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

Published version
Peer-reviewed

Repository DOI


Type

Article

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Authors

Choufani, Sanaa 
McNiven, Vanda 
Cytrynbaum, Cheryl 
Jangjoo, Maryam 
Adam, Margaret P 

Abstract

Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations.

Description

Keywords

Au-Kline syndrome, DNA methylation signature, HNRNPK, Kabuki syndrome, Okamoto syndrome, RNA processing gene, epigenetics, episignature, neurodevelopmental disorder, Abnormalities, Multiple, Chromatin, DNA Methylation, Epigenesis, Genetic, Face, Hematologic Diseases, Heterogeneous-Nuclear Ribonucleoprotein K, Humans, Intellectual Disability, Phenotype, Vestibular Diseases

Journal Title

Am J Hum Genet

Conference Name

Journal ISSN

0002-9297
1537-6605

Volume Title

109

Publisher

Elsevier BV