共查询到20条相似文献,搜索用时 15 毫秒
1.
Jessica R. C. Priestley Alyssa L. Rippert Courtney Condit Kosuke Izumi Staci Kallish Theodore G. Drivas 《American journal of medical genetics. Part C, Seminars in medical genetics》2023,193(2):128-138
Kabuki syndrome is a recognizable Mendelian disorder characterized by the clinical constellation of childhood hypotonia, developmental delay or intellectual impairment, and characteristic dysmorphism resulting from monoallelic pathogenic variants in KMT2D or KDM6A. In the medical literature, most reported patients are children, and data is lacking on the natural history of the condition across the lifespan, with little known about adult-specific presentations and symptoms. Here, we report the results of a retrospective chart review of eight adult patients with Kabuki syndrome, seven of whom are molecularly confirmed. We use their trajectories to highlight the diagnostic challenges unique to an adult population, expand on neurodevelopmental/psychiatric phenotypes across the lifespan, and describe adult-onset medical complications, including a potential cancer risk and unusual and striking premature/accelerated aging phenotype. 相似文献
2.
3.
Dina A. Schott Constance T. R. M. Stumpel Merel Klaassens 《American journal of medical genetics. Part A》2019,179(2):219-223
Kabuki syndrome (KS) is a multiple congenital malformation syndrome which has been described across all ethnic groups. Most KS patients possess two genetic subtypes: KMT2D‐associated, autosomal‐dominant KS type 1 (KS1; OMIM 147920); and KDM6A‐associated, X‐linked‐dominant KS type 2. Generalized joint hypermobility is one feature of KS, but its exact incidence and pattern is not well described in the literature. As part of our prospective study on the metabolic and growth effect of GH treatment, we assessed children from our Dutch Kabuki cohort who were eligible for growth hormone therapy. We assessed severity and pattern of joint hypermobility, both before and after 24 months of growth hormone replacement therapy. The prevalence of hypermobility was 31% in boys and 14% in girls using the Beighton score and 69% in boys and 57% in girls using the Bulbena score. This varies from the general population where girls are more affected. After 2 years of growth hormone treatment, there was a statistically significant decrease in the presence of joint hypermobility to 6% using the Bulbena score and none with respect to the Beighton score. We hypothesized that this result suggests a direct effect of growth hormone on connective tissue in patients with KS. 相似文献
4.
Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring 下载免费PDF全文
J. Paděrová A. Holubová M. Simandlová A. Puchmajerová M. Vlčková M. Malíková R. Pourová S. Vejvalková M. Havlovicová M. Šenkeříková N. Ptáková J. Drábová J. Geryk A. Maver A. Křepelová M. Macek Jr. 《Clinical genetics》2016,90(3):230-237
Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the ‘MLL2‐Kabuki score’ defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome‐wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2–Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield. 相似文献
5.
Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X‐Linked Kabuki Syndrome Subtype 2 下载免费PDF全文
Nina Bögershausen Vincent Gatinois Vera Riehmer Hülya Kayserili Jutta Becker Michaela Thoenes Pelin Özlem Simsek‐Kiper Mouna Barat‐Houari Nursel H. Elcioglu Dagmar Wieczorek Sigrid Tinschert Guillaume Sarrabay Tim M. Strom Aurélie Fabre Gareth Baynam Elodie Sanchez Gudrun Nürnberg Umut Altunoglu Yline Capri Bertrand Isidor Didier Lacombe Carole Corsini Valérie Cormier‐Daire Damien Sanlaville Fabienne Giuliano Kim‐Hanh Le Quan Sang Honorine Kayirangwa Peter Nürnberg Thomas Meitinger Koray Boduroglu Barbara Zoll Stanislas Lyonnet Andreas Tzschach Alain Verloes Nataliya Di Donato Isabelle Touitou Christian Netzer Yun Li David Geneviève Gökhan Yigit Bernd Wollnik 《Human mutation》2016,37(9):847-864
Kabuki syndrome (KS) is a rare but recognizable condition that consists of a characteristic face, short stature, various organ malformations, and a variable degree of intellectual disability. Mutations in KMT2D have been identified as the main cause for KS, whereas mutations in KDM6A are a much less frequent cause. Here, we report a mutation screening in a case series of 347 unpublished patients, in which we identified 12 novel KDM6A mutations (KS type 2) and 208 mutations in KMT2D (KS type 1), 132 of them novel. Two of the KDM6A mutations were maternally inherited and nine were shown to be de novo. We give an up‐to‐date overview of all published mutations for the two KS genes and point out possible mutation hot spots and strategies for molecular genetic testing. We also report the clinical details for 11 patients with KS type 2, summarize the published clinical information, specifically with a focus on the less well‐defined X‐linked KS type 2, and comment on phenotype–genotype correlations as well as sex‐specific phenotypic differences. Finally, we also discuss a possible role of KDM6A in Kabuki‐like Turner syndrome and report a mutation screening of KDM6C (UTY) in male KS patients. 相似文献
6.
