ESPN基因罕见纯合突变导致常染色体隐性遗传耳聋的基因诊断及人工耳蜗康复效果评价

［摘要］　目的　鉴定1例重度感音神经性耳聋患者的遗传病因,明确检出突变的致病性,以及患者人工耳蜗康复效果,为该家庭再生育提供遗传指导。方法　采集广西壮族自治区一个耳聋小家系样本3例,包括1例重度感音神经性耳聋患儿和其正常听力父母。对该家系成员进行病史调查、体格及听力学检查,采集外周静脉血。进行全基因组测序和生物信息学分析鉴定致病基因,评估人工耳蜗术后听觉与言语康复效果。结果　ESPN基因c.1916-1G>A纯合突变是该家系的致聋原因,人工耳蜗术后听觉与言语康复效果良好。结论　研究发现了ESPN基因一个新的突变,是该耳聋家系的致病原因。回访发现人工耳蜗术后患儿言语康复效果好。该研究丰富了遗传性聋的突变谱,并对人工耳蜗植入的术前评估具有指导意义。     

中国人群MYO15A基因同义突变引起剪接异常导致的非综合征型耳聋分析

［摘要］　目的　对一个遗传性非综合征型耳聋家系的临床特征进行分析并鉴定其致聋基因突变,同时在大规模耳聋人群队列中对鉴定出的致病性突变致中国人群耳聋的特征进行分析。方法　完善家系成员的问卷调查、听力学检查、体格检査等临床检查,同时采集血液样本,通过耳聋相关基因的大规模平行测序(MPS)和生物信息学分析进行致病基因鉴定。总结及分析鉴定出的致病性突变在中国耳聋基因研究战略联盟(CDGC)耳聋数据库中的检出情况。结果　在一个早发性极重度感音神经性耳聋家系中鉴定出MYO15A基因NM_016239.4:c.8182C>G（p.Arg2728Gly）/c.9861C>T（p.Gly3287=）复合杂合突变,为该家系耳聋患者的致聋原因。其中MYO15A基因c.9861C>T（p.Gly3287=）同义突变通过改变剪接导致基因功能缺陷,其在中国广西壮族人群中次要等位基因频率为0.2%（3/1 438）,在其他人群及公共数据库中均未检出。结论　研究确定了MYO15A基因c.9861C>T（p.Gly3287=）在中国非综合征型耳聋患者中的致病性,该突变在中国广西壮族自治区富集明显。通过研究强调了在致病基因鉴定时,高频与同义突变并非过滤的绝对指标,尤其是在某些地区富集格外明显的突变,应格外注意。     

遗传性家族性头颈副神经节瘤三个家系的SDH基因家族变异分析

［摘要］　目的　对三个遗传性家族性头颈副神经节瘤家系进行SDH基因家族变异分析。方法　选择2022年1月至2023年12月四川大学华西医院耳鼻咽喉头颈外科收治的3例头颈副神经节瘤患者（先证者）及其家系成员,采集研究对象外周静脉血200 μL,提取基因组DNA后进行测序,并对候选变异进行Sanger测序和致病性分析。结果　三个家系分别诊断为SDHD NM_003002.4:c.1A>G、SDHD NM_003002.4:c.274G>T和SDHB NM_003000.3:c.689G>A杂合变异导致的副神经节瘤,均为已报道过的变异。结论　对头颈副神经节瘤患者开展基因检测可以明确其致病原因,为遗传咨询提供参考。     

1个北方汉族家族性免疫球蛋白A肾病的家系分析和致病基因诊断

目的 研究1个家族性免疫球蛋白A(IgA)肾病的家系,并分析其致病基因。方法 调查1个家族性IgA肾病的家系,收集该家系成员的外周血提取基因组DNA,通过全外显子组测序寻找致病基因。结果 该家系共有5代26名成员,其中有12名成员临床表现为肾脏受累,6名成员临床表现为蛋白尿,3名成员临床表现为镜下血尿,3名成员肾脏病理活检诊断为系膜增生性IgA肾病。家系先证者基因组DNA行全外显子组测序发现INF2基因c.653G>A(p.R218Q)突变。结论 此家系存在家族性IgA肾病,全外显子组测序发现INF2基因c.653G>A(p.R218Q)突变,该突变为致病突变。     

