Cheryl Cytrynbaum | University of Toronto (original) (raw)

Papers by Cheryl Cytrynbaum

Research paper thumbnail of Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for rare disease patients in a publicly-funded healthcare system: a prospective cohort study

Genetics in Medicine

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Epigenetics

Elsevier eBooks, 2019

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Phenotypic spectrum associated with<i>PTCHD1</i>deletions and truncating mutations includes intellectual disability and autism spectrum disorder

Clinical Genetics, Oct 14, 2014

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spect... more Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD‐like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X‐linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of NSD1 mutations in Sotos syndrome alter the DNA methylation landscape of genes involved in somatic growth and neuronal transmission

Sotos syndrome (OMIM 117550) is a rare genetic overgrowth disorder associated with malformations ... more Sotos syndrome (OMIM 117550) is a rare genetic overgrowth disorder associated with malformations and neurodevelopmental problems including intellectual and behavioural issues. Individuals with Sotos syndrome are haploinsufficient for NSD1 (nuclear receptor-binding SET domain protein 1), a histone lysine methyltransferase important for multiple aspects of normal development. Recently, NSD1 was shown to bind near various promoter elements, regulating multiple genes via interactions with H3K36me and RNA polymerase II. These data suggest a potential role for NSD1 in regulating trans…link_to_OA_fulltex

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Functional impact of global rare copy number variation in autism spectrum disorders

Nature, Jun 9, 2010

Bookmarks Related papers MentionsView impact

Research paper thumbnail of The utility of DNA methylation signatures in directing genome sequencing workflow: Kabuki syndrome and CDK13‐related disorder

American Journal of Medical Genetics Part A, 2022

Kabuki syndrome (KS) is a neurodevelopmental disorder characterized by hypotonia, intellectual di... more Kabuki syndrome (KS) is a neurodevelopmental disorder characterized by hypotonia, intellectual disability, skeletal anomalies, and postnatal growth restriction. The characteristic facial appearance is not pathognomonic for KS as several other conditions demonstrate overlapping features. For 20‐30% of children with a clinical diagnosis of KS, no causal variant is identified by conventional genetic testing of the two associated genes, KMT2D and KDM6A. Here, we describe two cases of suspected KS that met clinical diagnostic criteria and had a high gestalt match on the artificial intelligence platform Face2Gene. Although initial KS testing was negative, genome‐wide DNA methylation (DNAm) was instrumental in guiding genome sequencing workflow to establish definitive molecular diagnoses. In one case, a positive DNAm signature for KMT2D led to the identification of a cryptic variant in KDM6A by genome sequencing; for the other case, a DNAm signature different from KS led to the detection o...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants

Clinical Epigenetics, 2019

Bookmarks Related papers MentionsView impact

Research paper thumbnail of A specific DNA methylation signature associated with NSD1+/- mutations in Sotos syndrome reveals a significant genome-wide loss of DNA methylation (DNAm) targeting CGs in regulatory regions of key developmental genes

Sotos syndrome (SS) is characterized by somatic overgrowth and intellectual disability. Most SS c... more Sotos syndrome (SS) is characterized by somatic overgrowth and intellectual disability. Most SS cases (>75%) have mutations in NSD1 (nuclear receptor-binding SET domain protein 1). NSD1 binds near promoter elements and regulates transcription initiation and elongation via interactions with H3-K36Me and RNA polymerase II. To determine if NSD1 mutations impact stable epigenetic marks such as DNA methylation (DNAm), we compared DNAm in peripheral blood DNA from SS cases with NSD1 mutations (NSD1+/-; n=20) to controls (n=30) using the Illumina Infinium450methylation BeadChip. Differential DNAm analysis using non-parametric statistics (with correction for multiple testing) coupled with permutation analyses identified a surprisingly high number (n=2157) of differentially methylated (DM) CG sites (with >20% difference in DNAm) between SS and controls. These sites were distributed across the genome; 95% demonstrated loss of DNAm. Using unsupervised hierarchical clustering of the 2157 DM CG sites, all SS cases with NSD1 +/- clustered as a distinct group separate from controls. Moreover, DNAm at these sites clearly distinguished SS (NSD1+/-) from Weaver syndrome (EZH2+/-, n=5), another overgrowth syndrome which has considerable phenotypic overlap with SS. These results suggest that these DM CG sites constitute a DNAm signature that is specific for NSD1+/-. Also, the DNAm signature was successfully used to reclassify NSD1 variants of unknown significance (VUS) in six cases of SS into functionally damaging (n=1) and non-pathogenic (n=5) variants. The majority of these DM CGs mapped to enhancers and CpG island shores. Analysis of ChIP-seq data showed that NSD1+/- specific CG sites are associated with reduced H3K36me3 marks in both normal blood and embryonic stem cells. Also, Ingenuity analysis showed enrichment in neural and cellular development pathways (p<0.001). We then searched for binding motifs enriched in these NSD1+/- DNAm targets using MEME and JASPAR CORE database; SP1 was the most enriched with binding sites in 41% of the targets (NCOR=0.62). This is the first report of an NSD1+/- specific DNAm signature in SS and that loss-of-function mutations in NSD1 can deregulate the intricate transcriptional balance of key developmental genes. Further elucidation of this signature will significantly impact our understanding of the molecular pathophysiology of SS and identify the specific molecular targets for NSD1 that govern its action in early development.link_to_OA_fulltex