Novel KDM6A (UTX) mutations and a clinical and molecular review of the X‐linked Kabuki syndrome (KS2) 下载免费PDF全文
V. Benoit E. Jenkins E. Howard S. Bunstone B. Kerr S. McKee I.C. Lloyd D. Shears H. Stewart S.M. White R. Savarirayan G.M.S. Mancini D. Beysen R.D. Cohn B. Grisart I. Maystadt D. Donnai 《Clinical genetics》2015,87(3):252-258
We describe seven patients with KDM6A (located on Xp11.3 and encodes UTX) mutations, a rare cause of Kabuki syndrome (KS2, MIM 300867) and report, for the first time, germ‐line missense and splice‐site mutations in the gene. We demonstrate that less than 5% cases of Kabuki syndrome are due to KDM6A mutations. Our work shows that similar to the commoner Type 1 Kabuki syndrome (KS1, MIM 147920) caused by KMT2D (previously called MLL2) mutations, KS2 patients are characterized by hypotonia and feeding difficulties during infancy and poor postnatal growth and short stature. Unlike KS1, developmental delay and learning disability are generally moderate–severe in boys but mild–moderate in girls with KS2. Some girls may have a normal developmental profile. Speech and cognition tend to be more severely affected than motor development. Increased susceptibility to infections, join laxity, heart, dental and ophthalmological anomalies are common. Hypoglycaemia is more common in KS2 than in KS1. Facial dysmorphism with KDM6A mutations is variable and diagnosis on facial gestalt alone may be difficult in some patients. Hypertrichosis, long halluces and large central incisors may be useful clues to an underlying KDM6A mutation in some patients. 相似文献
7.
Tara Daly Abra Roberts Edward Yang Ganeshwaran H. Mochida Olaf Bodamer 《American journal of medical genetics. Part A》2020,182(3):441-445
Kabuki syndrome is a rare, multi‐systemic disorder of chromatin regulation due to mutations in either KMT2D or KDM6A that encode a H3K4 methyltransferase and an H3K27 demethylase, respectively. The associated clinical phenotype is a direct result of temporal and spatial changes in gene expression in various tissues including the brain. Although mild to moderate intellectual disability is frequently recognized in individuals with Kabuki syndrome, the identification of brain anomalies, mostly involving the hippocampus and related structures remains an exception. Recently, the first two cases with alobar holoprosencephaly and mutations in KMT2D have been reported in the medical literature. We identified a de novo, pathogenic KMT2D variant (c.6295C > T; p.R2099X) using trio whole‐exome sequencing in a 2‐year‐old female with lobar holoprosencephaly, microcephaly and cranio‐facial features of Kabuki syndrome. This report expands the spectrum of brain anomalies associated with Kabuki syndrome underscoring the important role of histone modification for early brain development. 相似文献
8.
