Novel In-Frame Deletion Mutation in NOTCH1 in a Chinese Sporadic Case of Adams-Oliver Syndrome.
- 作者列表："Huang S","Yang L","Zhao L","Xu R","Wu Y
:Adams-Oliver syndrome (AOS) is a rare hereditary disorder characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects. The etiology of AOS has remained largely unknown, although mutations in the notch receptor 1 (NOTCH1) gene are most common genetic alteration associated with this disease. In this study, we aimed to identify the case of a 6-year-old boy, who presented with large ACC of the scalp and aortic valve stenosis, suggesting the possibility of AOS. Whole-exome sequencing identified a novel, de novo, in-frame deletion in the NOTCH1 gene (NOTCH1 c.1292_1294del, p.Asn431del) in the patient. The p.Asn431del variant was evaluated by several in silico analyses, which predicted that the mutant was likely to be pathogenic. In addition, molecular modeling with the PyMOL Molecular Graphics System suggested that the NOTCH1-N431del destabilizes calcium ion chelation, leading to decreased receptor-ligand binding efficiency. Quantitative reverse transcription PCR showed further significant downregulation of the Notch target genes, hes-related family bHLH transcription factor with YRPW motif 1 (HEY1) and hes family bHLH transcription factor 1 (HES1), suggesting that this mutation causes disease through dysregulation of the Notch signaling pathway. Our study provides evidence that the NOTCH1-N431del mutation is responsible for this case of AOS. To our knowledge, this is the first report of a patient with AOS caused by NOTCH1 mutation in Asia, and this information will be useful for providing the family with genetic counseling that can help to guide their future plans.
: Adams-Oliver综合征 (AOS) 是一种罕见的遗传性疾病，以先天性皮肤发育不全 (ACC) 和终末横肢缺损为特征。AOS的病因在很大程度上仍然未知，尽管notch受体 1 (NOTCH1) 基因的突变是与该疾病相关的最常见的遗传改变。在这项研究中，我们旨在确定一例 6 岁男孩，表现为头皮和主动脉瓣狭窄的大ACC，提示AOS的可能性。全外显子组测序鉴定了患者NOTCH1 基因 (NOTCH1 c.1292 _ 1294del，p.Asn431del) 中一个新的、从头开始的框内缺失。P.Asn431del变异体通过几个计算机分析进行评价，预测该突变体可能是致病性的。此外，PyMOL分子图形系统的分子建模表明，NOTCH1-N431del不稳定钙离子螯合，导致受体-配体结合效率降低。定量逆转录PCR显示Notch靶基因、具有YRPW基序 1 的hes相关家族bHLH转录因子 (HEY1) 和hes家族bHLH转录因子 1 (HES1) 进一步显著下调，提示该突变通过Notch信号通路失调引起疾病。我们的研究提供了NOTCH1-N431del突变导致AOS的证据。据我们所知，这是亚洲首次报道NOTCH1 突变导致AOS患者，这些信息将有助于为家庭提供遗传咨询，帮助指导他们未来的计划。
METHODS::Impairments in social cognition have been frequently described in 22q11.2 deletion syndrome (22q11.2DS) and are thought to be a hallmark of difficulties in social interactions. The present study addresses aspects that are critical for everyday social cognitive functioning but have received little attention so far. Sixteen children with 22q11.2DS and 22 controls completed 1 task of facial expression recognition, 1 task of attribution of facial expressions to faceless characters involved in visually presented social interactions, and 1 task of attribution of facial expressions to characters involved in aurally presented dialogues. All three tasks have in common to involve processing of emotions. All participants also completed two tasks of attention and two tasks of visual spatial perception, and their parents completed some scales regarding behavioural problems of their children. Patients performed worse than controls in all three tasks of emotion processing, and even worse in the second and third tasks. However, they performed above chance level in all three tasks, and the results were independent of IQ, age and gender. The analysis of error patterns suggests that patients tend to coarsely categorize situations as either attractive or repulsive and also that they have difficulties in differentiating emotions that are associated with threats. An isolated association between the tasks of emotion and behaviour was found, showing that the more frequently patients with 22q11.2DS perceive happiness where there is not, the less they exhibit aggressive behaviour.
METHODS:BACKGROUND:We describe the first radiographic clinic in the literature for DDH and how this novel clinic can significantly improve the efficiency and cost-effectiveness of service in a tertiary referral centre. AIMS:A radiographic clinic for the management of developmental dysplasia of the hip was introduced in 2017 in our institution. We performed a detailed cost analysis to assess the economic savings made with the introduction of this new clinic. We assessed the efficiency of the service by identifying how many unnecessary outpatient visits were prevented. We also assessed the difference in times from referral to review between the two clinics. METHODS:Analysis of the clinic activity in 2017 was possible as all data was collected prospectively by the DDH CNS and stored in our database. Cost analysis was performed, and the savings made per patient along with the financial benefit to our institution was recorded. RESULTS:The new radiographic clinic reduced the cost of reviewing one patient by €162.51 per patient. There was a 73% discharge rate from the clinic which prevented 251 unnecessary patient visits to the outpatient department over the course of the year. There was a significant 11-day reduction in waiting times between referral and review when comparing the radiographic to the conventional clinic (p < 0.05). CONCLUSIONS:A radiographic clinic for the management of developmental dysplasia of the hip has a significant effect on the efficiency and overall cost-effectiveness of service provision in a tertiary referral centre.
METHODS:INTRODUCTION:Triple pelvic osteotomy (TPO) involves periacetabular osteotomies of the ilium, ischium, and pubis to reorient the acetabulum. This operation is indicated in certain situations for the treatment of developmental dysplasia of the hip, dysplastic neuromuscular hips, and for containment of the femoral head in cases of Legg-Calvé-Perthes disease. METHODS:This retrospective cohort study compares radiographic outcomes of patients who underwent TPO using two different techniques and describes a novel single-incision direct lateral approach. TPO was performed on 22 patients by the senior author. The first 10 patients underwent TPO through a single-incision anterolateral approach. The last 12 patients underwent TPO using the direct lateral approach. Preoperative and postoperative pelvic radiographs were reviewed for each patient, and the migration index and center-edge angle were recorded. RESULTS:The migration index and center-edge angle were evaluated and were not found to be significantly different between the anterolateral and direct lateral groups. The direct lateral approach is described. CONCLUSION:The direct lateral approach for TPO is equivalent to the anterolateral approach on radiographic evaluation. Advantages of the direct lateral approach include direct visualization of the ischial osteotomy, effective mobilization of the acetabulum, and safety of the sciatic nerve.