Estimating the number of potential family members eligible for BRCA1 and BRCA2 mutation testing in a “Traceback” approach

U.S. guidelines recommend BRCA1/2 mutation testing for women diagnosed with high‐grade ovarian cancer (HGOC) to increase recognition of carriers, but most remain unidentified and at risk. Accordingly, an approach termed “Traceback” has been proposed in which probands are retrospectively identified by testing archived pathology specimens, and family members are traced to provide genetic counseling and testing. We used population‐based data to estimate the number of family members who might be contacted through such a program. We used incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program to estimate the number of women diagnosed with HGOC from 2005 to 2016, and census data to estimate the number of spouses, offspring, and siblings (both sexes). Using overall survival for HGOC from SEER and all‐cause mortality rates from the Centers for Diseases Control and Prevention, we estimated the number of patients, spouses, offspring, and siblings of HGOC cases living in 2017. Due to the high mortality rate of HGOC, consent from living probands may be possible in only 42% of the cases; consent to test pathology specimens would need to be sought from next of kin for the remainder. In 2017, an estimated 406,919 living next of kin (spouses, siblings, offspring) would be available for potential consent. Testing archived ovarian cancer pathology specimens may enable the identification of BRCA1/2 mutation carriers, but consent from next of kin would be required in in 58% of cases. Although Traceback offers the possibility of identifying unaffected BRCA1/2 mutation carriers, pilot feasibility studies that include assessment of methods to secure consent are needed.     

The cost-utility of magnetic resonance imaging for breast cancer in BRCA1 mutation carriers aged 30–49

Recent evidence has investigated the cost-effectiveness of magnetic resonance imaging (MRI) in younger women with a BRCA1 mutation. However, this evidence has not been contrasted with existing cost-effectiveness standards to determine whether screening is appropriate, given limited societal resources. We constructed a Markov model investigating surveillance tools (mammography, MRI, both in parallel) under a National Health Service (NHS) perspective. The key benefit of MRI is that increased sensitivity leads to early detection, and improved prognosis. For a 30- to 39-year-old cohort, the cost per quality-adjusted life year (QALY) of mammography relative to no screening was ￡5,200. The addition of MRI to this costs ￡13,486 per QALY. For a 40- to 49-year-old cohort, the corresponding values were ￡2,913 and ￡7,781. Probabilistic sensitivity analysis supported the cost-effectiveness of the parallel approach of mammography and MRI. It is necessary to extend this analysis beyond BRCA1 carriers within this age group, and also to other age groups.     

Vitamin D and Diseases of Mineral Homeostasis: A Cyp24a1 R396W Humanized Preclinical Model of Infantile Hypercalcemia Type 1

Infantile hypercalcemia type 1 (HCINF1), previously known as idiopathic infantile hypercalcemia, is caused by mutations in the 25-hydroxyvitamin D 24-hydroxylase gene, CYP24A1. The R396W loss-of-function mutation in CYP24A1 is the second most frequent mutated allele observed in affected HCINF1 patients. We have introduced the site-specific R396W mutation within the murine Cyp24a1 gene in knock-in mice to generate a humanized model of HCINF1. On the C57Bl6 inbred background, homozygous mutant mice exhibited high perinatal lethality with 17% survival past weaning. This was corrected by crossbreeding to the CD1 outbred background. Mutant animals had hypercalcemia in the first week of life, developed nephrolithiasis, and had a very high 25(OH)D₃ to 24,25(OH)₂D₃ ratio which is a diagnostic hallmark of the HCINF1 condition. Expression of the mutant Cyp24a1 allele was highly elevated while Cyp27b1 expression was abrogated. Impaired bone fracture healing was detected in CD1-R396^w/w mutant animals. The augmented lethality of the C57Bl6-R396W strain suggests an influence of distinct genetic backgrounds. Our data point to the utility of unique knock-in mice to probe the physiological ramifications of CYP24A1 variants in isolation from other biological and environmental factors.     