The identification of de novo dominant mutations in KMT2D (MLL2) as the main cause of Kabuki syndrome (KS) has shed new light on the pathogenesis of this well‐delineated condition consisting of a peculiar facial appearance, short stature, organ malformations and a varying degree of intellectual disability. Mutation screening studies have confirmed KMT2D as the major causative gene for KS and have at the same time provided evidence for its genetic heterogeneity. In this review, we aim to summarize the current clinical and molecular genetic knowledge on KS, provide genotype–phenotype correlations and propose a strategic clinical and molecular diagnostic approach for patients with suspected KS. 相似文献
9.
10.
11.
Dustin Baldridge Rebecca C. Spillmann Daniel J. Wegner Jennifer A. Wambach Frances V. White Kathleen Sisco Tomi L. Toler Patricia I. Dickson F. Sessions Cole Vandana Shashi Dorothy K. Grange 《American journal of medical genetics. Part A》2020,182(5):1053-1065
Pathogenic variants in KMT2D, which encodes lysine specific methyltransferase 2D, cause autosomal dominant Kabuki syndrome, associated with distinctive dysmorphic features including arched eyebrows, long palpebral fissures with eversion of the lower lid, large protuberant ears, and fetal finger pads. Most disease‐causing variants identified to date are putative loss‐of‐function alleles, although 15–20% of cases are attributed to missense variants. We describe here four patients (including one previously published patient) with de novo KMT2D missense variants and with shared but unusual clinical findings not typically seen in Kabuki syndrome, including athelia (absent nipples), choanal atresia, hypoparathyroidism, delayed or absent pubertal development, and extreme short stature. These individuals also lack the typical dysmorphic facial features found in Kabuki syndrome. Two of the four patients had severe interstitial lung disease. All of these variants cluster within a 40‐amino‐acid region of the protein that is located just N‐terminal of an annotated coiled coil domain. These findings significantly expand the phenotypic spectrum of features associated with variants in KMT2D beyond those seen in Kabuki syndrome and suggest a possible new underlying disease mechanism for these patients. 相似文献
12.
S Banka E Howard S Bunstone KE Chandler B Kerr K Lachlan S McKee SG Mehta ALT Tavares J Tolmie D Donnai 《Clinical genetics》2013,83(5):467-471
Kabuki syndrome (KS) is a rare multi‐system disorder that can result in a variety of congenital malformations, typical dysmorphism and variable learning disability. It is caused by MLL2 point mutations in the majority of the cases and, rarely by deletions involving KDM6A. Nearly one third of cases remain unsolved. Here, we expand the known genetic basis of KS by presenting five typical patients with the condition, all of whom have novel MLL2 mutation types– two patients with mosaic small deletions, one with a mosaic whole‐gene deletion, one with a multi‐exon deletion and one with an intragenic multi‐exon duplication. We recommend MLL2 dosage studies for all patients with typical KS, where traditional Sanger sequencing fails to identify mutations. The prevalence of such MLL2 mutations in KS may be comparable with deletions involving KDM6A. These findings may be helpful in understanding the mutational mechanism of MLL2 and the disease mechanism of KS. 相似文献
13.
N. Miyake Y. Tsurusaki E. Koshimizu N. Okamoto T. Kosho N.J. Brown T.Y. Tan P.J.J. Yap H. Suzumura T. Tanaka T. Nagai M. Nakashima H. Saitsu N. Niikawa N. Matsumoto 《Clinical genetics》2016,89(1):115-119
Wiedemann–Steiner syndrome (WSS) is an autosomal dominant congenital anomaly syndrome characterized by hairy elbows, dysmorphic facial appearances (hypertelorism, thick eyebrows, downslanted and vertically narrow palpebral fissures), pre‐ and post‐natal growth deficiency, and psychomotor delay. WSS is caused by heterozygous mutations in KMT2A (also known as MLL), a gene encoding a histone methyltransferase. Here, we identify six novel KMT2A mutations in six WSS patients, with four mutations occurring de novo. Interestingly, some of the patients were initially diagnosed with atypical Kabuki syndrome, which is caused by mutations in KMT2D or KDM6A, genes also involved in histone methylation. KMT2A mutations and clinical features are summarized in our six patients together with eight previously reported patients. Furthermore, clinical comparison of the two syndromes is discussed in detail. 相似文献
14.
