Detection of high-frequency mutant genes in extranodal NK/T cell lymphoma by next-generation sequencing technology and its clinical significance / 中国肿瘤生物治疗杂志

@# Objective: To analyze the mutation of target genes in extranodal natural killer/T-cell lymphoma (ENKTL) by using nextgeneration sequencing, and to explore its relationship with prognosis and clinical characteristics, as to provide evidence for the pathogenesis, clinical diagnosis and targeted therapy of ENKTL. Methods: According to previous literature reports, the genes whose mutations can affect the development of lymphoma were selected as the target genes for this study. 29 patients with ENKTL, who were newly diagnosed at the Fourth Hospital of Hebei Medical University from August 2010 to October 2018, were selected for this study. The mutation of 9 target genes in the specimen was detected by thenext-generationsequencingtechnology.Therelationshipsamongclinicalfeatures,diseaseprognosisandmutationofthetargetgeneswereanalyzedbySPSS21.0statisticalsoftware.Results： ：Ninetargetgenes were were screened. AT-rich interactive-domain 1A(ARID1A) gene showed the highest mutation rate in ENKTL (10 cases, 34.48%) followedbylysinemethyltransferase2D(KMT2D)gene(31.03%)andtumorprotein P53 (TP53) gene (24.13%). Kaplan-Meier survival analysis showed that the overall survival of ENKTL patients with KMT2D gene wild type was significantly better than patients with KMT2D gene mutation (P=0.006). The KMT2D gene mutation was found to besignificantlyrelatedtoclinicalstage,CRP,albumin,lymphocyte count and Ki67 expression in ENKTL patients (all P<0.05). COX regression analysis showed that KMT2D gene mutation was an independent adverse prognostic factor (P<0.05). Conclusion: The KMT2D gene has a high mutant frequency in ENKTL and is associated with patients’prognosis, suggesting that KMT2D gene plays an important role in the initiation and development of ENKTL. It could be used as a clinical therapeutic target for ENKTL.

Kabuki syndrome:two case report / 临床儿科杂志

Objective To summarize the clinical features and genetic diagnosis of Kabuki syndrome. Methods The clinical data of Kabuki syndrome in 2 children were retrospectively analyzed. Results Both of them were male and over 1 year old. They had special facial features and febrile convulsion. Gene detection indicated that both of them had mutation in KMT2D (or MLL2) gene, but the clinical phenotypes were different. Conclusion Children with clinically suspected Kabuki syndrome can be confirmed by gene detection.

Clinical and laboratory characteristics and genetic diagnosis of Kabuki syndrome / 中华儿科杂志

Objective@#To investigate the clinical features, laboratory characteristics and genetic diagnosis of Kabuki syndrome (KS).@*Methods@#Between September 2014 and September 2016, seven children with clinically diagnosed KS from the neurology department, Beijing Children Hospital, Capital Medical University were included in this study. Three of them were male and 4 were female aged from 19 days to 6 years and 4 months with a median age of 3 years and 1 month. The clinical features, laboratory and imaging materials, gene tests were analyzed prospectively.@*Results@#Clinical manifestation: cephalofacial anomaly: all seven cases had unusual facies presented as long palpebral fissures, eversion of the lateral third of lower eyelids, arched eyebrow with brow sparse, epicanthus, orbital hypertelorism, short columella with broad and depressed nasal tip; six cases presented with palatal arch deformity; four cases presented with ptosis; three cases presented with dental abnormalities and hearing impairment respectively; two cases presented with strabismus and earlap malformation respectively; one case presented with amblyopia. Six cases presented with skeletal anomalies. Six cases presented with dermatoglyphic anomalies. All cases presented with mild to moderate mental retardation. Three cases presented with short stature. Four cases presented with cardiac abnormalities. Three cases presented with epileptic seizures. Others: three cases presented with dystonia and neonatal hyperbilirubinemia respectively; two cases presented with feeding problem and hypoglycemia respectively; one case presented with micropenis and fetal finger pads respectively. All seven patients received magnetic resonance imaging (MRI) tests, and none demonstrated an abnormal finding. Five patients received electroencephalogram (EEG) tests, and three of them presented with seizures and EEG abnormalities. Five patients received genetic testing and all presented with KMT2D heterozygous mutations which were new mutations proved by parents validation (three cases were nonsense mutations, one was frameshift mutation, one was missense mutation). All patients received rehabilitation training and symptomatic treatments. Three patients presented with epileptic seizures received antiepileptic therapy. At a median follow-up of 11 months (from 4 months to 2 years), one patient died, one lost to follow-up and five had improved intellectual and physical development. Epileptic seizures were controlled or reduced significantly in three patients presented with epileptic seizures.@*Conclusions@#KS is a multisystem disease with complicated manifestations, which needs a combination of various diagnosis and treatments. Genetic testing can help determine the diagnosis. Unusual facies and mental retardation are the main clinical features and diagnostic clue. It is important to improve prognosis through increasing the knowledge of KS, early diagnosis, and treatment.