SCN8A基因突变相关癫痫患儿8例的临床与遗传学特征分析

［摘要］　目的　分析SCN8A基因突变相关癫痫脑病的临床与遗传学特征。方法　选择2018年1月至2020年12月福建省立医院儿科收治的SCN8A基因突变相关癫痫病患儿8例，均经医学外显子测序及Sanger测序验证。收集其临床病历资料和基因检测结果进行总结分析。结果　8例患儿起病年龄中位数为6个月，男6例，女2例。癫痫发作类型有7种，3例存在≥3种发作类型。出现言语迟缓5例，肌张力低下4例，共济失调4例，步态障碍2例，智力低下5例。除1例脑电图正常外，其余7例发作间期脑电图异常，主要为多灶性放电。8例均为错义突变，其中未报道突变4例。新发突变5例，遗传杂合突变3例，临床表型各有差异。3例位于结构域C端内的突变，表型也有差异。结论　SCN8A基因相关癫痫是一种谱系疾病，新发突变可出现轻度温和至重度癫痫脑病表现，遗传杂合突变也可出现癫痫脑病的表现。突变方式与表型无相关性。突变位点在结构域中分布与突变来源及临床表型无关联。     

外显子测序技术在一个尿道下裂家系基因分析及产前诊断中的应用

目的采用外显子测序(exon sequencing,ES)联合Sanger测序技术检测1个尿道下裂家系的致病基因,并对这一致病基因进行产前诊断。方法采集先证者及其父母的外周血,并提取DNA。对先证者的DNA进行性腺疾病相关基因的外显子测序找到致病基因,并针对该致病基因对先证者父母的DNA进行Sanger验证,明确是遗传自亲代。对先证者母亲再次妊娠的羊水标本提取DNA,采用Sanger测序对该致病基因行产前诊断。结果先证者SRD5A2(NM_000348):c.607GA,P.(Gly203Ser)杂合突变及c.680GA,P.(Arg227Gln)杂合突变组成的复合杂合突变。而其表型正常的母亲为SRD5A2(NM_000348):c.607GA,P.(Gly203Ser)杂合突变;其表型正常的父亲为SRD5A2(NM_000348):c.680GA,P.(Arg227Gln)杂合突变。先证者母亲再次妊娠产前诊断结果为SRD5A2(NM_000348):c.680GA,P.(Arg227Gln)杂合突变。结论 ES联合Sanger测序可用于检测尿道下裂家系的致病基因及进行产前诊断。且此方法快速、准确、经济。     

胰岛素基因R46Q突变导致青少年的成人起病型糖尿病一个家系分析

本文报道1个经基因检测确诊为青少年起病的成人型糖尿病(MODY)10型家系。提取先证者外周血DNA,进行特殊类型糖尿病检测包的二代测序。将基因检测结果与遗传学数据库比对,从而发现可疑致病突变,并对先证者亲属相应位点进行Sanger测序验证,结果发现先证者及其两名家系成员于胰岛素基因第2外显子区域发生错义突变c.137G>A(p.R46Q),未检测到该位点突变的家系成员未发病。对先证者及其家系成员的临床资料,包括胰岛β细胞功能评估、并发症及合并症筛查、血糖控制情况等进行分析,并通过文献检索总结国内外已报道的MODY10的临床特点及分子机制。     

十个汉族家族性肥厚型心肌病MYH7、MYBPC3和TNNT2基因筛查结果及相应的临床特征

目的研究10个汉族家族性肥厚型心肌病的致病基因及突变特点,分析基因型与临床表型的相互关系。方法对10个无血缘关系的汉族家族性肥厚型心肌病的家系的MYH7基因、MYBPC3基因和TNNT2基因进行扫描,聚合酶链式反应扩增其外显子及剪接部位基因组DNA片段,直接测序分析,并分析各突变患者相应临床表型特点。结果10个汉族家族性肥厚型心肌病的家系中5个家系发现上述基因突变,3个家系MYH7基因发生错义突变,分别为Arg663His、Glu924Lys和Ile736Thr,Glu924Lya在中国患者中首次发现。这3个家系中3例患者猝死;2个家系MYBPC3基因发生错义突变、剪接突变和移码突变,1个家系先证者为复合突变即18外显子错义突变ArgS02Trp及27外显子剪接突变即IVS27＋12C〉T,先证者之母携带错义突变,先证者之父携带剪接突变;在另一家系首次发现Gly347fa移码突变,该家系中1例猝死。10个家系中未发现TNNT2基因的功能区突变,但在内含子3中发现一个STR多态性即CTTCT5个碱基的插入／缺失,7个家系先证者发现D基因型。结论MYH7基因为中国汉族家族性肥厚型心肌病最常见致病基因,临床表现较重,猝死率较高。MYBPC3突变也较常见,症状较轻,发病较晚,但复合突变发病早、症状重。同一突变的临床表型存在异质性提示多因素参与了肥厚型心肌病的发生与发展。     

