哮喘易感基因的研究进展

支气管哮喘(哮喘)是一种多基因遗传病,由易感基因和环境因素共同作用而发病.通过候选基因法、定位克隆法和全基因组关联研究共确定了数百个哮喘易感基因,主要包括β2肾上腺素能受体基因、白细胞介素4受体基因、微丝蛋白基因、心房利钠素前体A基因、Ⅰ型肌醇多聚磷酸4磷酸酶基因、解整合素.金属蛋白酶33基因、双肽酶10基因、视蛋白3...     

哮喘易感基因的研究进展

支气管哮喘(哮喘)是一种多基因遗传病,由易感基因和环境因素共同作用而发病.通过候选基因法、定位克隆法和全基因组关联研究共确定了数百个哮喘易感基因,主要包括β2肾上腺素能受体基因、白细胞介素4受体基因、微丝蛋白基因、心房利钠素前体A基因、Ⅰ型肌醇多聚磷酸4磷酸酶基因、解整合素.金属蛋白酶33基因、双肽酶10基因、视蛋白3基因、血清类黏蛋白1样蛋白3基因、磷酸二酯酶4D基因、几丁质酶3类1基因等,其中多个基因在独立人群中得到验证.     

儿童阅读障碍易感基因研究进展

儿童发展性阅读障碍（developmental dyslexia）是神经发育障碍性疾病之一,受到多个易感基因的影响。近年来学者们通过染色体分析、全基因组关联研究以及关联分析与基因功能研究、神经影像、神经生理技术相结合等研究方法发现一些阅读障碍易感基因。该文对儿童发展性阅读障碍的易感基因研究进展进行综述。以阅读障碍易感基因研究为起点,为其“基因-大脑-行为”层面的深入研究奠定基础,进而为探究阅读障碍的病因和发病机制提供科学线索。     

非综合征型唇腭裂易感基因位点研究进展

非综合征型唇腭裂是一种常见的出生缺陷,病因复杂,目前普遍认为是遗传因素和环境因素共同作用的结果.先天性唇腭裂易感基因是自全基因组测序以来的研究热点,筛选出的众多候选基因正不断被基因位点多态性检测、病例对照研究、Meta分析等方法验证,但结果迥异.该文就近年来研究较多的非综合征型唇腭裂易感基因以及环境因素与唇腭裂相互关系方面的研究进展展开综述.     

T型钙通道基因CACNA1H是儿童失神癫痫的易感基因

目的 在既往工作的基础上，进一步明确T型钙通道CACNA1H基因是否为儿童失神癫痫(CAE)的易感基因。方法 本组48例，分别来源于北京大学第一医院、首都医科大学附属北京儿童医院、首都儿科研究所附属医院以及山西省儿童医院。对本组患儿进行T型钙通道CACNAlH基因外显子6-12及其相邻的部分内含子PCR产物测序，寻找突变。96个正常对照来自同一地区的无关个体，均无癫痫病史或遗传病家族史。结果 共发现13个单核苷酸多态性，还发现4个突变位点只在CAE中出现，其中2个为错义突变：G773D和HS15Y，均为杂合突变。突变H515Y是新发现的错义突变，患儿从其母亲接受该突变。G773D在第3个CAE家系中发现相同的突变，本例从其父亲接受该突变。结论 T型钙通道CACNA1H基因很可能是CAE的易感基因。     

诊断横纹肌肉瘤的一个Li-Fraumeni综合征家系报道并文献复习

Li-Fraumeni综合征(LFS)为一种遗传易感肿瘤综合征,肿瘤发病年龄早,个体肿瘤发生率高。先证者为2岁6个月男童,病理诊断为左颌下胚胎型横纹肌肉瘤;其哥哥因横纹肌肉瘤去世,外祖母患乳腺癌。对患儿及部分家庭成员进行TP53基因突变检测,发现患儿存在EXON 8的错义突变:c.844CT(p.Arg282Trp)(杂合),患儿母亲、姐姐均检测出该突变。符合LFS诊断标准。TP53基因是比较明确的LFS致病基因。儿童患者LFS疾病谱系中最常见的依次为骨肉瘤、肾上腺皮质癌、中枢神经系统肿瘤及软组织肿瘤,其它可能相关的包括白血病、淋巴瘤等。LFS患者有较大的几率患二次甚至多次肿瘤。因此对于儿童肿瘤患者,尤其是某些具有遗传易感性的肿瘤,有必要进行遗传学评估,如果存在TP53基因突变,治疗上则应当更为积极,并对LFS家系进行系统监测管理。     

