2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Identification of a Novel, Deep-Intronic Alteration in <em>KDM6A</em>: How a Multi-Omics Approach Ended a 10+ Year Diagnostic Odyssey.

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A case study published in Genes described the use of a multi-omics approach to diagnose a patient with Kabuki syndrome who had been on a diagnostic odyssey for over 10 years. Kabuki syndrome is a neurodevelopmental disorder characterized by intellectual disabilities, facial dysmorphisms, and poor growth. In this case, the patient presented with congenital hypotonia, feeding difficulties, and a high, narrow palate. Despite extensive testing, a diagnosis had not been reached. <br /><br />The researchers performed DNA methylation "episignature" analysis, which compares the patient's CpG sites to disease-specific episignatures. This analysis identified the Kabuki syndrome episignature, but further sequencing and analysis did not identify any causative alterations in the KDM6A gene. However, genome sequencing eventually revealed a novel deep-intronic alteration in KDM6A. This alteration was confirmed to be maternal in origin and resulted in an in-frame insertion of seven amino acids. Multiple lines of evidence, including the episignature analysis, absence of the variant in reference population databases, and cDNA analysis, supported the pathogenicity of the variant. <br /><br />The researchers performed various techniques in their analysis, including DNA methylation analysis using bisulfite conversion and Illumina BeadChips, genome sequencing, and X-inactivation studies using HpaII digestion and fragment analysis. They also conducted cDNA studies to analyze the effect of the variant on gene expression. <br /><br />The study concluded that a multi-omics approach combining epigenomics, genomics, and transcript analysis was effective in finally diagnosing this patient with Kabuki syndrome. The strategy allowed for a clinical diagnosis, identified the causative alteration, and provided evidence to support the pathogenicity of the variant. It is suggested that a similar approach could be used for other undiagnosed cases. The researchers expressed their gratitude to the patient's family and healthcare providers for their participation in the study.

Asset Subtitle

Presenting Author - Matthew L. Tedder, PhD; Co-Author - Jessica A. Cooley Coleman, PhD; Co-Author - Anna Childers, MS; Co-Author - Jennifer Kerkhof, BSc; Co-Author - Raymond J. Louie, PhD, FACMG; Co-Author - Jennifer A. Lee, PhD, FACMG; Co-Author - Michael J. Friez, PhD; Co-Author - Bekim Sadikovic, PhD, FACMG; Co-Author - David B. Everman, MD; Co-Author - Richard C. Rogers, MD; Co-Author - Raymond C. Caylor, PhD, FACMG;

Meta Tag

Cognitive Disorders

Epigenetics

Genetic Testing

Genome sequencing

Genomic Methodologies

Intellectual disability

Methylation

Microarray

Sequencing

X-Inactivation/X-Linked Disease

Co-Author Jessica A. Cooley Coleman, PhD

Co-Author Anna Childers, MS

Co-Author Jennifer Kerkhof, BSc

Co-Author Raymond J. Louie, PhD, FACMG

Co-Author Jennifer A. Lee, PhD, FACMG

Co-Author Michael J. Friez, PhD

Co-Author Bekim Sadikovic, PhD, FACMG

Co-Author David B. Everman, MD

Co-Author Richard C. Rogers, MD

Co-Author Raymond C. Caylor, PhD, FACMG

Presenting Author Matthew L. Tedder, PhD

Keywords

multi-omics approach

diagnosis

Kabuki syndrome

neurodevelopmental disorder

DNA methylation

episignature analysis

KDM6A gene

deep-intronic alteration

genome sequencing

cDNA analysis