Bi-allelic truncating variants in CASP2 underlie a neurodevelopmental disorder with lissencephaly

Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function

Analysis of allelic imbalances and local DNA copy number changes in neuroblastic tumors

Periferal nöroblastik tümörler, özellikle nöroblastom (NB), en sık gözlenen çocukluk çağı neoplastik oluşumudur. klinik davranış bakımından kendiliğinden spontan gerileyen benign ganglionöromdan agresif ve metastatik malign tipe kadar farklılık gösterebilmektedir. NB karmaşık ve heterojen genetik değişiklikler içermektedir. En sık gözlenen değişiklikler; ploidi sapmaları, MYCN geninin amplifikasyonu, 1p, 3p, 11q delesyonları ve 17q kol kazanımlarıdır. Bu çalışmada, 249 NB tümörü olan olguda genomik skalada gözlenen genetik değişikler (MYCN geninin amplifikasyonu, 1p, 3p, 11q delesyonları ve 17q kol kazanımı) ve klinik özellikler (yaş, tümör evresi ve histolojisi) çok değişkenli lojistik regresyon analiziyle değerlendirildi. Ayrıca 11q delesyonu ve 3p delesyonu gözlenen olgularda dizin CGH çalışmaları yapıldı. Aynı zamanda amplikon gözlenen hücre hatlarında replikasyonunun hücre döngüsünün herhangi bir aşamasında olabileceğinin gösterilmesi amaçlanmıştır. Olguların tamamında; 1, 2, 3, 4, 7, 9, 11, 12, 14 ve 17. kromozom kollarında 100?den fazla prob kullanılarak hibridizasyon gerçekleştirildi. PCR ile çoğaltılan ürünlerin nicel analizi kapiller elektroforez ile gerçekleştirildi. NB tanılı olgularda MYCN amplifikasyonu % 23.3, 1p delesyonu % 31.7, 3p delesyonu % 20.8, 11q delesyonu % 26.2, 17q kazanımı % 77.2 oranında gözlendi. NAG, DDX1 ve ALK gen amplifikasyonu ile MYCN amplifikasyonu arasındaki ilişki istatistiksel olarak anlamlı bulundu. SiMa hücre hattına DM yapılarının kendini eşlemesinin hücre döngüsünden bağımsız olmadığı ve S-fazında olduğu gösterildi. MLPA sonuçlarına göre 4 tümör grubu oluşmuştur. Grup1; MYCN amplifikasyonu ve 1p delesyonundan en az birini taşıyanlar. Grup2; 11q delesyonu ve 3p delesyonundan en az birini taşıyanlar. Grup3; MYCN amplifikasyonu veya 1p ve 11q veya 3p delesyonlarından en az ikisini taşıyanlar. Grup4 ise bu anomalileri taşımayan tümörler. Grup1, 2 ve 3?de olguların çoğunluğu 12 ay üstü yaş, yüksek evre, kötü histoloji grubunda olduğu saptandı. Sonuç olarak, NB?de çoklu genetik değişikliklerin saptanmasında MLPA kullanılması etkin ve duyarlı bir yaklaşım olup, tümörlerin çoklu genetik özellikleri bakımından sınıflandırılmasını ve tedavi protokollerinin etkin bir biçimde uygulanmasına destek sağlayabilecektir. Neuroblastoma (NB) is a neoplasm of sympathetic nervous system and the most frequent extra cranial solid tumor of early childhood. The tumors have variable clinical presentation, ranging from a benign tumor which is regress spontaneously or mature into ganglioneuroma to an aggressive and metastatic malignant progression. NB has very complex and heterogeneous genetic alterations. The most common alterations are ploidy changes, amplification of the MYCN, deletions of chromosomes arms 1p, 3p and 11q and gains of 17q arm. In this study, we analyzed genomic scale of the genetic alterations and clinical parameters of the primary neuroblastic tumors in 249 cases with MLPA. Also, we investigated a significance of association between clinical (age, tumor stage and histology) and genetic (MYCN amplification, 1p, 3p, 11q deletions and 17q gain) parameters with multivariate logistic regression analyses. In addition, array CGH analyses were observed in tumors with 11q and 3p deletions. At the same time, we thought that amplicons observed in cell lines may be replicated at any stage of the cell cycle. MLPA analyses of multiple loci at chromosomes 1, 2, 3, 4, 7, 9, 12, 14, and 17 were performed using more than one hundred probes. Amplified PCR products were separated with a capillary electrophoresis and fragments were analyzed with it. Major anomalies in NB were MYCN amplification (23.3%), 1p (31.7%), 3p (20.8%), 11q (26.2%) deletions and 17q (77.2%) gain. There was a highly significant amplification of MYCN gene and NAG, DDX1 and ALK amplifications. Replication of double minutes on SiMa cell line was shown dependent on the cell cycle (S phase). Genetic analysis of multiple loci by MLPA revealed four different tumor groups: (Grup1) Tumors with MYCN amplification and 1p deletion or at least one of them, (Grup2) Tumors with 11q and 3p deletions or at least one of them, (Grup3) MYCN amplification and/or 1p deletion and 11q and/or 3p deletions at least one of them, (Grup4) tumor with anomalies other than 1p, 3p, 11q deletions or MYCN amplification. The majority of the patients in the Group1, 2 and 3 were detected over 12 months of age, high stage and poor histology. In conclusion, our results show that MLPA can confidently and effectively be utilized to detect multiple genomic imbalances at a time, and these changes can be classified into genetic subtypes of NB. Also, MLPA applications could be effectively supported by treatment protocol