法洛四联症相关易感基因的研究进展

先天性心脏病是胚胎发育过程中存在心血管结构或功能异常的一类疾病,是胎儿时期心血管系统发育异常、发育障碍或出生后未能退化所造成的心血管畸形,但其具体发病机制仍未阐明.法洛四联症是先天性心脏病中最严重的类型之一,包括室间隔缺损、主动脉骑跨、肺动脉狭窄和右心室肥厚.近年来的多项研究显示遗传因素参与了法洛四联症的发生,部分基因突变与法洛四联症的发生有很大关系,其中NKX2-5、GATA4、TBX5及TBX20已被证实与法洛四联症高度相关.该文主要围绕上述4个基因的研究进展,阐述法洛四联症的病因及发病机制.     

孤独症谱系障碍易感基因相关研究进展

孤独症谱系障碍(ASD)是神经发育过程中的一种发育障碍性疾病,是多个易感基因参与发病的多基因疾病。目前已报道的易感基因有100 多个,相关研究包括易感基因的染色体位点研究、易感基因筛查研究和易感基因的表观遗传学异常。已报道的易感基因编码的蛋白质有:神经细胞粘着分子;离子通道蛋白;支架蛋白;蛋白激酶、受体、载体;信号通路调控蛋白以及昼夜节律相关蛋白。易感基因突变和表达调控机制的研究进展有助了解ASD 的遗传参与的发病机制,可望能给ASD 的诊断和治疗提供新的思路。该文对ASD 易感基因方面的研究现状进行了综述。     

p53和淋巴系统恶性肿瘤

抑癌基因ｐ５３通过控制细胞增殖，诱导细胞凋亡来维持细胞遗传物质的稳定性，其功能失活与否成为影响肿瘤发生、发展及对放疗、化疗敏感性的关键因素。淋巴系统恶性肿瘤中存在频繁的ｐ５３基因突变，本文拟综述ｐ５３与淋巴系统恶性肿瘤的发生、发展、治疗以及预后的关系。     

川崎病易感基因研究进展

川崎病(KD)是一种病因不明的儿童发热性疾病,目前关于KD病因的研究主要集中在感染、免疫紊乱和遗传易感性3个方面.目前对KD易感基因的研究多采用侯选基因的关联分析法,且主要集中在一些免疫调节因子上.本研究分别从KD易感性、冠状动脉损伤和丙种球蛋白不敏感3个方面与基因多态性的关系展开,现就国内外关于这些方面的研究进展作一综述.     

Malignant triton tumor in a patient with Li-Fraumeni syndrome and a novel TP53 mutation

We report a 3-year-old boy with a malignant triton tumor (MTT) involving the left masticator space with local invasion and regional lymph node metastasis. Family history and detection of a novel germline TP53 mutation confirmed his diagnosis of Li Fraumeni syndrome (LFS). MTT has not been previously described in association with LFS. This case along with a comprehensive review of the literature, illustrate the importance of both somatic and germline TP53 mutations in the pathogenesis MTT. The tumor could not be resected and he was successfully treated with intensive induction chemotherapy, irradiation, and high-dose chemotherapy with autologous stem cell transplantation.     

How I approach hereditary cancer predisposition in a child with cancer

Approximately 10% of all children with cancer are affected by a monogenic cancer predisposition syndrome. This has important implications for both the child and her/his family. The assessment of hereditary cancer predisposition is a challenging task for clinicians and genetic counselors in daily routine. It includes consideration of tumor genetics, specific features of the patient, and the medical/family history. To keep up with the pace of this rapidly evolving and increasingly complex field of genetic susceptibility, we suggest a systematic approach for the evaluation of the child with cancer and her/his family by an interdisciplinary team specialized in hereditary cancer predisposition.     