Bookmarks Related papers MentionsView impact

Research paper thumbnail of NSD1+/- DNA methylation (DNAm) signature: A novel functional diagnostic tool for Sotos syndrome

Session - 32. Molecular Insights into Mendelian Disorders: no. 130Sotos syndrome (SS) is characte... more Session - 32. Molecular Insights into Mendelian Disorders: no. 130Sotos 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.link_to_OA_fulltex

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications

Brain

The blood–brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an... more The blood–brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood–brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype–phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder inv...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Development of a storytelling communication facilitation tool (SCFT) to facilitate discussion of complex genetic diagnoses between parents and their children: A pilot study using 22q11.2 deletion syndrome as a model condition

PEC Innovation

Bookmarks Related papers MentionsView impact

Research paper thumbnail of NSD1+/-DNA methylation (DNAm) signature: A novel functional diagnostic tool for Sotos syndrome

Session - 32. Molecular Insights into Mendelian Disorders: no. 130Sotos syndrome (SS) is characte... more Session - 32. Molecular Insights into Mendelian Disorders: no. 130Sotos 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.link_to_OA_fulltex

Bookmarks Related papers MentionsView impact

Research paper thumbnail of ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome

Human Molecular Genetics

Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS),... more Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood, termed DNAm signatures. Given ANKRD11’s role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3 and 28 typically developing individuals, using Illumina’s Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with ...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Epigenetics

Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Phenotypic spectrum associated withPTCHD1deletions and truncating mutations includes intellectual disability and autism spectrum disorder

Clinical Genetics, 2014

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spect... more Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome

The American Journal of Human Genetics

Bookmarks Related papers MentionsView impact

Research paper thumbnail of The health risks of ART

EMBO reports, 2013

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Location, location, location: protein truncating variants in different loci of SRCAP cause three distinct neurodevelopmental disorders, associated with distinctive DNA methylation signatures

European Journal of Human Genetics, 2020

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

American Journal of Medical Genetics Part A, 2021

Wiedemann‐Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants... more Wiedemann‐Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype–phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty‐nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants. This study identifies genotype–phenotype correlations as well as race‐facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long‐term outcomes in individuals with WSS.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of The Clinician-reported Genetic testing Utility InDEx (C-GUIDE): Preliminary evidence of validity and reliability

Genetics in Medicine, 2021

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for rare disease patients in a publicly-funded healthcare system: a prospective cohort study

Genetics in Medicine

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Epigenetics

Elsevier eBooks, 2019

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Phenotypic spectrum associated with<i>PTCHD1</i>deletions and truncating mutations includes intellectual disability and autism spectrum disorder

Clinical Genetics, Oct 14, 2014

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spect... more Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD‐like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X‐linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of NSD1 mutations in Sotos syndrome alter the DNA methylation landscape of genes involved in somatic growth and neuronal transmission

Sotos syndrome (OMIM 117550) is a rare genetic overgrowth disorder associated with malformations ... more Sotos syndrome (OMIM 117550) is a rare genetic overgrowth disorder associated with malformations and neurodevelopmental problems including intellectual and behavioural issues. Individuals with Sotos syndrome are haploinsufficient for NSD1 (nuclear receptor-binding SET domain protein 1), a histone lysine methyltransferase important for multiple aspects of normal development. Recently, NSD1 was shown to bind near various promoter elements, regulating multiple genes via interactions with H3K36me and RNA polymerase II. These data suggest a potential role for NSD1 in regulating trans…link_to_OA_fulltex