COL1A2新发突变致新生儿成骨不全症1例报告并文献复习

目的 对COL1A2新发突变致1例新生儿成骨不全症的临床表型及基因变异特征进行分析,提高对成骨不全症(OI)的诊断和认识。方法 回顾福建中医药大学附属厦门市第三医院儿科2017年8月确诊的1例新生儿成骨不全症临床资料及辅助检查,并提取患儿及其父母外周血DNA,采用全序列外显子基因检测技术检测成骨不全症相关基因,对突变基因进一步分析并复习相关文献。结果 患儿的COL1A1基因未检出致病性变异,而COL1A2 基因检测发现一杂合错义突变(c.G2882A,p.G961D),PubMed及HGMD数据库均未见报道,该错义突变来自母亲,而其父正常。结论 依据本例患儿临床信息、疾病遗传模式和Exomiser软件综合评价,预测COL1A2 基因新发突变(c.G2882A,p.G961D)是成骨不全症致病突变。     

原纤维蛋白1基因新突变致新生儿马方综合征并文献复习

目的 探讨原纤维蛋白(FBN)1基因新发突变致新生儿马方综合征(MFS)的临床特征、基因检测结果和诊治方案.方法 选择2018年3月8日在陕西省人民医院新生儿科住院,并确诊为FBN1基因新突变致新生儿MFS的1例患儿为研究对象,确诊时年龄为生后10 h.同时,检索国内数据库中FBN1突变所致患儿发生MFS的相关文献,并...     

A novel MYT1L mutation in a boy with syndromic obesity: Case report and literature review

BackgroundPathogenic variants involving the MYT1L gene lead to an autosomal dominant form of syndromic obesity, characterized by polyphagia, intellectual disability/developmental delay, and behavioral problems, and that a characteristic facial phenotype does not seem to be recognizable.MethodsTrio whole exome sequencing was performed in a 10-year-old Brazilian male presenting polyphagia, severe early-onset obesity, intellectual disability, speech delay, macrocephaly, frontal bossing, telecanthus, strabismus, and hypogenitalism. Additionally, we performed a literature review of patients carrying non-copy number MYT1L variants.ResultsA de novo genetic variant not previously reported in MYT1L (NM_015025.4:c.2990C > A) was identified in the proband and classified as pathogenic. From a literature search, 22 further patients carrying non-copy number MYT1L variants were identified, evidencing that although the associated phenotype is quite variable, intellectual disability/developmental and speech delays are always present. Further, most patients have obesity or overweight due to polyphagia. Macrocephaly, strabismus, behavioral problems, and hand/feet malformations are also recurrent features.ConclusionsWe described the first Brazilian case of MYT1L related syndrome and highlighted clinical characteristics based on the literature. Other syndromic forms of obesity such as Prader-Willi, Bardet-Biedl, Börjeson-Forssman-Lehmann, MORM, Cohen, Alstrom, and Kleefstra type 1 syndromes should be considered in the differential diagnosis. Further, although obesity is frequent, it is not an obligatory feature of all carriers of MYT1L mutations.     

ARCAD: A method for estimating age-dependent disease risk associated with mutation carrier status from family data

We present ARCAD, a method to estimate the disease risk associated with mutation carrier status using data on families ascertained by affected individuals, in which a germline mutation has been detected. Because the event of interest, the age of onset, is a censored variable, the method uses the survival analysis approach to formulate the likelihood. Provided that selection criteria are clearly defined, the ascertainment bias is removed by including a correction term in the likelihood computation. We simulated family data and selected those with a proband affected before age 17, and at least one or at least two relatives affected before age 46. We show that including the correction for the ascertainment provides reliable estimates of the risk, even when many individuals are not tested for the mutation. An application to cancer risk and germline p53 mutations is presented. We routinely investigate the p53 status for all the children treated in the Department of Pediatric Oncology at the Institute Gustave Roussy, whose family displays at least one relative affected by cancer before age 46. We identified 5 families with an inherited germline p53 mutation. The risk for any cancer for a mutation carrier estimated by ARCAD was 42% within the age class 0–16 years, 38% within the age class 17–45 years, and 63% after 45 years, with a lifetime risk of 85%. These risks are almost entirely explained by the occurrence of the six most frequent cancers encountered in the Li-Fraumeni syndrome. © Wiley-Liss, Inc.     

