199 research outputs found
Prenatal exome sequencing in central nervous system anomalies: diagnostic yield and challenges
No full textTrio-based prenatal exome sequencing (pES) showed a significant incremental diagnostic yield over karyotype and chromosomal microarray (CMA) in fetuses with structural anomalies. However, optimized indications, detection rates in different categories of fetal anomalies, and interpretation of variants pathogenicity are still under investigation.
The aim of this study was to assess the incremental diagnostic yield of trio-based pES after karyotype and CMA inconclusive result in Central Nervous System (CNS) anomalies.
Between January 2019 and December 2022, a cohort of 33 fetuses presenting apparently isolated or non-isolated CNS anomalies was enrolled. In all cases karyotype and CMA analyses were performed. In non-conclusive cases, pES was offered. Trio-based pES was performed in 15 cases on genomic DNA extracted from fetal samplings and parental leukocytes. Library preparation and targeted enrichment were performed using the Twist Human Core Exome Kit and sequenced on the Illumina NovaSeq 6000 platform. Then, a systematic review on the published cohorts of fetuses specifically selected for CNS anomalies was performed according to PRISMA guidelines, including n=12 papers.
The incremental diagnostic yield of pES over CMA/karyotype was calculated for each study and pooled in a meta‐analysis using a logistic random mixed-effect model.
In our cohort in 4/33 cases (12%) standard karyotype was conclusive. CMA was not diagnostic in any case. In 5/15 cases (33%), pES disclosed likely pathogenic (LP) or pathogenic (P) variants in BICD2, NFIA, ARID1A, RPGRIP1L and ZIC2 genes fitting the fetal phenotypes. In 6/15 (40%) cases, multiple Variants of Uncertain Significance (VUSs) were detected. In one case both VUSs and LP variants were detected, partially related to the fetal phenotype. In three cases no variants were disclosed. Systematic literature review showed an incremental yield ranging from 19% to 57% in antenatal cohorts focused on CNS anomalies. The pooled incremental diagnostic yield estimate resulted 36% (95% C.I.: [28%;44%]) including all CNS anomalies, 22% (95% C.I.: [15%;31%] in apparently isolated CNS anomalies, 32% (95% C.I.: [22%;45%]) in CNS-only related anomalies (one or more) and 45% (95% C.I.: [37%;53%]) in non-isolated CNS anomalies (either ≥ 2 anomalies in CNS, or extra-CNS).
In conclusion, meta-analysis showed a substantial diagnostic improvement in performing genome wide sequencing analysis over standard and molecular cytogenetics, supporting the proposal of performing pES earlier in the diagnostic route of CNS anomalies
Prenatal Genome-Wide Sequencing analysis (Exome or Genome) in detecting pathogenic Single Nucleotide Variants in fetal Central Nervous System Anomalies: systematic review and meta-analysis
No full text: Prenatal Exome (pES) or Genome (pGS) Sequencing analysis showed a significant incremental diagnostic yield over karyotype and chromosomal microarray analysis (CMA) in fetal structural anomalies. Optimized indications and detection rates in different fetal anomalies are still under investigation. The aim of this study was to assess the incremental diagnostic yield in prenatally diagnosed Central Nervous System (CNS) anomalies. A systematic review on antenatal CNS anomalies was performed according to PRISMA guidelines, including n = 12 paper, accounting for 428 fetuses. Results were pooled in a meta-analysis fitting a logistic random mixed-effect model. The effect of interest was the incremental diagnostic rate of pES over karyotype/CMA in detecting likely pathogenic/pathogenic Single Nucleotide Variants (SNVs). A further meta-analysis adding the available pGS studies (including diagnostic coding SNVs only) and submeta-analysis on three CNS subcategories were also performed. The pooled incremental diagnostic yield estimate of pES studies was 38% (95% C.I.: [29%;47%]) and 36% (95% C.I.: [28%;45%]) when including diagnostic SNVs of pGS studies. The point estimate of the effect resulted 22% (95% C.I.: [15%;31%]) in apparently isolated anomalies, 33% (95% C.I.: [22%;46%]) in CNS-only related anomalies (≥1) and 46% (95% C.I.: [38%;55%]) in non-isolated anomalies (either ≥ 2 anomalies in CNS, or CNS and extra-CNS). Meta-analysis showed a substantial diagnostic improvement in performing Prenatal Genome-Wide Sequencing analysis (Exome or Genome) over karyotype and CMA in CNS anomalies
Enrica Lexie Incident Award and its Implication
No full textOn 21 May 2020, the Arbitral Tribunal under Annex VII to the United Nations Convention on the Law of the Sea in respect of the Enrica Lexie Incident adopted its Award. It was notified to the Parties on 9 June 2020. On 2 July 2020, the Arbitral Tribunal published the operative part(dispositif) of the Award on the PCA Case Repository.