扩张型心肌病家系罕见受磷蛋白致病基因突变

目的 对一扩张型心肌病(dilated cardiomyopathy, DCM)家系行候选致病基因全外显子高通量测序,以寻找该家系的致病基因,并分析其基因型和表型的关系。方法 收集在武汉大学人民医院就诊的一位DCM患者及其家系成员的临床资料及血液标本。与先证者及其家属签订知情同意书,绘制家谱图,由我院临床分子诊断中心对先证者进行候选致病基因全外显子高通量测序,获得可疑突变后,用Sanger测序对家系其他成员进行验证,寻找致病基因。结果 家系先证者6号染色体外显子上存在受磷蛋白(phospholamban, PLN)基因的精氨酸缺失突变c.36_38delAAG (p.Arg13del),为该家系的可疑致病基因。先证者目前心脏扩大,心功能显著下降,且超声心动图提示左心室附壁血栓形成,心电图提示肢导低电压以及胸导联R波极度减低。先证者母亲及其大姐因心脏病死亡,二姐目前患有扩张型心肌病,其子女未检测到致病基因。受磷蛋白作为肌质网钙离子循环中的调节蛋白,它的基因表达、分布、功能与心室的收缩功能密切相关。结论 本研究发现DCM家系中存在PLN基因缺失突变：PLN c.36_38delAAG (p.Arg13del),是家族性扩张型心肌病的重要致病基因,此突变在汉族人群中尚属首次报道。     

肥厚型心肌病致病基因型与临床表现的关系及基因筛查在肥厚型心肌病筛查及疾病鉴别诊断中的作用

目的:分析肥厚型心肌病(HCM)致病基因型与临床表现的关系及基因筛查在HCM筛查及疾病鉴别诊断中的作用。方法:选择一个HCM家系共14人,多重靶向测序技术对先证者的26个已知最常见的HCM致病基因进行全外显子捕获测序,用Sanger测序对发现的突变进行验证并对其他家系成员及307名健康对照进行该突变位点的筛查,分析其基因型与临床表型的特点。结果:先证者及其子携带MYH7基因c.2146 GA(Gly716Arg)突变,该突变位于MYH7基因19号外显子,导致第716位氨基酸残基由Gly变为Arg,其他25个基因未发现突变。Sanger测序验证后对其他家系成员进行突变筛查,其他家庭成员及对照组未发现该突变,该突变与HCM在该家系中共分离。先证者携带的致病突变为从头突变,并遗传给其子。先证者临床表现为发病早(14岁)、劳力性呼吸困难、胸痛、心悸、心力衰竭,其子出生时即发现心肌肥厚。其父虽然室间隔肥厚(15 mm),但结合其年轻时曾为运动员的经历及遗传筛查的阴性结果,可基本排除其为HCM患者,考虑为生理性肥厚。结论:该家系HCM由MYH7基因从头突变p.Gly716Arg导致,该突变临床发病早,症状较重,预后较差,为恶性突变。基因筛查在HCM家系筛查及疾病鉴别诊断中有重要意义。     

Ochronosis: a report of a case and a review of literature

A patient with alkaptonuria and ochronotic pigment deposited in articular cartilage and sclerae clinically manifested a serious osteoarthritis of the peripheral and axial joints and synchondrosis, typically involved in long lasting cases of this hereditary defect of homogentisic acid oxidase. This is the first patient with this disorder reported, where a non-cemented total knee prosthesis (PCAR) was applied on both knees. This was possible due to the good quality of the bone stock, which did not seem to be impaired by ochronosis. Our patient had no cardiac symptoms or murmurs, but had a slight calcification in the annulus of aorta observed with echocardiography, a useful new method for screening this disease manifestation. A third new aspect reported is the immunopathology of the synovial tissue. Small pieces of torn-off cartilage were seen embedded in the synovial stroma. This was associated with a slight hyperplasia of the C3bi-receptor positive and proline hydroxylase positive type A and B synovial lining cells. Perivenular infiltrates contained CD2 positive T lymphocytes, mostly belonging to the CD4 subset, and some C3bi-receptor positive monocytes. Activated CD25 positive and immunoglobulin light chain positive T and B lymphocytes were absent or few. Because modern medicine has much to offer to those suffering from this ancient inborn error of metabolism in the form of new specific diagnostic methods and new surgical modes of treatment, such as endoprosthesis surgery and cardiac valve replacement, we also present a literature overview of this interesting condition.     

