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      A novel deletion mutation in KMT2A identified in a child with ID/DD and blood eosinophilia

      case-report

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          Abstract

          Background

          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).

          Case presentation

          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.

          Conclusions

          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.

          Electronic supplementary material

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

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          Most cited references 22

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          Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.

          To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient-parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.
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            Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database.

            Currently, many studies on neuropsychiatric disorders have utilized massive trio-based whole-exome sequencing (WES) and whole-genome sequencing (WGS) to identify numerous de novo mutations (DNMs). Here, we retrieved 17,104 DNMs from 3555 trios across four neuropsychiatric disorders: autism spectrum disorder, epileptic encephalopathy, intellectual disability and schizophrenia, in addition to unaffected siblings (control), from 36 studies by WES/WGS. After eliminating non-exonic variants, we focused on 3334 exonic DNMs for evaluation of their association with these diseases. Our results revealed a higher prevalence of DNMs in the probands of all four disorders compared with the one in the controls (P<1.3 × 10(-7)). The elevated DNM frequency is dominated by loss-of-function/deleterious single-nucleotide variants and frameshift indels (that is, extreme mutations, P<4.5 × 10(-5)). With extensive annotation of these 'extreme' mutations, we prioritized 764 candidate genes in these four disorders. A combined analysis of Gene Ontology, microRNA targets and transcription factor targets revealed shared biological process and non-coding regulatory elements of candidate genes in the pathology of neuropsychiatric disorders. In addition, weighted gene co-expression network analysis of human laminar-specific neocortical expression data showed that candidate genes are convergent on eight shared modules with specific layer enrichment and biological process features. Furthermore, we identified that 53 candidate genes are associated with more than one disorder (P<0.000001), suggesting a possibly shared genetic etiology underlying these disorders. Particularly, DNMs of the SCN2A gene are frequently occurred across all four disorders. Finally, we constructed a freely available NPdenovo database, which provides a comprehensive catalog of the DNMs identified in neuropsychiatric disorders.
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              World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management.

               Jason Gotlib (2017)
              The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary, clonal) disorders with potential for end-organ damage.
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                Author and article information

                Contributors
                Zhhxia520@163.com
                15058302377@163.com
                wzchenhui@126.com
                chenxiangnj2005@aliyun.com
                tcai@nih.gov
                Journal
                BMC Med Genet
                BMC Med. Genet
                BMC Medical Genetics
                BioMed Central (London )
                1471-2350
                6 March 2019
                6 March 2019
                2019
                : 20
                Affiliations
                [1 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Second Xiangya Hospital, , Central South University, ; Changsha, 410002 Hunan China
                [2 ]ISNI 0000 0004 1764 2632, GRID grid.417384.d, Physical Medicine and Rehabilitation Center, , The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, ; Zhejiang, China
                [3 ]ISNI 0000 0004 1764 2632, GRID grid.417384.d, The Second Affiliated Hospital of Wenzhou Medical University, ; Zhejiang, China
                [4 ]ISNI 0000 0001 2297 5165, GRID grid.94365.3d, Experimental Medicine Section, National Institute of Dental and Craniofacial Research, , National Institutes of Health, ; Bethesda, MD 20892 USA
                Article
                776
                10.1186/s12881-019-0776-0
                6402113
                30841869
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004735, Natural Science Foundation of Hunan Province;
                Award ID: 2017JJ3461
                Funded by: FundRef http://dx.doi.org/10.13039/501100005890, Ministry of Health of the People's Republic of China;
                Award ID: 201302002
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000072, National Institute of Dental and Craniofacial Research;
                Award ID: Intramural Research
                Award Recipient :
                Categories
                Case Report
                Custom metadata
                © The Author(s) 2019

                Genetics

                kmt2a mutation, intellectual disability, eosinophilia, whole exome sequencing, case report

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