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A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

ABSTRACT: PURPOSE:To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). METHODS:Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. RESULTS:The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ?-helical transition. CONCLUSION:KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.

SUBMITTER: Cuvertino S

PROVIDER: S-EPMC7200597 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

Cuvertino Sara S Hartill Verity V Colyer Alice A Garner Terence T Nair Nisha N Al-Gazali Lihadh L Canham Natalie N Faundes Victor V Flinter Frances F Hertecant Jozef J Holder-Espinasse Muriel M Jackson Brian B Lynch Sally Ann SA Nadat Fatima F Narasimhan Vagheesh M VM Peckham Michelle M Sellers Robert R Seri Marco M Montanari Francesca F Southgate Laura L Squeo Gabriella Maria GM Trembath Richard R van Heel David D Venuto Santina S Weisberg Daniel D Stals Karen K Ellard Sian S Barton Anne A Kimber Susan J SJ Sheridan Eamonn E Merla Giuseppe G Stevens Adam A Johnson Colin A CA Banka Siddharth S

Genetics in medicine : official journal of the American College of Medical Genetics 20200117 5

<h4>Purpose</h4>To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1).<h4>Methods</h4>Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism.<h4>Results</h4>The consistent clinical features of the affe ...[more]

PMID: 31949313

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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

A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

Publications

A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

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