2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-<em>NSD2</em> duplication results in distinct phenotype and DNA methylation signature

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This study investigates the clinical features and DNA methylation (DNAm) signature in cases with partial 4p trisomy, specifically focusing on the NSD2 gene. Wolf-Hirschhorn syndrome (WHS) is caused by a partial deletion of chromosome 4p and is characterized by developmental delay, growth deficiency, and craniofacial features. The NSD2 gene, located in the critical region on 4p16.3, is associated with a syndrome called Rauch-Steindl syndrome (RAUST) that presents with similar features. Recent studies have reported missense gain-of-function variants in the NSD2 gene in cases with a distinct phenotype from WHS and RAUST, suggesting NSD2's involvement in 4p trisomy syndrome.<br /><br />The researchers aimed to define a DNAm signature specific to NSD2 duplication-associated syndrome and compare it to cases with partial 4p trisomy without NSD2 duplication, as well as cases with partial 4p deletion, truncating variants, and missense variants in the NSD2 gene. They developed an episignature using 13 rare cases of partial 4p trisomy, including those with NSD2 gene duplication and those with duplication breakpoints proximal to NSD2. The episignature was specific to NSD2 duplication, as the four cases without NSD2 duplication did not cluster with the NSD2 duplication cases.<br /><br />The study found that NSD2 gene duplication is associated with a global hypermethylation profile, and the developed episignature can be used to diagnose NSD2 duplication-associated syndrome. A support vector machine (SVM) classifier model using the episignature probes showed the specificity of the episignature. The study also compared the DNAm profile of NSD2 duplication-associated syndrome to other neurodevelopmental disorders and confirmed its distinctness.<br /><br />In conclusion, NSD2 gene duplication is associated with a specific DNAm episignature that can be used for the diagnosis of NSD2 duplication-associated syndrome. The developed episignature is unique to NSD2 duplication and demonstrates the potential for using DNAm patterns as a diagnostic tool for patients with suspected genetic disorders.

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Presenting Author - Benjamin A. Hilton, PhD; Co-Author - Bekim Sadikovic, PhD, FACMG; Co-Author - Alfredo A. Brusco, PhD; Co-Author - Giovanni Battista Ferrero, MD PhD; Co-Author - Barbara R. DuPont, PhD, FACMG; Co-Author - Matthew L. Tedder, PhD; Co-Author - Raymond J. Louie, PhD, FACMG; Co-Author - Nikhil S. Sahajpal, PhD; Co-Author - Erica F. Andersen, PhD, FACMG; Co-Author - Zoe K. Lewis, MS, CGC; Co-Author - Amanda S. Openshaw, MS, CGC; Co-Author - Jennifer Kerkhof, BSc; Co-Author - Haley McConkey, MSc; Co-Author - Raissa Relator, PhD; Co-Author - Sadegheh Haghshenas, PhD; Co-Author - Kathleen Rooney, BSc MLT; Co-Author - Jack Reilly, MS;

Meta Tag

Chromosomal Abnormalities

Chromosome Structure/Function

Clinical Applications of Molecular Cytogenetics

Clinical Cytogenetics

Cognitive Disorders

Congenital Anomaly

Epigenetics

Co-Author Bekim Sadikovic, PhD, FACMG

Co-Author Alfredo A. Brusco, PhD

Co-Author Giovanni Battista Ferrero, MD PhD

Co-Author Barbara R. DuPont, PhD, FACMG

Co-Author Matthew L. Tedder, PhD

Co-Author Raymond J. Louie, PhD, FACMG

Co-Author Nikhil S. Sahajpal, PhD

Co-Author Erica F. Andersen, PhD, FACMG

Co-Author Zoe K. Lewis, MS, CGC

Co-Author Amanda S. Openshaw, MS, CGC

Co-Author Jennifer Kerkhof, BSc

Co-Author Haley McConkey, MSc

Co-Author Raissa Relator, PhD

Co-Author Sadegheh Haghshenas, PhD

Co-Author Kathleen Rooney, BSc MLT

Co-Author Jack Reilly, MS

Presenting Author Benjamin A. Hilton, PhD

Keywords

clinical features

DNA methylation

DNAm signature

partial 4p trisomy

NSD2 gene

Wolf-Hirschhorn syndrome

Rauch-Steindl syndrome

episignature

global hypermethylation profile

neurodevelopmental disorders