Description of the molecular and phenotypic spectrum of Wiedemann-Steiner syndrome in Chinese patients

Abstract

BackgroundWiedemann–Steiner syndrome (WDSTS) is a rare genetic disorder characterized by facial gestalt, neurodevelopmental delay, skeletal anomalies and growth retardation, which is caused by variation of KMT2A gene. To date, only 2 Chinese WDSTS patients have been reported. Here, we report the phenotypes and KMT2A gene variations in 14 unrelated Chinese WDSTS patients and investigate the phenotypic differences between the Chinese and French cohorts. MethodsNext generation sequencing was performed for each patient, and the variants in the KMT2A gene were validated by Sanger sequencing. The phenotypes of 16 Chinese WDSTS patients were summarized and compared to 33 French patients.ResultsGenetic sequencing identified 13 deleterious de novo KMT2A variants in 14 patients, including 10 truncating, 2 missenses and 1 splicing variants. Of the 13 variants, 11 are novel and two have been reported previously. One of the patients is mosaic in the KMT2A gene. The variation spectra and phenotypic profiles of the Chinese WDSTS patients showed no difference with patients of other ethnicities; however, differ in the frequencies of several clinical features. We demonstrated that variations in the KMT2A gene can lead to both advanced and delayed bone age. We identified 6 novel phenotypes, which include microcephaly, deep palmar crease, external ear deformity, carpal epiphyseal growth retardation, dyslipidemia, and glossoptosis. In addition, patients harbored missense variants in the CXXC zinc finger domain of KMT2A showed more severe neurophenotypes.ConclusionOur study consists of the largest cohort of Chinese WDSTS patients that continues to expand the WDSTS phenotypic and variation spectrum. Our results support the notion that the CXXC zinc finger domain of KMT2A gene is a hotspot for missense variants associated with more severe neurophenotypes.Electronic supplementary materialThe online version of this article (10.1186/s13023-018-0909-0) contains supplementary material, which is available to authorized users.

Impaired Regulation of Histone Methylation and Acetylation Underlies Specific Neurodevelopmental Disorders

“…Wiedemann-Steiner syndrome (WDSTS; OMIM #605130) is a rare congenital malformation and neurodevelopmental disorder first described by Wiedemann et al in 1989 and later by Steiner and Marques in 2000 (Wiedemann et al, 1989 ; Steiner and Marques, 2000 ). WDSTS is characterized by intellectual disability, language and motor delays, hypertrichosis cubiti, delayed bone age, and distinct craniofacial features (Koenig et al, 2010 ; Jones et al, 2012 ; Miyake et al, 2016 ; Li et al, 2018 ).…”

“…Several mutations of KMT2A have been reported, which include single nucleotide missense mutations, non-sense mutations, insertion/deletion alterations that cause frame-shift mutations, and mutations affecting splice site sequences (Li et al, 2018 ). Most of the known mutations alter the reading frame and introduce termination codons in a non-terminal exon.…”

Chromatinopathies: A focus on Cornelia de Lange syndrome

“…In addition, genetic variants in KMT2A can also cause Wiedemann‐Steiner syndrome (WDSTS, OMIM #605130) . With the establishment and application of exome sequencing and other NGS in molecular diagnostics the number of identified pathogenic variants in KMT2A is rapidly increasing . KMT2A is a histone methyltransferase that preferentially targets histone H3 lysine 4, known to play fundamental role in controlling transcription with direct effects on embryogenesis and cell‐cycle progression .…”

Wiedemann–Steiner Syndrome: A Rare Differential Diagnosis of Neurodevelopmental Delay and Dysmorphic Features

“…The prevalence of feeding difficulty varies in French and Chinese cohorts (31-65%). 12,13 The previous medical history of present case revealed that she had feeding difficulty and tube fed. The main complaint of our patient was neuromotor developmental delay.…”