Further delineation of the phenotype of truncating <i>KMT2A</i> mutations: The extended Wiedemann–Steiner syndrome

Sun, Yu; Hu, Guorui; Liu, Huili; Zhang, Xia; Huang, Zhuo; Yan, Hui; Wang, Lili; Fan, Yanjie; Gu, Xuefan; Yu, Yongguo

doi:10.1002/ajmg.a.38025

Cited by 43 publications

(52 citation statements)

References 11 publications

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“…The most frequent and probably the most characteristic combination More than 20 additional cases have been mentioned in exomesequencing studies of patients with ID; however, clinical descriptions were absent or lacked detail. 16,[18][19][20][21][22][23][24][25][26][27][28] We decided to exclude the first 5 cases described from our statistical analysis, because they didn't have a molecular diagnosis. In 2013, 7 members of a large family were identified with a mutation in KMT2A; 4 of them had primary mediastinal large β-cell lymphoma but none had the dysmorphic features or ID suggestive of WSS.…”

Section: Phenotypic Analysismentioning

confidence: 99%

Wiedemann‐Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases

et al. 2018

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Wiedemann-Steiner syndrome (WSS) is a rare syndromic condition in which intellectual disability (ID) is associated with hypertrichosis cubiti, short stature, and characteristic facies. Following the identification of the causative gene (KMT2A) in 2012, only 31 cases of WSS have been described precisely in the literature. We report on 33 French individuals with a KMT2A mutation confirmed by targeted gene sequencing, high-throughput sequencing or exome sequencing. Patients' molecular and clinical features were recorded and compared with the literature data. On the molecular level, we found 29 novel mutations. We observed autosomal dominant transmission of WSS in 3 families and mosaicism in one family. Clinically, we observed a broad phenotypic spectrum with regard to ID (mild to severe), the facies (typical or not of WSS) and associated malformations (bone, cerebral, renal, cardiac and ophthalmological anomalies). Hypertrichosis cubiti that was supposed to be pathognomonic in the literature was found only in 61% of our cases. This is the largest series of WSS cases yet described to date. A majority of patients exhibited suggestive features, but others were less characteristic, only identified by molecular diagnosis. The prevalence of WSS was higher than expected in patients with ID, suggesting than KMT2A is a major gene in ID.

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Section: Phenotypic Analysismentioning

confidence: 99%

Wiedemann‐Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases

et al. 2018

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“…In these five patients the KMT2A variants were predicted to result in premature termination of translation and to a nonsensemediated decay (NMD) of the corresponding transcripts [7]. Since this first description additional WSS patients, including a pair of monozygotic twins, have been reported, especially by using exome analysis approaches, bringing to more than 25 the total number of patients carrying KMT2A variants leading to a premature stop codon [7,[16][17][18][19][20][21][22][23][24][25][26]. KMT2A missense variants have been reported in five patients with WSS, one of them having a severe form of the disease and congenital immunodeficiency [16].…”

Section: Introductionmentioning

confidence: 99%

Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome

et al. 2017

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Variants in KMT2A, encoding the histone methyltransferase KMT2A, are a growing cause of intellectual disability (ID). Up to now, the majority of KMT2A variants are non-sense and frameshift variants causing a typical form of Wiedemann-Steiner syndrome. We studied KMT2A gene in a cohort of 200 patients with unexplained syndromic and non-syndromic ID and identified four novel variants, one splice and three missense variants, possibly deleterious. We used primary cells from the patients and molecular approaches to determine the deleterious effects of those variants on KMT2A expression and function. For the putative splice variant c.11322-1G>A, we showed that it led to only one nucleotide deletion and loss of the C-terminal part of the protein. For two studied KMT2A missense variants, c.3460C>T (p.(Arg1154Trp)) and c.8558T>G (p.(Met2853Arg)), located at the cysteine-rich CXXC domain and the transactivation domain of the protein, respectively, we found altered KMT2A target genes expression in patient's fibroblasts compared to controls. Furthermore, we found a disturbed subcellular distribution of KMT2A for the c.3460C>T mutant. Taken together, our results demonstrated the deleterious impact of the splice variant and of the missense variants located at two different functional domains and suggested reduction of KMT2A function as the disease-causing mechanism.

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“…The library was sequenced by Illumina HiSeq 4000 to generate 150 bp paired end reads. Data analysis was performed as previously described [14]. In general, the raw data was aligned to the human reference hg19 by BWA.…”

Section: Ngs and Validationmentioning

confidence: 99%

Genetic Evaluation of 114 Chinese Short Stature Children in the Next Generation Era: a Single Center Study

Huang

Sun

Fan

et al. 2018

Cell Physiol Biochem

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Background/Aims: The genetics of human height is a frequently studied and complex issue. However, there is limited genetic research of short stature. To uncover the subgroup of patients to have higher yield and to propose a simplified diagnostic algorithm in the next generation era. Methods: This study included 114 Chinese children with height SDS ≤ -2.5 and unknown etiology from 2014 to 2015. Target/whole exome sequencing (referred as NGS) and chromosomal microarray analysis (CMA) were performed on the enrolled patients sequentially to identify potential genetic etiologies. The samples solved by NGS and CMA were retrospectively studied to evaluate the clinical pathway of the patients following a standard diagnostic algorithm. Results: In total, a potential genetic etiology was identified in 41 (36%) patients: 38 by NGS (33.3%), two by CMA (1.8%), and an additional one by both (0.9%). There were 46 different variants in 29 genes and 2 pathogenic CNVs identified. The diagnostic yield was significantly higher in patients with facial dysmorphism or skeletal abnormalities than those without the corresponding phenotype (P=0.006 and P=0.009, respectively, Pearson’s χ² test). Retrospectively study the cohort indicate 83.3% patients eventually would be evaluated by NGS/CMA. Conclusion: This study confirms the utility of high-throughput molecular detection techniques for the etiological diagnosis of undiagnosed short stature and suggests that NGS could be used as a primary diagnostic strategy. Patients with facial dysmorphism and/or skeletal abnormalities are more likely to have a known genetic etiology. Moving NGS forward would simplified the diagnostic algorithm.

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Further delineation of the phenotype of truncating KMT2A mutations: The extended Wiedemann–Steiner syndrome

Cited by 43 publications

References 11 publications

Wiedemann‐Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases

Wiedemann‐Steiner syndrome as a major cause of syndromic intellectual disability: A study of 33 French cases

Molecular and cellular issues of KMT2A variants involved in Wiedemann-Steiner syndrome

Genetic Evaluation of 114 Chinese Short Stature Children in the Next Generation Era: a Single Center Study

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