According to Italy, the dispute arises from an incident that occurred on 15 February 2012 approximately 20.5 nautical miles off the coast of India involving the “Enrica Lexie”, an oil tanker flying the Italian flag, and India’s subsequent exercise of criminal jurisdiction over the incident and over two Italian marines from the Italian Navy. According to India, the incident in question concerns the killing of two Indian fishermen on board an Indian vessel named the “St. Antony”, and India’s subsequent exercise of jurisdiction. It is alleged that the two Italian marines aboard the “Enrica Lexie” killed the fishermen.
Author would like to explaine that there is a sligltly different noteworthy point on this Case. The point is that the Arbitral Tribunal placed much emphasis on the statements of the individuals involved in the case, when the Arbitral Tribunal deal with the fact findinding and jurisprudence. This paper aims to focus on how the Arbitral Tribunal handles the testimony of the individuals involved in this case in the process of deleberating the case of Enrica Lexie Incident.22Nkc
Prenatal Exome Sequencing: Background, Current Practice and Future Perspectives—A Systematic Review
No full textThe introduction of Next Generation Sequencing (NGS) technologies has exerted a significant impact on prenatal diagnosis. Prenatal Exome Sequencing (pES) is performed with increasing frequency in fetuses with structural anomalies and negative chromosomal analysis. The actual diagnostic value varies extensively, and the role of incidental/secondary or inconclusive findings and negative results has not been fully ascertained. We performed a systematic literature review to evaluate the diagnostic yield, as well as inconclusive and negative-result rates of pES. Papers were divided in two groups. The former includes fetuses presenting structural anomalies, regardless the involved organ; the latter focuses on specific class anomalies. Available findings on non-informative or negative results were gathered as well. In the first group, the weighted average diagnostic yield resulted 19%, and inconclusive finding rate 12%. In the second group, the percentages were extremely variable due to differences in sample sizes and inclusion criteria, which constitute major determinants of pES efficiency. Diagnostic pES availability and its application have a pivotal role in prenatal diagnosis, though more homogeneity in access criteria and a consensus on clinical management of controversial information management is envisageable to reach widespread use in the near future
Clustering of extrasynaptic GABAA receptors modulates tonic inhibition in cultured hippocampal neurons
No full textMolecular Approaches in Fetal Malformations, Dynamic Anomalies and Soft Markers: Diagnostic Rates and Challenges—Systematic Review of the Literature and Meta-Analysis
No full textFetal malformations occur in 2–3% of pregnancies. They require invasive procedures for cytogenetics and molecular testing. “Structural anomalies” include non-transient anatomic alterations. “Soft markers” are often transient minor ultrasound findings. Anomalies not fitting these definitions are categorized as “dynamic”. This meta-analysis aims to evaluate the diagnostic yield and the rates of variants of uncertain significance (VUSs) in fetuses undergoing molecular testing (chromosomal microarray (CMA), exome sequencing (ES), genome sequencing (WGS)) due to ultrasound findings. The CMA diagnostic yield was 2.15% in single soft markers (vs. 0.79% baseline risk), 3.44% in multiple soft markers, 3.66% in single structural anomalies and 8.57% in multiple structural anomalies. Rates for specific subcategories vary significantly. ES showed a diagnostic rate of 19.47%, reaching 27.47% in multiple structural anomalies. WGS data did not allow meta-analysis. In fetal structural anomalies, CMA is a first-tier test, but should be integrated with karyotype and parental segregations. In this class of fetuses, ES presents a very high incremental yield, with a significant VUSs burden, so we encourage its use in selected cases. Soft markers present heterogeneous CMA results from each other, some of them with risks comparable to structural anomalies, and would benefit from molecular analysis. The diagnostic rate of multiple soft markers poses a solid indication to CMA
Critical prenatal diagnosis and management of incidental exon 43-44 deletion in the dystrophin gene
No full textCritical prenatal diagnosis and management of incidental exon 43-44 deletion in the dystrophin gen
Unusual Segregation of APP Mutations in Monogenic Alzheimer Disease
No full textAPP gene mutations causing Alzheimer disease (AD) segregate in an autosomal dominant pattern. We report on a 40-year-old woman with a severe cognitive decline starting at 36 years, while her affected relatives presented symptoms onset in the 6th decade. The proband carried an APP missense variant in homozygous state (NM_000484.4: c.2032G>A; NP_000475.1: p.Asp678Asn; rs63750064) and showed a more severe clinical picture than the other AD relatives, as regards the age of onset and the rate of disease progression. This mutation behaves as a semi-dominant trait. The very rare chance of studying APP mutations in the homozygous state demonstrates they are not always dominant and other segregation models are possible
Unusual Association of Scn2a Epileptic Encephalopathy with Severe Cortical Dysplasia Detected by Prenatal Mri
No full textTlr4 t399i polymorphism and endometriosis in a cohort of italian women
No full textEndometriosis is a widespread multifactorial disease in which environmental, genetic, and epigenetic factors contribute to the phenotype. Single Nucleotide Polymorphisms (SNPs) in genes implicated in pivotal molecular mechanisms have been investigated as susceptible risk factors in distinct populations. Among these, Toll-like receptor 4 (TLR4) represents a good candidate due to its role in the immune/inflammatory response and endometriosis pathogenesis
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