Multiple Malignancies in a Child with de novo TP53 Mutation

The authors present the case of an 8.5-year-old boy diagnosed with embryonal rhabdomyosarcoma of the infratemporal fossa at 21 months old. Five years later he developed an osteosarcoma of the tibia, for which he was treated with standard chemotherapy and resection. Soon after completing this treatment, ptosis of the right eye developed. A mass in the cavernous sinus was found, interpreted as an osteogenic metastatsis, although a third primary tumor could not be ruled out. Molecular genetic investigation revealed a de novo germline TP53 mutation, and heralded an aggressive clinical progression of multiple malignancies in a child.     

Composite adrenal anaplastic neuroblastoma and virilizing adrenocortical tumor with germline TP53 R248W mutation

Composite tumors are extremely rare. Such tumors in adrenal glands are usually of neuroendocrine-neural type and occur mostly in adults. Their pathogenesis remains elusive. We report a patient with composite neuroblastoma (NB), adrenocortical tumor (ACT), and Li-Fraumeni syndrome (LFS) with germline TP53 R248W mutation. LFS predisposes to the development of leukemia, sarcomas, adrenocortical and breast carcinomas, brain tumors and, questionably, NB. A unique correlation between a single TP53 mutation (R337H) and ACT has been reported in southern Brazilian children. It remains unclear at this time whether a similar association of NB and R248W in patients with LFS exists.     

Paediatric cancer predisposition syndromes in the genomic age

Cancer predisposition syndromes (CPSs) are heritable conditions that confer an increased risk of one or more types of cancer. They most often arise due to germline mutations in tumour suppressor genes. Genomic sequencing studies have found that around 10% of paediatric oncology patients have an underlying CPS. Li Fraumeni syndrome is a classic example of such a condition; affected individuals are at increased risk of developing a wide range of cancers throughout life. Diagnosis of a CPS has wide-ranging implications for patients and their families. However, it also brings with it the possibility of targeted treatment strategies, as well as opportunities for surveillance and risk-reducing interventions. These in turn can lower morbidity and mortality. Further, genetic counselling enables those with a known CPS to explore a range of reproductive options which may help to ensure that future offspring are not affected. This short article offers advice to healthcare professionals working with children, explaining how CPSs may be identified. Diagnosis requires an index of suspicion, a thorough history and examination and appropriate genetic testing. A multi-disciplinary team approach is required, with input from Clinical Genetics at an early stage.     

TP53 codon 72 polymorphisms in favorable histology Wilms tumors

In Wilms tumor (WT), mutations in the gene encoding p53, TP53, are correlated with anaplasia; however TP53 variants have not been studied in favorable histology (FH) WTs. A single nucleotide polymorphism of TP53 encoding either arginine or proline at codon 72 is suggested to alter in vitro p53 behavior. Therefore, we analyzed tissue from 23 consecutive patients with FHWT to determine allelic and genotypic frequencies of Pro72 and Arg72 variants and correlate this with clinical outcomes. Interestingly, our cohort showed a statistically significant over-representation of the Arg allele and Arg/Arg genotype. However, the genotypic and allelic frequencies showed no significant correlation with age, stage, or disease recurrence.     

TP53 germline pathogenic variant frequency in anaplastic rhabdomyosarcoma: A Children's Oncology Group report

Rhabdomyosarcoma (RMS) is a well-described cancer in Li–Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are associated with a high rate of germline TP53 PVs. This study provides updated estimates of the prevalence of TP53 germline PVs in RMS (3%) and anRMS (11%) from a large cohort (n = 239) enrolled in five Children's Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in patients with anRMS in this series is much lower than previously reported, this prevalence remains elevated. Germline evaluation for TP53 PVs should be strongly considered in patients with anRMS.