DGAT1基因突变所致先天性腹泻与肠病临床分析并文献复习

目的 探讨二酰甘油O-酰基转移酶(DGAT)1基因突变所致先天性腹泻与肠病(CODEs)患儿的临床及基因突变特点。方法 选择2020年12月,于华中科技大学同济医学院附属武汉儿童医院诊治的1例DGAT1基因突变所致CODEs患儿(以下以示区别称其为本例患儿)为研究对象。采用回顾性分析方法,分析本例患儿的临床病例资料,检索国内外数据库中关于DGAT1基因突变CODEs患儿相关研究的中、英文文献,总结该病患儿的临床及基因突变特点。本研究通过本院伦理委员会审查(审批文号：2021R045-E01)。监护人对本例患儿的诊治知情同意。结果 (1)本例患儿为女性,生后50 d时,因呕吐、腹泻就诊,入院查体发现其伴营养不良,实验室检查主要为低蛋白血症及高甘油三酯血症,基因检测结果为DGAT1基因exon 1:c.133delG(p.Asp45Thrfs*22)移码突变,为纯合突变,其父母均为DGAT1基因该位点突变携带者。本例患儿经低脂奶粉喂养及对症支持等治疗26 d后,临床治愈出院。其出院诊断为,CODEs(DGAT1基因纯合突变)。(2)文献检索获得关于DGAT1基因突变CODEs患儿相关研究文...     

Mitogen-activated lymphocytes: a good model for characterising lung CYP1A1 inducibility

The CYP1A1 hyperinducibility phenotype occurring in some 10% of the human population corresponds to a higher risk of developing lung cancer. This study was undertaken to assess whether the inducibility factor, generally evaluated on mitogen- activated lymphocytes after PAH induction, represents correctly the lung situation. Optimal experimental conditions were determined for evaluating, on both lymphocytes and lung tissue explants, the inducibility factor, defined as the ratio of EROD activity (CYP1A1-specific) to cytochrome c reductase activity (unaffected by PAH induction). Paired results for lymphocytes and lung tissue samples from 10 lung cancer patients were compared. A good correlation was observed between lymphocyte and lung tissue inducibilities (R = 0.809; p = 0.005). In conclusion, mitogen- activated lymphocyte inducibility is indicative of lung tissue inducibility and constitutes a good marker for evaluating individual PAH inducibilities.     

儿童时期以癫痫起病的早发型阿尔茨海默病患者及其家系早老素基因1突变研究

目的探讨1例儿童时期以癫痫起病的早发型阿尔茨海默病患者及其大家系的早老素基因1(PSEN1)突变情况。 方法选择2014年11月28日至2015年11月14日在北京大学第一医院神经内科门诊确诊为早发型阿尔茨海默病患者(先证者)及其大家系(Ⅰ～Ⅳ代)为研究对象。本例先证者为男性,现年36岁,因"癫痫,异常家族史"就诊,于本院进行遗传咨询,希望明确病因。早发型阿尔茨海默病诊断标准：①发病年龄<65岁;②临床检查结果支持痴呆的证据;③超过2个领域存在认知障碍;④进行性记忆力下降伴其他认知障碍;⑤无意识障碍;⑥无其他系统性疾病或脑疾病可解释的记忆和认知障碍。收集先证者及其家系成员临床资料,采用靶向捕获二代测序(TGS)技术对其进行基因分析,发现PSEN1突变后,对所有外显子和内含子边界PSEN1进行聚合酶链反应(PCR)检测,采用Sanger方法进行基因突变验证。本研究遵循的程序符合北京大学第一医院人体试验委员会所制定的伦理学标准,得到该委员会批准,并与受试者签署临床研究知情同意书。 结果①本例先证者(Ⅲ₁₆)于12岁时出现癫痫发作,15岁开始口服丙戊酸钠治疗后癫痫发作被控制,33岁停药后复发,再次采取丙戊酸钠缓释片治疗后癫痫被控制。本例先证者在本院进行相关检查的结果显示,智力、运动功能发育正常,头颅MRI检查结果未见异常,最终临床诊断为"原发性癫痫" 。但是,患者自述于35岁开始出现记忆力下降,定向功能减退。②先证者的祖母(Ⅰ₂)于30多岁出现精神障碍,40岁左右死亡。先证者的父亲(Ⅱ₆)、2位伯父(Ⅱ₂与Ⅱ₃)、2位姑姑(Ⅱ₄与Ⅱ₅)均于35岁左右出现进行性记忆力下降、智能倒退,均于40岁左右死亡,并符合早发型阿尔茨海默病诊断标准,而被诊断为早发型阿尔茨海默病患者。③TGS检测结果显示,先证者PSEN1基因的第5外显子c.346G>A(p.Glu116Lys)杂合突变,先证者之子(Ⅳ₁₈,12岁),先证者四姑的长子(Ⅲ₁₁,45岁)及长子之子(Ⅳ₁₁,7岁),先证者五姑的三女儿(Ⅲ₁₅,29岁),均为PSEN1基因的第5外显子c.346G>A(p.Glu116Lys)杂合突变携带者,均尚无进行性记忆力下降、智能倒退等早发型阿尔茨海默病临床症状。 结论明确早发型阿尔茨海默病患者家系的临床和分子遗传学特征,可为该病患者准确的遗传咨询和进一步的产前诊断奠定基础。     