Diagnosis and treatment of Kabuki syndrome and its recent progress in molecular mechanisms / 国际儿科学杂志

Kabuki syndrome(KS),also called kabuki make-up syndrome,is characterized by backward growth retardation,skeletal developmental delay,major facial dysmorphic features,multi-organ abnormalities and abnormal dermatoglyphic pattern and mild or moderate mental retardation.For the molecular genetic pathogenesis of KS,KTM2D and KDM6A gene mutations have been identified as pathogenic genes of KS,which regulate the gene expression through chromatin remodelling and histone modification.At present,the etiology and pathogenesis of KS are still unknown.There is no useful biochemical index and standard radiographic findings for the diagnosis of KS.Molecular genetic diagnosis is still to be explored.Currently,the diagnosis of KS is mainly based on five cardinal manifestations:a peculiar face,skeletal anomalies,dermatoglyphic abnormalities,mild to moderate mental retardation and postnatal growth deficiency.For these patients,it can reach a better prognosis the by clinical early detection,early diagnosis,early intervention,as well as improving the growth level,symptomatic treatment,active prevention and treatment of complications as far as possible.

Mutational Analysis of Extranodal NK/T-Cell Lymphoma Using Targeted Sequencing with a Comprehensive Cancer Panel

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (NKTCL), is a malignant disorder of cytotoxic lymphocytes of NK or T cells. It is an aggressive neoplasm with a very poor prognosis. Although extranodal NKTCL reportedly has a strong association with Epstein-Barr virus, the molecular pathogenesis of NKTCL has been unexplored. The recent technological advancements in next-generation sequencing (NGS) have made DNA sequencing cost- and time-effective, with more reliable results. Using the Ion Proton Comprehensive Cancer Panel, we sequenced 409 cancer-related genes to identify somatic mutations in five NKTCL tissue samples. The sequencing analysis detected 25 mutations in 21 genes. Among them, KMT2D, a histone modification-related gene, was the most frequently mutated gene (four of the five cases). This result was consistent with recent NGS studies that have suggested KMT2D as a novel driver gene in NKTCL. Mutations were also found in ARID1A, a chromatin remodeling gene, and TP53, which also recurred in recent NGS studies. We also found mutations in 18 novel candidate genes, with molecular functions that were potentially implicated in cancer development. We suggest that these genes may result in multiple oncogenic events and may be used as potential bio-markers of NKTCL in the future.

Kabuki syndrome: clinical and molecular characteristics / 소아과

Kabuki syndrome (KS) is a rare syndrome characterized by multiple congenital anomalies and mental retardation. Other characteristics include a peculiar facial gestalt, short stature, skeletal and visceral abnormalities, cardiac anomalies, and immunological defects. Whole exome sequencing has uncovered the genetic basis of KS. Prior to 2013, there was no molecular genetic information about KS in Korean patients. More recently, direct Sanger sequencing and exome sequencing revealed KMT2D variants in 11 Korean patients and a KDM6A variant in one Korean patient. The high detection rate of KMT2D and KDM6A mutations (92.3%) is expected owing to the strict criteria used to establish a clinical diagnosis. Increased awareness and understanding of KS among clinicians is important for diagnosis and management of KS and for primary care of KS patients. Because mutation detection rates rely on the accuracy of the clinical diagnosis and the inclusion or exclusion of atypical cases, recognition of KS will facilitate the identification of novel mutations. A brief review of KS is provided, highlighting the clinical and genetic characteristics of patients with KS.

Diagnóstico clínico en el síndrome de Kabuki: fenotipo y anomalías asociadas en dos casos nuevos / Clinical diagnosis of Kabuki syndrome: phenotype and associated abnormalities in two new cases

El síndrome de Kabuki es una entidad génica caracterizada por discapacidad intelectual asociada con múltiples anomalías sistémicas. El diagnóstico es fundamentalmente clínico y se basa en dismorfas faciales típicas, anomalías esqueléticas menores, persistencia de las almohadillas del pulpejo de los dedos y défcit de crecimiento posnatal. Otros hallazgos incluyen cardiopatía congénita, anomalías genitourinarias, fisura de paladar y/o labial, atresia anal y défcits funcionales, como mayor susceptibilidad a infecciones, enfermedades autoinmunes y endocrinológicas e hipoacusia. El objetivo de este trabajo es describir dos pacientes con diagnóstico clínico de síndrome de Kabuki, destacando los hallazgos fenotípicos y malformaciones asociadas.

Kabuki syndrome is a genetic entity with multiple anomalies associated with intellectual disability. The clinical diagnosis is based on typical facial features, minor skeletal abnormalities, fnger pads, and postnatal growth defcit. Other fndings may include congenital heart disease, genitourinary anomalies, oral clefts, anal atresia, increased susceptibility to infections, autoimmune and endocrine disease and hearing loss. The objective of this paper is to describe two patients with clinical diagnosis of Kabuki syndrome, highlighting the phenotypic fndings and associated malformations.