Valuation of life: a concept and a scale

OBJECTIVES. The objective was to derive and test the psychometric characteristics of a scale to measure Valuation of Life (VOL). METHODS. Four samples were used in successive phases of exploratory factor analysis, confirmatory factor analysis, reliability and validity testing, and exploration of response-error effects. Estimates of Years of Desired Life were obtained under a variety of hypothetical quality-of-life (QOL)-compromising conditions of poor health. RESULTS. Confirmed 13-item (Positive VOL) and 6-item (Negative VOL) factors were obtained. A significant relationship between VOL and most Years of Desired Life estimates remained when demographic, health, quality of life, and mental health measures were controlled. Analysis of Negative VOL revealed that some respondents misunderstand the meaning of an agree response to negatively phrased items. DISCUSSION. VOL is a cognitive-affective schema whose function as a mediator and moderator between health and end-of-life decisions deserves further research.     

Simultaneous Perforation of a Gastric and a Duodenal Ulcer

This is a case report of simultaneous perforation of a gastric and duodenal ulcer. Perusal of the literature shows the rarity of this occurrence. Consideration is given to the difficulty of handling such a ease in the presence of severe generalized peritonitis and the precarious condition of the patient.     

Disclosing a dementia diagnosis: a review of opinion and practice, and a proposed research agenda

PURPOSE: The ethical and practical issues in disclosing a dementia diagnosis remain subjects of some debate. In this review of the literature we document previous opinion and practice in the area of diagnostic disclosure. DESIGN AND METHODS: We identified sources for this review with a MEDLINE and PsycINFO database search, followed by collection of additional articles from reference lists. RESULTS: Across sources we were able to identify a broad list of arguments both for and against diagnostic disclosure. We briefly discuss some of the ethical principles that undergird those reasons. IMPLICATIONS: Practice guidelines and professional opinion regarding disclosure appear to depart from the actual experience reported by clinicians, patients, and family members. At a more detailed level, process issues in disclosure, such as who is told, how and what they are told, and the impact of disclosure, are poorly understood. Sensitivity to individual differences may promote an optimal approach to disclosure. Research in this area is sparse and often contradictory, and throughout the review we propose research questions that, when answered, could clarify issues in disclosure that are essential to sound dementia care.     

Comparison of musculoskeletal ultrasound practices of a rheumatologist and a radiologist

OBJECTIVE: There is considerable debate regarding the role of the rheumatologist ultrasonographer and how this development will impact on musculoskeletal ultrasound (MSUS) performed by radiologists. We compared the MSUS practices of a rheumatologist and a radiologist working within the same National Health Service Trust. METHODS: A retrospective review of MSUS reports of consecutive scans performed by a consultant rheumatologist with a special interest in MSUS and a consultant musculoskeletal radiologist. Reports were analysed for referring specialties, indications for MSUS, joint regions scanned, MSUS findings, frequency with which patients were referred for injection and how often injection was performed. RESULTS: A total of 170 patients were referred to the rheumatologist for MSUS of 282 joint regions (91% referred by rheumatologists). Of those, 84 (49%) patients had MSUS examination of more than one joint region, with up to five regions scanned per sitting. One hundred patients were referred to the radiologist for MSUS of 111 joint regions (49% referred by orthopaedic surgeons). The most frequently requested primary indication for MSUS performed by the rheumatologist was detection of synovitis [74 (44%) patients] while MSUS performed by the radiologist was most frequently for assessment for major structural changes [44 (44%) patients]. The rheumatologist performed MSUS-guided injection in 59 of 170 (35%) patients scanned and the radiologist in 13 of 100 (13%). CONCLUSION: MSUS performed by the rheumatologist was predominantly requested by rheumatologists to aid diagnosis of synovial and tendon inflammation and to guide injections, while MSUS performed by the radiologist was predominantly requested by orthopaedic surgeons to aid diagnosis of structural pathology. Curriculums in MSUS designed for rheumatologists may need to place appropriate emphasis on the identification of synovial and tendon inflammation, and injection guidance.