A patient decision aid for risk‐reducing surgery in premenopausal BRCA1/2 mutation carriers: Development process and pilot testing

Background

BRCA1/2 mutation carriers’ choice between risk‐reducing salpingo‐oophorectomy (RRSO) and salpingectomy with delayed oophorectomy is very complex. Aim was to develop a patient decision aid that combines evidence with patient preferences to facilitate decision making.

Design

Systematic development of a patient decision aid in an iterative process of prototype development, alpha testing by patients and clinicians and revisions using International Patient Decision Aid Standards (IPDAS) quality criteria. Information was based on the available literature and current guidelines. A multidisciplinary steering group supervised the process.

Setting and participants

Pre‐menopausal BRCA1/2 mutation carriers choosing between RRSO and salpingectomy with delayed oophorectomy in Family Cancer Clinics in the Netherlands.

Main outcome measures

IPDAS quality criteria, relevance, usability, clarity.

Results

The patient decision aid underwent four rounds of alpha testing and revisions. Finally, two paper decision aids were developed: one for BRCA1 and one for BRCA2. They both contained a general introduction, three chapters and a step‐by‐step plan containing a personal value clarification worksheet. During alpha testing, risk communication and information about premature menopause and hormone therapy were the most revised items. The patient decision aids fulfil 37 of 43 (86%) IPDAS criteria for content and development process.

Discussion and conclusions

Both BRCA1/2 mutation carriers and professionals are willing to use or offer the developed patient decision aids for risk‐reducing surgery. The patient decision aids have been found clear, balanced and comprehensible. Future testing among patients facing the decision should point out its effectiveness in improving decision making.     

Foot-and-mouth disease marker vaccine: cattle protection with a partial VP1 G-H loop deleted virus antigen

Contrary to the dogma that the VP1 G-H loop is essential for FMD vaccine efficacy, it has been previously shown that foot-and-mouth disease 146s antigen containing heterologous VP1 G-H loops confers complete protection in pigs and cattle. Moreover, serological evaluation of cattle vaccinated with an antigen lacking a large proportion of the VP1 G-H loop indicated that these animals should be protected against infection with FMD.Absence of this loop provides opportunity for the development of an FMD negative marker vaccine, allowing infection to be detected by antibodies against this missing region.Cattle vaccinated with this negative marker vaccine were fully protected following virus challenge 28 days post vaccination as determined by the absence of generalised lesions on their feet. Furthermore, use of our improved differentiation ELISA identified animals exposed to infection as early as 7 days post-challenge.We thus demonstrate, for the first time, the ability of this FMD negative marker vaccine to fully protect cattle from experimental challenge and rapidly distinguish animals that are subsequently exposed to infection.     

