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

Choufani, Sanaa; McNiven, Vanda; Cytrynbaum, Cheryl; Jangjoo, Maryam; Adam, Margaret P; Björnsson, Hans T.; Harris, Jacqueline; Dyment, David A.; Graham, Gail E.; Nezarati, Marjan M.; Aul, Ritu; Castiglioni, Claudia; Breckpot, Jeroen; Devriendt, Koen; Stewart, Helen; Banos-Pinero, Benito; Mehta, Sarju G.; Sandford, Richard; Dunn, Carolyn; Mathevet, Remi; Maldergem, Lionel Van; Piard, Juliette; Brischoux‐Boucher, Elise; Vitobello, Antonio; Faivre, Laurence; Bournez, Marie; Tran-Mau, Frederic; Maystadt, Isabelle; Fernández-Jaén, A; Álvarez, Sara; García-Prieto, Irene Díez; Alkuraya, Fowzan S.; Alsaif, Hessa S.; Rahbeeni, Zuhair; El‐Akouri, Karen; Al‐Mureikhi, Mariam; Spillmann, Rebecca C.; Shashi, Vandana; Sanchez‐Lara, Pedro A.; Graham, John M.; Roberts, Amy; Chorin, Odelia; Evrony, Gilad D.; Kraatari, Minna; Dudding‐Byth, Tracy; Richardson, Anamaria; Hunt, David; Hamilton, Laura S.; Dyack, Sarah; Mendelsohn, Bryce A.; Rodríguez, Nicolás; Sánchez-Martínez, Rosario; Tenorio-Castaño, Jair; Nevado, Julián; Lapunzina, Pablo; Tirado, Pilar; Rodrigues, Maria-Teresa Carminho Amaro; Quteineh, Lina; Innes, A. Micheil; Kline, Antonie D.; Au, Ping Yee Billie; Weksberg, Rosanna

doi:10.1016/j.ajhg.2022.08.014

Cited by 17 publications

(20 citation statements)

References 32 publications

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“…Lastly, it may be informative to determine whether the severity of the KBGS phenotype is consistently reflected by the DNAm data. We have demonstrated this relationship for missense variants and DNAm in the HNRNPK gene associated with Au-Kline syndrome ( 30 ). In the future, DNAm profiling could be helpful in predicting pathogenicity and severity of the KBGS phenotype as we have shown for a missense ANKRD11 variant inherited from a clinically unaffected parent.…”

Section: Discussionmentioning

confidence: 70%

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

Awamleh

Choufani

Cytrynbaum

et al. 2022

Human Molecular Genetics

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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, 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 KBGS and pathogenic variants in ANKRD11 (n = 14) from typically developing controls (n = 28) and was also validated in seven additional individuals with pathogenic ANKRD11 variants. We generated a machine learning model from the KBGS DNAm signature and classified the DNAm profiles of 4 individuals with variants of uncertain significance (VUS) in ANKRD11. We identified an intermediate classification score for an inherited missense variant transmitted from a clinically unaffected mother to her affected child. In conclusion, we show the DNAm profile of two individuals with 16q24.3 microdeletions, was indistinguishable from the DNAm profile of individuals with pathogenic variants in ANKRD11 and we demonstrate the diagnostic utility of the new KBGS signature by classifying the DNAm profiles of individuals with VUS in ANKRD11.

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Section: Discussionmentioning

confidence: 70%

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

Awamleh

Choufani

Cytrynbaum

et al. 2022

Human Molecular Genetics

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“…Whereas Choufani et al (16) used a methylation bead array platform targeting ~ 850,000 CpGs for methylation pro ling, we used a NGS-based assay targeting > 2M CpGs. The difference in methodology and analytical approaches used by Choufani et al (2022) and us limits the detailed comparison of the methylation episignatures from the two conditions. Whereas Choufani et al (16) identi ed 429 statistically signi cant CpG DMPs in their AKS discovery cohort (n = 6) using a false discovery rate adjusted p-value of 0.05 and a minimum methylation difference of 10%, we employed a p-value of less than 0.01 and a more stringent minimum methylation difference of 20% and identi ed 227 DMPs in our HNRNPU-NDD cohort (n = 7).…”

Section: Discussionmentioning

confidence: 99%

Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome

Lee

Ochoa

Badura‐Stronka

et al. 2023

Preprint

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HNRNPU encodes a multifunctional RNA-binding protein that plays critical roles in regulating pre-mRNA splicing, mRNA stability, and translation. Aberrant expression and dysregulation of HNRNPU have been implicated in various human diseases, including cancers and neurological disorders. We applied a next generation sequencing based assay (EPIC-NGS) to investigate genome-wide methylation profiling for > 2M CpGs for 7 individuals with a neurodevelopmental disorder associated with HNRNPU germline pathogenic loss-of-function variants. Compared to healthy individuals, 227 HNRNPU-associated differentially methylated positions were detected. Both hyper- and hypomethylation alterations were identified but the former predominated. The identification of a methylation episignature for HNRNPU-associated neurodevelopmental disorder (NDD) implicates HNPRNPU-related chromatin alterations in the aetiopathogenesis of this disorder and suggests that episignature profiling should have clinical utility as a predictor for the pathogenicity of HNRNPU variants of uncertain significance. The detection of a methylation episignaure for HNRNPU-associated NDD is consistent with a recent report of a methylation episignature for HNRNPK-associated NDD.

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“…Several studies have shown that pathogenic variants in disease-causing genes can induce stable changes in DNA methylation patterns at multiple positions across the genome, referred to as episignatures. [131][132][133][134][135][136][137][138][139][140][141] They are typically detected by conducting epigenome-wide association studies and then training binary or multi-class machine learning classifiers. 142 To date, episignatures have been described for more than 65 Mendelian neurodevelopmental disorders.…”

Section: Dna Methylation Episignatures and Epivariationsmentioning

confidence: 99%

“…In recent years, the detection of DNA methylation episignatures has gained the most popularity among epigenetic approaches for rare disease diagnosis. Several studies have shown that pathogenic variants in disease‐causing genes can induce stable changes in DNA methylation patterns at multiple positions across the genome, referred to as episignatures 131–141 . They are typically detected by conducting epigenome‐wide association studies and then training binary or multi‐class machine learning classifiers 142 .…”

Section: Dna Methylation Episignatures and Epivariationsmentioning

confidence: 99%

Integrative omics approaches to advance rare disease diagnostics

Smirnov

Konstantinovskiy

Prokisch

2023

J of Inher Metab Disea

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Over the past decade high‐throughput DNA sequencing approaches, namely whole exome and whole genome sequencing became a standard procedure in Mendelian disease diagnostics. Implementation of these technologies greatly facilitated diagnostics and shifted the analysis paradigm from variant identification to prioritisation and evaluation. The diagnostic rates vary widely depending on the cohort size, heterogeneity, and disease and range from around 30% to 50% leaving the majority of patients undiagnosed. Advances in omics technologies and computational analysis provide an opportunity to increase these unfavourable rates by providing evidence for disease‐causing variant validation and prioritisation. This review aims to provide an overview of the current application of several omics technologies including RNA‐sequencing, proteomics, metabolomics and DNA‐methylation profiling for diagnostics of rare genetic diseases in general and inborn errors of metabolism in particular.This article is protected by copyright. All rights reserved.

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

Cited by 17 publications

References 32 publications

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

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

Germline pathogenic variants in HNRNPU are associated with alterations in blood methylome

Integrative omics approaches to advance rare disease diagnostics

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