Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Abstract The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared to information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known non-pathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification. This article is protected by copyright. All rights reserved.Peer reviewe

Reducing unnecessary neonatal testing in infants of mothers with thyroid disease

Aim To examine the numbers of asymptomatic infants <8 weeks who had appropriate thyroid function tests (TFTs) in addition to the newborn screening test, because of maternal thyroid disease, before and after the implementation of an updated institutional guideline and staff education. Methods A medical record audit of infants <8 weeks born at a metropolitan teaching hospital, who had TFTs between 1 July 2017 and 31 October 2017 was performed as part of a quality improvement project. Records were reviewed to determine the indication for testing and whether this complied with the current 2011 institutional guideline. A multidisciplinary staff education package was developed to coincide with the publication of an updated guideline in August 2018. Staff education and resources were provided throughout July 2018. A post‐intervention audit was repeated between 1 August 2018 and 1 December 2018, assessing compliance with the 2018 guideline. Results In the baseline period, 40 of 457 infants born had TFTs performed, of which 26 of 40 (65%) were for maternal thyroid disease. Of these 10 of 26 (38%) met the 2011 criteria for testing; 1 of 26 (4%) met the updated 2018 criteria. In the post‐intervention period, 14 of 412 infants born had TFTs of which 5 of 14 (36%) were tested due to maternal thyroid disease and all were compliant with the new guideline. Conclusions Baseline audit revealed unnecessary neonatal thyroid function testing of healthy babies. Implementation of an updated guideline and a brief, targeted education package successfully increased awareness of the updated recommendations, reduced unnecessary testing and led to improved practice

El colecho favorece la práctica de la lactancia materna y no aumenta el riesgo de muerte súbita del lactante. Dormir con los padres [Ded-sharing favours the practice of breastfeeding and does not increase the risk of sudden infant death syndrome. sleeping with parents]

La práctica de los padres de dormir junto a sus hijos ha sido una constante en la humanidad. Con el aumento en la prevalencia y duración de la lactancia materna, se ha observado paralelamente un aumento de esa práctica, que posiblemente se dé con más frecuencia que la reconocida en las encuestas. Los estudios han demostrado interrelación y mutua potenciación entre lactancia materna y colecho. Las asociaciones y organizaciones pediátricas recomiendan evitar el colecho, por relacionarlo con la muerte súbita del lactante. Se basan, sin embargo, en estudios en su mayoría no controlados, bajo la influencia de factores de riesgo no tenidos en cuenta. Los autores, tras una revisión exhaustiva sobre colecho, lactancia y muerte súbita del lactante, encuentran el colecho como una práctica beneficiosa para la lactancia y concluyen que, bien practicado, evitando factores de riesgo, no guarda relación con la muerte súbita del lactante. The practice of bed-sharing by parents and their offspring has been a common behaviour among humans. In parallel with the increase of breastfeeding rates, a higher frequency of bed-sharing has been observed worldwide. And, it is probable that it occurs more frequently than what appears reflected in surveys. There seems to be an interrelated and mutually enhanced effect between breastfeeding and bed-sharing. Pediatric associations and health organizations have warned against the practice of bed-sharing based on studies that describe a link between this practice and Sudden Infant Death Syndrome (SIDS). However, many were non-controlled studies that did not include other potentially risky circumstances. After a thoroughly review of the available literature, the authors have found the practice of bed-sharing to be of benefit on the basis of a warm and close-up infant care approach and calls for recognition and avoidance of risky situations that could represent a threat for infant life

Versatile gene-specific sequence tags for Arabidopsis functional genomics: Trancript profiling and reverse genetics applications

Microarray transcript profiling and RNA interference are two new technologies crucial for large-scale gene function studies in multicellular eukaryotes. Both rely on sequence-specific hybridization between complementary nucleic acid strands, inciting us to create a collection of gene-specific sequence tags (GSTs) representing at least 21,500 Arabidopsis genes and which are compatible with both approaches. The GSTs were carefully selected to ensure that each of them shared no significant similarity with any other region in the Arabidopsis genome. They were synthesized by PCR amplification from genomic DNA. Spotted microarrays fabricated from the GSTs show good dynamic range, specificity, and sensitivity in transcript profiling experiments. The GSTs have also been transferred to bacterial plasmid vectors via recombinational cloning protocols. These cloned GSTs constitute the ideal starting point for a variety of functional approaches, including reverse genetics. We have subcloned GSTs on a large scale into vectors designed for gene silencing in plant cells. We show that in planta expression of GST hairpin RNA results in the expected phenotypes in silenced Arabidopsis lines. These versatile GST resources provide novel and powerful tools for functional genomics