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function.Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien-Dindo classification system.Results: A total of 3288 patients were included in the analysis, of whom 301 (9.2 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4-7) and 7 (6-8) days respectively (P < 0.001). There were no significant differences in rates of readmission between these groups (6.6 versus 8.0 per cent; P = 0.499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0.90, 95 per cent c.i. 0.55 to 1.46; P = 0.659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34.7 versus 39.5 per cent; major 3.3 versus 3.4 per cent; P = 0.110).Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients

Timing of nasogastric tube insertion and the risk of postoperative pneumonia: an international, prospective cohort study

Aim: Aspiration is a common cause of pneumonia in patients with postoperative ileus. Insertion of a nasogastric tube (NGT) is often performed, but this can be distressing. The aim of this study was to determine whether the timing of NGT insertion after surgery (before versus after vomiting) was associated with reduced rates of pneumonia in patients undergoing elective colorectal surgery. Method: This was a preplanned secondary analysis of a multicentre, prospective cohort study. Patients undergoing elective colorectal surgery between January 2018 and April 2018 were eligible. Those receiving a NGT were divided into three groups, based on the timing of the insertion: routine NGT (inserted at the time of surgery), prophylactic NGT (inserted after surgery but before vomiting) and reactive NGT (inserted after surgery and after vomiting). The primary outcome was the development of pneumonia within 30 days of surgery, which was compared between the prophylactic and reactive NGT groups using multivariable regression analysis. Results: A total of 4715 patients were included in the analysis and 1536 (32.6%) received a NGT. These were classified as routine in 926 (60.3%), reactive in 461 (30.0%) and prophylactic in 149 (9.7%). Two hundred patients (4.2%) developed pneumonia (no NGT 2.7%; routine NGT 5.2%; reactive NGT 10.6%; prophylactic NGT 11.4%). After adjustment for confounding factors, no significant difference in pneumonia rates was detected between the prophylactic and reactive NGT groups (odds ratio 1.03, 95% CI 0.56–1.87, P = 0.932). Conclusion: In patients who required the insertion of a NGT after surgery, prophylactic insertion was not associated with fewer cases of pneumonia within 30 days of surgery compared with reactive insertion