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Functional impact of global rare copy number variation in autism spectrum disorders

Nature, Jun 9, 2010

Bookmarks Related papers MentionsView impact

Research paper thumbnail of The utility of DNA methylation signatures in directing genome sequencing workflow: Kabuki syndrome and CDK13‐related disorder

American Journal of Medical Genetics Part A, 2022

Kabuki syndrome (KS) is a neurodevelopmental disorder characterized by hypotonia, intellectual di... more Kabuki syndrome (KS) is a neurodevelopmental disorder characterized by hypotonia, intellectual disability, skeletal anomalies, and postnatal growth restriction. The characteristic facial appearance is not pathognomonic for KS as several other conditions demonstrate overlapping features. For 20‐30% of children with a clinical diagnosis of KS, no causal variant is identified by conventional genetic testing of the two associated genes, KMT2D and KDM6A. Here, we describe two cases of suspected KS that met clinical diagnostic criteria and had a high gestalt match on the artificial intelligence platform Face2Gene. Although initial KS testing was negative, genome‐wide DNA methylation (DNAm) was instrumental in guiding genome sequencing workflow to establish definitive molecular diagnoses. In one case, a positive DNAm signature for KMT2D led to the identification of a cryptic variant in KDM6A by genome sequencing; for the other case, a DNAm signature different from KS led to the detection o...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants

Clinical Epigenetics, 2019

Bookmarks Related papers MentionsView impact

Research paper thumbnail of A specific DNA methylation signature associated with NSD1+/- mutations in Sotos syndrome reveals a significant genome-wide loss of DNA methylation (DNAm) targeting CGs in regulatory regions of key developmental genes

Sotos syndrome (SS) is characterized by somatic overgrowth and intellectual disability. Most SS c... more Sotos syndrome (SS) is characterized by somatic overgrowth and intellectual disability. Most SS cases (>75%) have mutations in NSD1 (nuclear receptor-binding SET domain protein 1). NSD1 binds near promoter elements and regulates transcription initiation and elongation via interactions with H3-K36Me and RNA polymerase II. To determine if NSD1 mutations impact stable epigenetic marks such as DNA methylation (DNAm), we compared DNAm in peripheral blood DNA from SS cases with NSD1 mutations (NSD1+/-; n=20) to controls (n=30) using the Illumina Infinium450methylation BeadChip. Differential DNAm analysis using non-parametric statistics (with correction for multiple testing) coupled with permutation analyses identified a surprisingly high number (n=2157) of differentially methylated (DM) CG sites (with >20% difference in DNAm) between SS and controls. These sites were distributed across the genome; 95% demonstrated loss of DNAm. Using unsupervised hierarchical clustering of the 2157 DM CG sites, all SS cases with NSD1 +/- clustered as a distinct group separate from controls. Moreover, DNAm at these sites clearly distinguished SS (NSD1+/-) from Weaver syndrome (EZH2+/-, n=5), another overgrowth syndrome which has considerable phenotypic overlap with SS. These results suggest that these DM CG sites constitute a DNAm signature that is specific for NSD1+/-. Also, the DNAm signature was successfully used to reclassify NSD1 variants of unknown significance (VUS) in six cases of SS into functionally damaging (n=1) and non-pathogenic (n=5) variants. The majority of these DM CGs mapped to enhancers and CpG island shores. Analysis of ChIP-seq data showed that NSD1+/- specific CG sites are associated with reduced H3K36me3 marks in both normal blood and embryonic stem cells. Also, Ingenuity analysis showed enrichment in neural and cellular development pathways (p<0.001). We then searched for binding motifs enriched in these NSD1+/- DNAm targets using MEME and JASPAR CORE database; SP1 was the most enriched with binding sites in 41% of the targets (NCOR=0.62). This is the first report of an NSD1+/- specific DNAm signature in SS and that loss-of-function mutations in NSD1 can deregulate the intricate transcriptional balance of key developmental genes. Further elucidation of this signature will significantly impact our understanding of the molecular pathophysiology of SS and identify the specific molecular targets for NSD1 that govern its action in early development.link_to_OA_fulltex

