450methylation BeadChip (450k array). Differential DNAm analysis using non-parametric statistics (with correction for multiple testing) identified a surprisingly high number of differentially methylated (DM) CG sites between SS and controls. The majority (99.3%) of these sites demonstrated loss of DNAm and were distributed across the genome. Using unsupervised hierarchical clustering of the significant DM sites, all SS cases with loss of function mutations in NSD1 clustered as a distinct group. The specificity of this signature was 100%; in comparison to DNAm profiles of 450k data from the GEO database for blood samples (n= 1200). The sensitivity of the NSD1+/- signature was tested in an independent replication cohort of 19 SS cases from Hong Kong with NSD1 loss of function mutations. The NSD1+/- signature demonstrated a sensitivity of 100%; highlighting its exceptional power in defining pathogenicity for mutations in NSD1. The classification of single nucleotide substitutions into benign or disease causing (damaging) variants represents an ongoing challenge in clinical diagnostics. To test the hypothesis that the NSD1+/- DNAm signature will inform the functional classification of NSD1 variants into benign or disease causing, we analyzed 16 cases with reported missense variants in NSD1. Using hierarchical clustering we classified these variants as pathogenic (n=9) or benign (n=7). Clinical re-assessment of 11/16 of these cases, for whom photos and adequate clinical information were available, was conducted by two experienced dysmorphologists (RW and DC) who were blinded to the methylation results. There was 100%; concordance between clinical impression and DNAm data. In comparison, 4/5 algorithms (SIFT, Polyphen-2, etc) were inconsistent in their prediction of pathogenicity. Our data suggest that the NSD1+/- DNAm signature reflects the functional effect of NSD1 variants on the methylome and can be used as a more robust predictor than existing algorithms for the functional classification of NSD1 variants in overgrowth disorders.-
dc.languageengen_US
dc.publisherAmerican Society of Human Genetics.-
dc.relation.ispartof64th ASHG Annual Meeting 2014en_US
dc.subjectClinical Genetics and Dysmorphology-
dc.subjectKW042 - diagnostics-
dc.subjectKW008 - bioinformatics-
dc.subjectKW107 - intellectual and developmental disability-
dc.subjectKW110 - methylation-
dc.subjectKW040 - development-
dc.titleNSD1+/- DNA methylation (DNAm) signature: A novel functional diagnostic tool for Sotos syndromeen_US
dc.typeConference_Paperen_US
dc.identifier.emailChung, BHY: bhychung@hku.hken_US
dc.identifier.emailLuk, HM: lukhm@hku.hken_US
dc.identifier.authorityChung, BHY=rp00473en_US
dc.description.naturelink_to_OA_fulltext-
dc.identifier.hkuros241661en_US
dc.publisher.placeUnited States-

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