15.
16.
Noriko Miyake Seiji Mizuno Nobuhiko Okamoto Hirofumi Ohashi Masaaki Shiina Kazuhiro Ogata Yoshinori Tsurusaki Mitsuko Nakashima Hirotomo Saitsu Norio Niikawa Naomichi Matsumoto 《Human mutation》2013,34(1):108-110
Kabuki syndrome (KS) is a rare congenital anomaly syndrome characterized by a unique facial appearance, growth retardation, skeletal abnormalities, and intellectual disability. In 2010, MLL2 was identified as a causative gene. On the basis of published reports, 55–80% of KS cases can be explained by MLL2 abnormalities. Recently, de novo deletion of KDM6A has been reported in three KS patients, but point mutations of KDM6A have never been found. In this study, we investigated KDM6A in 32 KS patients without an MLL2 mutation. We identified two nonsense mutations and one 3‐bp deletion of KDM6A in three KS cases. This is the first report of KDM6A point mutations associated with KS. 相似文献
17.
18.
Tim Phetthong Thipwimol Tim‐Aroon Arthaporn Khongkrapan Preamrudee Poomthavorn Duangrurdee Wattanasirichaigoon 《American journal of medical genetics. Part A》2020,182(8):1873-1876
Kabuki syndrome (KS) is a rare heterogeneous phenotypic genetic syndrome, characterized by hypotonia, developmental delay and/or intellectual disability with typical facial features. It is challenging to diagnose KS in newborn and young infant. We report a Thai girl who presented with two rare co‐occurrence phenotypes, hyperinsulinemic hypoglycemia and midgut malrotation. She had not have distinctive facial dysmorphism during neonatal period. At 4 months of age, she had poor weight gain with some facial features suggestive KS. Singleton whole exome sequencing (WES) was carried out followed by Sanger sequencing of the supposed variant. The result indicated a novel de novo heterozygous KMT2D mutation, c.15364A>T (p.Lys5122*), confirming KS. Our patient revealed rare clinical manifestations from the diverse population and address the benefit of WES in establishing early diagnosis of KS before typical facial gestalt exhibited, which allows timely and appropriate management to maximize developmental achievement. 相似文献
19.
Emmanuel de Billy Luisa Strocchio Antonella Cacchione Emanuele Agolini Maria Gnazzo Antonio Novelli Rita De Vito Rossella Capolino Maria Cristina Digilio Roberta Caruso Angela Mastronuzzi Franco Locatelli 《American journal of medical genetics. Part A》2019,179(1):113-117
Kabuki syndrome (KS) is an extremely rare genetic disorder, mainly caused by germline mutations at specific epigenetic modifier genes, including KMT2D. Because the tumor suppressor gene KMT2D is also frequently altered in many cancer types, it has been suggested that KS may predispose to the development of cancer. However, KS being a rare disorder, few data are available on the incidence of cancer in KS patients. Here, we report the case of a 5‐year‐old boy affected by KS who developed Burkitt lymphoma (BL). Genetic analysis revealed the presence of a novel heterozygous mutation in the splice site of the intron 4 of KMT2D gene in both peripheral blood‐extracted DNA and tumour cells. In addition, the tumour sample of the patient was positive for the classical somatic chromosomal translocation t(8;14) involving the c‐MYC gene frequently identified in BL. We propose that the mutated KMT2D gene contributes to the development of both KS and BL observed in our patient and we suggest that strict surveillance must be performed in KS patients. 相似文献
20.
Paulussen AD Stegmann AP Blok MJ Tserpelis D Posma-Velter C Detisch Y Smeets EE Wagemans A Schrander JJ van den Boogaard MJ van der Smagt J van Haeringen A Stolte-Dijkstra I Kerstjens-Frederikse WS Mancini GM Wessels MW Hennekam RC Vreeburg M Geraedts J de Ravel T Fryns JP Smeets HJ Devriendt K Schrander-Stumpel CT 《Human mutation》2011,32(2):E2018-E2025