Bookmarks Related papers MentionsView impact

Research paper thumbnail of NSD1+/- DNA methylation (DNAm) signature: A novel functional diagnostic tool for Sotos syndrome

Session - 32. Molecular Insights into Mendelian Disorders: no. 130Sotos syndrome (SS) is characte... more Session - 32. Molecular Insights into Mendelian Disorders: no. 130Sotos 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.link_to_OA_fulltex

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications

Brain

The blood–brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an... more The blood–brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood–brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype–phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder inv...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Development of a storytelling communication facilitation tool (SCFT) to facilitate discussion of complex genetic diagnoses between parents and their children: A pilot study using 22q11.2 deletion syndrome as a model condition

PEC Innovation

Bookmarks Related papers MentionsView impact

Research paper thumbnail of NSD1+/-DNA methylation (DNAm) signature: A novel functional diagnostic tool for Sotos syndrome

Session - 32. Molecular Insights into Mendelian Disorders: no. 130Sotos syndrome (SS) is characte... more Session - 32. Molecular Insights into Mendelian Disorders: no. 130Sotos 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.link_to_OA_fulltex

Bookmarks Related papers MentionsView impact

Research paper thumbnail of ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome

Human Molecular Genetics

Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS),... more Pathogenic variants in ANKRD11 or microdeletions at 16q24.3 are the cause of KBG syndrome (KBGS), a neurodevelopmental syndrome characterized by intellectual disability, dental and skeletal anomalies, and characteristic facies. The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development. Syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show unique patterns of DNA methylation (DNAm) in peripheral blood, termed DNAm signatures. Given ANKRD11’s role in chromatin modification, we tested whether pathogenic ANKRD11 variants underlying KBGS are associated with a DNAm signature. We profiled whole-blood DNAm in 21 individuals with ANKRD11 variants, 2 individuals with microdeletions at 16q24.3 and 28 typically developing individuals, using Illumina’s Infinium EPIC array. We identified 95 differentially methylated CpG sites that distinguished individuals with ...

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Epigenetics

Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Phenotypic spectrum associated withPTCHD1deletions and truncating mutations includes intellectual disability and autism spectrum disorder

Clinical Genetics, 2014

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spect... more Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome

The American Journal of Human Genetics

Bookmarks Related papers MentionsView impact

Research paper thumbnail of The health risks of ART

EMBO reports, 2013

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Location, location, location: protein truncating variants in different loci of SRCAP cause three distinct neurodevelopmental disorders, associated with distinctive DNA methylation signatures

European Journal of Human Genetics, 2020

Bookmarks Related papers MentionsView impact

Research paper thumbnail of Expanding the genotypic and phenotypic spectrum in a diverse cohort of 104 individuals with Wiedemann‐Steiner syndrome

American Journal of Medical Genetics Part A, 2021

Wiedemann‐Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants... more Wiedemann‐Steiner syndrome (WSS) is an autosomal dominant disorder caused by monoallelic variants in KMT2A and characterized by intellectual disability and hypertrichosis. We performed a retrospective, multicenter, observational study of 104 individuals with WSS from five continents to characterize the clinical and molecular spectrum of WSS in diverse populations, to identify physical features that may be more prevalent in White versus Black Indigenous People of Color individuals, to delineate genotype–phenotype correlations, to define developmental milestones, to describe the syndrome through adulthood, and to examine clinicians' differential diagnoses. Sixty‐nine of the 82 variants (84%) observed in the study were not previously reported in the literature. Common clinical features identified in the cohort included: developmental delay or intellectual disability (97%), constipation (63.8%), failure to thrive (67.7%), feeding difficulties (66.3%), hypertrichosis cubiti (57%), short stature (57.8%), and vertebral anomalies (46.9%). The median ages at walking and first words were 20 months and 18 months, respectively. Hypotonia was associated with loss of function (LoF) variants, and seizures were associated with non‐LoF variants. This study identifies genotype–phenotype correlations as well as race‐facial feature associations in an ethnically diverse cohort, and accurately defines developmental trajectories, medical comorbidities, and long‐term outcomes in individuals with WSS.

Bookmarks Related papers MentionsView impact

Research paper thumbnail of The Clinician-reported Genetic testing Utility InDEx (C-GUIDE): Preliminary evidence of validity and reliability

Genetics in Medicine, 2021

Bookmarks Related papers MentionsView impact