Healthcare workers under a mandated H1N1 vaccination policy with employment termination penalty: A survey to assess employee perception

The ethical debate over mandatory healthcare worker (HCW) influenza vaccination is a heated one. Our study hospital instituted a mandatory employee influenza vaccination policy for the 2009–2010 influenza season during the highly publicized pandemic of the H1N1 “Swine Flu.” Under this mandate there was no informed declination option, and termination of employment was the consequence for noncompliance. Our objective was to examine HCW perceptions of the H1N1 influenza virus, the vaccine, and the strict mandated vaccination policy. A survey was designed, distributed, and anonymously collected. In total, 202 completed questionnaires were obtained via accidental sampling by the investigators achieving a 100% response rate. Data analysis showed that 31.7% of surveyed HCWs felt the mandate was an infringement on their rights and 3.5% of HCWs would electively seek employment elsewhere. Significantly more nurses and clerks/technicians were opposed to the mandate compared to other types of employees. 96% felt that the mandating hospital should be liable should a significant adverse effect occur from receiving the vaccine. While the mandate helped to increase HCW influenza vaccination rates dramatically, the strict consequence of employment termination created negative feelings of coercion. Adopting a policy that includes a declination option with mandatory masking during influenza season might be a more widely acceptable and still adequate approach.     

2009年新型甲型H1N1流感不同剂型疫苗免疫效果Meta分析

为有效控制甲型H1N1流感疫情,接种疫苗是当前最为经济、科学的手段.当前已有研究报道了前期甲型H1N1流感疫苗人群免疫效果和安全性评估的研究情况,WHO也肯定了其效果.但目前对于不同剂型疫苗免疫效果结论不尽一致,缺乏全面、系统的权威报道.为此,本研究对国内外报道的不同剂型新型甲型H1N1流感疫苗免疫效果进行Meta分析,以提高研究的统计学效力,为下一步探索最佳的甲型H1N1流感疫苗免疫策略的循证决策提供科学数据[1,2].     

公共卫生危机报道中隐喻的使用与反思——以甲型H1N1流感的媒体阐释现象为例

隐喻不仅是一种语言现象,也是人类认识事物、建立概念的重要工具。媒体在公共卫生报道中经常使用大量的隐喻来传递抽象的疾病和现实,以形象地阐释健康信息、深入地解读卫生现状从而达到缓解公共卫生危机的目的。但是这些具有主观指向性的疾病隐喻在带来新闻表现力的同时也造成意义的误读和报道的失衡。本文以甲型流感报道为分析对象,从微观语言使用与宏观立意选择两方面总结了甲型流感事件中的隐喻现象。发现这些隐喻一方面增强了新闻的表现力一方面亦在某种程度上制造了恐慌和议程偏移。因此,在健康报道中媒体要采取措施对疾病隐喻的负向效应加以规避。     

Association between Vitamin Intake and Chronic Kidney Disease According to a Variant Located Upstream of the PTGS1 Gene: A Cross-Sectional Analysis of Shika Study

Chronic kidney disease (CKD) patients have been advised to take vitamins; however, the effects have been controversial. The individual differences in developing CKD might involve genetic variants of inflammation, including variant rs883484 located upstream of the prostaglandin-endoperoxide synthase 1 (PTGS1) gene. We aimed to identify whether the 12 dietary vitamin intake interacts with genotypes of the rs883484 on developing CKD. The population-based, cross-sectional study had 684 Japanese participants (≥40 years old). The study used a validated, brief, self-administered diet history questionnaire to estimate the intake of the dietary vitamins. CKD was defined as estimated glomerular filtration < 60 mL/min/1.73 m². The study participants had an average age of 62.1 ± 10.8 years with 15.4% minor homozygotes of rs883484, and 114 subjects had CKD. In the fully adjusted model, the higher intake of vitamins, namely niacin (odds ratio (OR) = 0.74, 95% confidence interval (CI): 0.57–0.96, p = 0.024), α-tocopherol (OR = 0.49, 95% CI: 0.26–0.95, p = 0.034), and vitamin C (OR = 0.97, 95% CI: 0.95–1.00, p = 0.037), was independently associated with lower CKD tendency in the minor homozygotes of rs883484. The results suggested the importance of dietary vitamin intake in the prevention of CKD in middle-aged to older-aged Japanese with minor homozygous of rs883484 gene variant.     

Basal Insulin Regimens for Adults with Type 1 Diabetes Mellitus: A Systematic Review and Network Meta-Analysis

Objective

To assess the relative efficacy and safety of basal insulin regimens in adults with type 1 diabetes mellitus (T1DM).