Clinical and Neurobehavioral Features of Three Novel Kabuki Syndrome Patients with Mosaic KMT2D Mutations and a Review of Literature

Lepri, Francesca Romana; Cocciadiferro, Dario; Augello, Bartolomeo; Alfieri, Paolo; Pes, Valentina; Vancini, Alessandra; Caciolo, Cristina; Squeo, Gabriella Maria; Malerba, Natascia; Adipietro, Iolanda; Novelli, Antonio; Sotgiu, Stefano; Gherardi, Renzo; Digilio, María Cristina; Dallapiccola, Bruno; Merla, Giuseppe

doi:10.3390/ijms19010082

Cited by 20 publications

(32 citation statements)

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“…We identified a nonsense variant of KMT2D with a mosaicism level of 37.0% in one male patient (KMS-025). Although he showed the typical facial features of KS and multisystem abnormalities, his features and intellectual disability were milder than those reported previously in mosaic cases (Banka et al, 2013;Lepri et al, 2017). He was enrolled in a special education class in preschool, but went on to attend a normal class in elementary school.…”

Section: Discussionmentioning

confidence: 69%

Update of the genotype and phenotype ofKMT2DandKDM6Aby genetic screening of 100 patients with clinically suspected Kabuki syndrome

Murakami

Tsurusaki

Enomoto

et al. 2020

American J of Med Genetics Pt A

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Kabuki syndrome is characterized by a variable degree of intellectual disability, characteristic facial features, and complications in various organs. Many variants have been identified in two causative genes, that is, lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A). In this study, we present the results of genetic screening of 100 patients with a suspected diagnosis of Kabuki syndrome in our center from July 2010 to June 2018. We identified 76 variants (43 novel) in KMT2D and 4 variants (3 novel) in KDM6A as pathogenic or likely pathogenic. Rare variants included a deep splicing variant (c.14000‐8C>G) confirmed by RNA sequencing and an 18% mosaicism level for a KMT2D mutation. We also characterized a case with a blended phenotype consisting of Kabuki syndrome, osteogenesis imperfecta, and 16p13.11 microdeletion. We summarized the clinical phenotypes of 44 patients including a patient who developed cervical cancer of unknown origin at 16 years of age. This study presents important details of patients with Kabuki syndrome including rare clinical cases and expands our genetic understanding of this syndrome, which will help clinicians and researchers better manage and understand patients with Kabuki syndrome they may encounter.

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Section: Discussionmentioning

confidence: 69%

Update of the genotype and phenotype ofKMT2DandKDM6Aby genetic screening of 100 patients with clinically suspected Kabuki syndrome

Murakami

Tsurusaki

Enomoto

et al. 2020

American J of Med Genetics Pt A

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“…The authors applied our proposed diagnostic criteria to three individuals with mosaic KS reported in the literature 37. Each reported patient had a mosaic heterozygous pathogenic variant in KMT2D and was reported to have mild clinical features of KS.…”

Section: Discussionmentioning

confidence: 99%

Kabuki syndrome: international consensus diagnostic criteria

et al. 2018

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BackgroundKabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in KMT2D or KDM6A. Understanding the function of these genes opens the door to targeted therapies. The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal.MethodsAn international group of experts created consensus diagnostic criteria for KS. Systematic PubMed searches returned 70 peer-reviewed publications in which at least one individual with molecularly confirmed KS was reported. The clinical features of individuals with known mutations were reviewed.ResultsThe authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, are presented.ConclusionAs targeted therapies for KS are being developed, it is important to be able to make the correct diagnosis, either with or without molecular genetic confirmation.

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“…Mhanni et al (1999) showed that all individuals with this syndrome presented similar physiognomy, which simplified the recognition of the syndrome in childhood. Three other case reports from different authors have shown 100% of physiognomy changes that are typical of the syndrome (MCGAUGHRAN et al, 2001;LEPRI et al, 2017;XIN et al, 2018), suggesting that such observations are of considerable importance and make it possible to diagnose the syndrome based on phenotype.…”

Section: Discussionmentioning

confidence: 95%

Systematic review of Kabuki Syndrome’s phenotype with KMT2D gene mutation

Fischetti

Zaccarelli-Magalhães

Fukushima

et al. 2019

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Kabuki Syndrome is rare and poorly documented, initially mentioned by Niikawa and Kuroki in 1981. The prevalence of the syndrome among live births is 1:32,000. Case reports are now available, which correlates to improved techniques for accurate diagnosis. This study focused on a systematic comparative review of the phenotypes of individuals with Kabuki Syndrome, with the purpose to facilitate diagnosis. The systematic review was done with a bibliographic survey of case studies using the following databases: Pubmed, Science Direct and Google Scholar, in conjunction with the following key-words: Kabuki syndrome, phenotype, KMT2D and case report. The literature shows that patients with this syndrome present five main characteristics, besides several types of secondary phenotypes. These characteristics present variations in permeability as well as expressivity of some genes in individuals, therefore, a characterization through phenotype alone becomes limited, making it necessary to perform genetic analysis for differential diagnosis. In order to increase the knowledge and elucidate mechanisms of Kabuki syndrome, we suggest further studies that utilize animal models.

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Clinical and Neurobehavioral Features of Three Novel Kabuki Syndrome Patients with Mosaic KMT2D Mutations and a Review of Literature

Cited by 20 publications

References 14 publications

Update of the genotype and phenotype ofKMT2DandKDM6Aby genetic screening of 100 patients with clinically suspected Kabuki syndrome

Update of the genotype and phenotype ofKMT2DandKDM6Aby genetic screening of 100 patients with clinically suspected Kabuki syndrome

Kabuki syndrome: international consensus diagnostic criteria

Systematic review of Kabuki Syndrome’s phenotype with KMT2D gene mutation

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