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

ABSTRACT: Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56-75% and 5-8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleotide change results in a new frameshift mutation (p.L1199HfsX7), and two with already-known nonsense mutations (p.R4484X and p.R5021X). Consistent with previously published cases, mosaic KMT2D mutations may result in mild KS facial dysmorphisms and clinical and neurobehavioral features, suggesting that these characteristics could represent the handles for genetic testing of individuals with slight KS-like traits.

SUBMITTER: Lepri FR

PROVIDER: S-EPMC5796032 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Lepri Francesca Romana FR Cocciadiferro Dario D Augello Bartolomeo B Alfieri Paolo P Pes Valentina V Vancini Alessandra A Caciolo Cristina C Squeo Gabriella Maria GM Malerba Natascia N Adipietro Iolanda I Novelli Antonio A Sotgiu Stefano S Gherardi Renzo R Digilio Maria Cristina MC Dallapiccola Bruno B Merla Giuseppe G

International journal of molecular sciences 20171228 1

Kabuki syndrome (KS) is a rare disorder characterized by multiple congenital anomalies and variable intellectual disability caused by mutations in KMT2D/MLL2 and KDM6A/UTX, two interacting chromatin modifier responsible respectively for 56-75% and 5-8% of the cases. To date, three KS patients with mosaic KMT2D deletions in blood lymphocytes have been described. We report on three additional subjects displaying KMT2D gene mosaics including one in which a single nucleot ...[more]

PMID: 29283410

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Project description:BackgroundKabuki syndrome type 1 (KS1), a rare multisystem congenital disorder, presents with characteristic facial features, intellectual disability, persistent fetal fingertip pads, skeletal abnormalities, and postnatal growth delays. KS1 results from pathogenic variants in the KMT2D gene, which encodes a histone methyltransferase protein involved in chromatin remodeling, promoter and enhancer regulation, and scaffold formation during early development. KMT2D also mediates cell signaling pathways, responding to external stimuli and organizing effector protein assembly. Research on KMT2D's molecular mechanisms in KS1 has primarily focused on its histone methyltransferase activity, leaving a gap in understanding the methyltransferase-independent roles in KS1 clinical manifestations.MethodsThis scoping review examines KMT2D's role in gene expression regulation across various species, cell types, and contexts. We analyzed human pathogenic KMT2D variants using publicly available databases and compared them to research organism models of KS1. We also conducted a systematic search of healthcare and governmental databases for clinical trials, studies, and therapeutic approaches.ResultsOur review highlights KMT2D's critical roles beyond methyltransferase activity in diverse cellular contexts and conditions. We identified six distinct groups of KMT2D as a cell signaling mediator, including evidence of methyltransferase-dependent and -independent activity. A comprehensive search of the literature, clinical databases, and public registries emphasizes the need for basic research on KMT2D's functional complexity and longitudinal studies of KS1 patients to establish objective outcome measurements for therapeutic development.ConclusionWe discuss how KMT2D's role in translating external cellular communication can partly explain the clinical heterogeneity observed in KS1 patients. Additionally, we summarize the current molecular diagnostic approaches and clinical trials targeting KS1. This review is a resource for patient advocacy groups, researchers, and physicians to support KS1 diagnosis and therapeutic development.

Project description:BackgroundKabuki syndrome 1 (KS1; OMIM:147920), which is characterized by distinctive dysmorphic facial features (such as arched eyebrows, long palpebral fissures with eversion of the lower lid, and large protuberant ears), intellectual disability, short stature, and dermatoglyphic and skeletal abnormalities, is brought on by pathogenic variants in KMT2D (OMIM:602113). In this work, three individuals with novel pathogenic KMT2D gene variants had their longitudinal audiological manifestations and ear structural characteristics outlined.MethodsThe longitudinal audiological data from neonatal hearing screening and a battery of several hearing tests were evaluated. The battery of hearing tests included tympanometry, distortion product otoacoustic emission (DPOAE), click-evoked air-conduction auditory brain-stem response (AC-ABR), click-evoked bone-conduction auditory brain-stem response (BC-ABR), narrow band CE-chirp auditory steady-state response (NB CE-chirp ASSR), and pure-tone audiometry (PTA). Phenotype identification and whole exome sequencing (WES) were performed on recruited individuals.ResultsAll three patients (two females and on male; last evaluations at 14 months, 11 months, and 5.7 years, respectively) failed the newborn hearing screening, and the audiological follow-up data revealed mild to profound fluctuating hearing loss, which was directly influenced by the incidence and severity of otitis media with effusion (OME). When OME occurred, the AC-ABR thresholds increased from 30-75 dBnHL to 45-90 dBnHL. The threshold for the BC-ABR and BC-PTA was between 25 and 50 dBnHL, indicating mild to moderate sensorineural hearing loss (SNHL). The high-resolution computed tomography (HRCT) pictures indicated that all three patients had middle and inner ear abnormalities. Middle ear anomalies showed as diminished mastoid gasification and ossicle dysplasia. Cochlear dysplasia, a dilated vestibule, fusion of the vestibule with the horizontal semicircular canals, and a short and thick horizontal semicircular canal were visible on images of the inner ear. This study recruited three individuals with three novel pathogenic variants (c.5104C>T, c.10205delA, and c.12840delC) of KMT2D who were identified at ages 27 days, 2 months, and 5.5 years.ConclusionsHearing characteristics of three individuals with three novel pathogenic variants of KMT2D range from mild to profound fluctuating hearing loss with mild to moderate SNHL. HRCT scans showed that all three individuals had anatomical middle and inner ear abnormalities. KS 1 patients must get clinical therapy for OME, frequent auditory monitoring, and prompt intervention.

Dataset Information

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

Publications

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

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