• hair disorder
• hypertrichosis
• hypertrichosis cubiti
• pediatric dermatology
• skin disorder

• CX3CR1
• GDF5
• developmental dysplasia of the hip
• single-nucleotide polymorphisms
• susceptibility gene

• ADAMTS8
• Dysplastic enamel
• Early teething
• KMT2A
• Rapid tooth replacement
• Wiedemann–Steiner syndrome

• KMT2A
• SBDS
• Shwachman-Diamond Syndrome
• dual molecular diagnosis
• eVai
• whole-exome sequencing

• Cell division
• DNA damage response
• Genetic disorders
• H3K4 methylation
• Histone–lysine N-methyltransferase 2 (KMT2)
• Metabolic activities

Posttranslational modification of histones and related gene regulation are shown to be affected in an increasing number of neurological disorders. SETD1A is a chromatin remodeler that influences gene expression through the modulation of mono- di- and trimethylation marks on Histone-H3-Lysine-4 (H3K4me1/2/3). H3K4 methylation is predominantly described to result in transcriptional activation, with its mono- di- and trimethylated forms differentially enriched at promoters or enhancers. Recently, dominant mostly de novo variants in SETD1A have clinically been linked to developmental delay, intellectual disability (DD/ID), and schizophrenia (SCZ). Affected individuals often display both developmental and neuropsychiatric abnormalities. The primary diagnoses are mainly dependent on the age at which the individual is assessed. Investigations in mouse models of SETD1A dysfunction have been able to recapitulate key behavioral features associated with ID and SCZ. Furthermore, functional investigations suggest disrupted synaptic and neuronal network function in these mouse models. In this review, we provide an overview of pre-clinical studies on the role of SETD1A in neuronal development. A better understanding of the pathobiology underlying these disorders may provide novel opportunities for therapeutic intervention. As such, we will discuss possible strategies to move forward in elucidating the genotype-phenotype correlation in SETD1A associated disorders.

• SETD1A
• chromatin modification
• histone methlyation
• neurodevelopmental disorders (NDD)
• psychiatric disorders
• schizophrenia

Wiedemann–Steiner syndrome (WSS) is an autosomal dominant disorder characterized by short stature, hypertrichosis, intellectual disability, developmental delay, along with facial dysmorphism. WSS patients exhibit great phenotypic heterogeneities. Some variants in KMT2A (MLL) gene have been identified as the cause of WSS.

Whole exome sequencing on the probands followed by Sanger sequencing validations in the family were applied to determine genetic variants. In silico analyses were used for predicting potential effects of the variants.

We identified three novel de novo heterozygous variants: c.883A>T (p.Lys295*), c.4171C>T (p.Gln1391*), and c.3499T>C (p.Cys1167Arg), in KMT2A gene from three unrelated Chinese WSS patients. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, these three variants were classified as pathogenic, pathogenic and likely pathogenic variant, respectively. By reviewing all the available cases with same mutated KMT2A regions as the three patients had, we found that in addition to the representative symptoms, our patients exhibited some sporadically observed symptoms, such as severe ophthalmological symptoms, endocardial fibroelastosis, cytomegalovirus infection, and feet eversion. We also revealed that variants in different KMT2A regions contribute to the phenotypic heterogeneity of WSS, highlighting challenges in the diagnosis of syndromic disorders spanning a broad phenotypic spectrum.

Our study would aid in further broadening our knowledge about the genotype–phenotype correlation of WSS.

• KMT2A
• Wiedemann-Steiner syndrome
• de novo variant
• endocardial fibroelastosis
• neurodevelopment delay

• dentistry
• genetics
• pediatric and adolescent medicine

• KMT2A
• Wiedemann-Steiner syndrome
• de novo mutation
• whole exome sequencing

Wiedemann-Steiner syndrome (OMIM #605130) is a rare congenital malformation syndrome characterized by hypertrichosis cubiti associated with short stature; consistent facial features, including long eyelashes, thick or arched eyebrows with a lateral flare, wide nasal bridge, and downslanting and vertically narrow palpebral fissures; mild to moderate intellectual disability; behavioral difficulties; and hypertrichosis on the back. It is caused by heterozygous pathogenic variants in KMT2A. This gene has an established role in histone methylation, which explains the overlap of Wiedemann-Steiner syndrome with other chromatinopathies, a heterogeneous group of syndromic conditions that share a common trigger: The disruption of one of the genes involved in chromatin modification, leading to dysfunction of the epigenetic machinery.

• Chromatin
• Chromatin remodeling
• Chromatinopathies
• Wiedemann-Steiner syndrome
• Hairy elbows
• KMT2A

The KMT2A gene encoded lysine methyltransferase plays an essential role in regulating gene expression during early development and hematopoiesis. To date, 92 different mutations of KMT2A have been curated in the human gene mutation database (HGMD), resulting in Wiedemann-Steiner syndrome (WDSTS) and intellectual disability (ID)/developmental delay (DD).

In this report, we present a de novo heterozygous deletion mutation [c.74delG; p. (Gly26Alafs*2)] in the KMT2A gene, which was identified by trio-based whole exome sequencing from a 5.5-year-old boy with ID/DD, stereotypic hand movements and blood eosinophilia. Many deleterious germline mutations of KMT2A have been documented to affect development of central nervous system, oral and craniofacial tissues, but not blood eosinophils.

This is the first report of a rare case with ID/DD as well as eosinophilia, resulting from a previously undescribed null mutation of KMT2A. Our findings expand the phenotypical spectrum in affected individuals with KMT2A mutations, and may shed some insight into the role of KMT2A in eosinophil metabolism.

The online version of this article (10.1186/s12881-019-0776-0) contains supplementary material, which is available to authorized users.

• Case report
• Eosinophilia
• Intellectual disability
• KMT2A mutation
• Whole exome sequencing

• KMT2A
• Wiedemann-Steiner syndrome
• hypertrichosis
• hypertrichosis cubiti
• lysine methyltransferase

Wiedemann–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.

Next 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.

Genetic 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.

Our 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.

The online version of this article (10.1186/s13023-018-0909-0) contains supplementary material, which is available to authorized users.

• Chinese patients
• KMT2A variation
• Phenotypic differences
• Wiedemann–Steiner syndrome

• KMT2A
• Wiedemann-Steiner syndrome
• hairiness
• histone methylation
• hypertrichosis
• intellectual disability

• KMT2A
• Wiedemann-Steiner syndrome
• preaxial polydactyly

• KMT2A
• Novel pathogenic variant
• Wiedemann-Steiner syndrome