Abstract
Wiedemann–Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies (typical or not) and other associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.
Highlights
Wiedemann–Steiner syndrome (WDSTS, MIM# 605130) is a rare severe autosomal dominant disorder, characterized by intellectual disability (ID), developmental delay, hypertrichosis cubiti and distinctive facial features [1,2,3,4,5,6,7,8]
Study of the DNA methylation episignatures has been useful to assign a diagnosis to patients with neurodevelopmental disorders (NDDs) that remained unresolved by conventional testing or in patients with incorrect initial clinical diagnosis [23,25,26]
The methylome analysis did highlight a substantial change in the global methylation pattern in WDSTS samples, and resulted in 87% hypomethylated and 13% hypermethylated probes
Summary
Wiedemann–Steiner syndrome (WDSTS, MIM# 605130) is a rare severe autosomal dominant disorder, characterized by intellectual disability (ID), developmental delay, hypertrichosis cubiti and distinctive facial features [1,2,3,4,5,6,7,8]. The phenotypic spectrum of WDSTS has recently been expanded with clinical features such as ocular abnormalities, recurrent infections of the genitourinary and/or respiratory tract, cardiac or urogenital malformations and skeletal abnormalities, including craniovertebral junction (CVJ) anomalies [6]. The. WDSTS phenotype and genotype–phenotype correlation is currently not fully understood. While phenotypical evaluation of patients has still remained critical for the process of diagnosis, the clinical diagnosis for chromatin-related disorders is often established only after identification of a causative genetic variant [9]
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