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The use of genome-scale sequencing allows for identification of genetic findings beyond the original indication for testing (secondary findings). The ClinGen Actionability Working Groups (AWG) protocol for evidence synthesis and semi-quantitative metric scoring evaluates four domains of clinical actionability for potential secondary findings: severity and likelihood of the outcome, and effectiveness and nature of the intervention. As of February 2018, the AWG has scored 127 genes associated with 78 disorders (up-to-date topics/scores are available at www.clinicalgenome.org). Scores across these disorders were assessed to compare genes/disorders recommended for return as secondary findings by the American College of Medical Genetics and Genomics (ACMG) with those not currently recommended. Disorders recommended by the ACMG scored higher on outcome-related domains (severity and likelihood), but not on intervention-related domains (effectiveness and nature of the intervention). Current practices indicate that return of secondary findings will expand beyond those currently recommended by the ACMG. The ClinGen AWG evidence reports and summary scores are not intended as classifications of actionability, rather they provide a resource to aid decision makers as they determine best practices regarding secondary findings. The ClinGen AWG is working with the ACMG Secondary Findings Committee to update future iterations of their secondary findings list.

Neurodevelopmental disorders (NDDs) are frequently associated with gastrointestinal symptoms (GIS) and sleep issues, but there are insufficient data on the occurrence of these symptoms in young children with autism spectrum disorder (ASD) compared with other NDDs. We abstracted data on 500 children aged 18 to 36 months with ASD and 146 children aged 18 to 47 months with non-ASD NDDs to compare the frequency of these symptoms. In the overall sample, there was a high rate of GIS (46.0%) and sleep difficulties (22.6%). In age-adjusted analyses, children with non-ASD NDDs were more likely to have GIS (61.0% vs 41.6%; adjusted odds ratio [OR] = 2.35; 95% confidence interval = 1.56-3.56) and sleep difficulties (34.9% vs 19.0%; adjusted OR = 2.08; 95% confidence interval = 1.33-3.26) compared with those with ASD. These findings demonstrate the need to assess these symptoms in all young children with developmental concerns to provide appropriate guidance to their families. [ABSTRACT FROM AUTHOR]

The ClinGen Inborn Errors of Metabolism Working Group was tasked with creating a comprehensive, standardized knowledge base of genes and variants for metabolic diseases. Phenylalanine hydroxylase (PAH) deficiency was chosen to pilot development of the Working Group's standards and guidelines. A PAH variant curation expert panel (VCEP) was created to facilitate this process. Following ACMG‐AMP variant interpretation guidelines, we present the development of these standards in the context of PAH variant curation and interpretation. Existing ACMG‐AMP rules were adjusted based on disease (6) or strength (5) or both (2). Disease adjustments include allele frequency thresholds, functional assay thresholds, and phenotype‐specific guidelines. Our validation of PAH‐specific variant interpretation guidelines is presented using 85 variants. The PAH VCEP interpretations were concordant with existing interpretations in ClinVar for 69 variants (81%). Development of biocurator tools and standards are also described. Using the PAH‐specific ACMG‐AMP guidelines, 714 PAH variants have been curated and will be submitted to ClinVar. We also discuss strategies and challenges in applying ACMG‐AMP guidelines to autosomal recessive metabolic disease, and the curation of variants in these genes. The ClinGen Inborn Errors of Metabolism Working Group chose phenylalanine hydroxylase (PAH) deficiency to pilot metabolic‐specific ACMG‐AMP variant interpretation guidelines. A PAH variant curation expert panel adjusted existing ACMG‐AMP rules based on disease (6) or strength (5) or both (2). Disease adjustments include allele frequency thresholds, functional assay thresholds, and phenotype‐specific guidelines. Our validation of PAH‐specific variant interpretation guidelines are presented. Using these guidelines 714 PAH variants have been curated and will be submitted to ClinVar. [ABSTRACT FROM AUTHOR]

Background: To truly achieve personalized medicine in oncology, it is critical to catalog and curate cancer sequence variants for their clinical relevance. The Somatic Working Group (WG) of the Clinical Genome Resource (ClinGen), in cooperation with ClinVar and multiple cancer variant curation stakeholders, has developed a consensus set of minimal variant level data (MVLD). MVLD is a framework of standardized data elements to curate cancer variants for clinical utility. With implementation of MVLD standards, and in a working partnership with ClinVar, we aim to streamline the somatic variant curation efforts in the community and reduce redundancy and time burden for the interpretation of cancer variants in clinical practice. Methods: We developed MVLD through a consensus approach by i) reviewing clinical actionability interpretations from institutions participating in the WG, ii) conducting extensive literature search of clinical somatic interpretation schemas, and iii) survey of cancer variant web portals. A forthcoming guideline on cancer variant interpretation, from the Association of Molecular Pathology (AMP), can be incorporated into MVLD. Results: Along with harmonizing standardized terminology for allele interpretive and descriptive fields that are collected by many databases, the MVLD includes unique fields for cancer variants such as Biomarker Class, Therapeutic Context and Effect. In addition, MVLD includes recommendations for controlled semantics and ontologies. The Somatic WG is collaborating with ClinVar to evaluate MVLD use for somatic variant submissions. ClinVar is an open and centralized repository where sequencing laboratories can report summary-level variant data with clinical significance, and ClinVar accepts cancer variant data. Conclusions: We expect the use of the MVLD to streamline clinical interpretation of cancer variants, enhance interoperability among multiple redundant curation efforts, and increase submission of somatic variants to ClinVar, all of which will enhance translation to clinical oncology practice. [ABSTRACT FROM AUTHOR]

This case study of Salmon Grumbach offers new perspectives on French Jewish use of the public sphere during the interwar years, particularly during the refugee crisis of the 1930s. An Alsatian Jew, journalist and interwar socialist politician, Grumbach cultivated a web-like system of connections with diverse individuals and groups, from official organizations in Paris to efforts well outside the capital. He used this informal network to influence public opinion on political and human rights issues, even when not in elected office. In the 1930s, as an anti-fascist politician and a vocal champion for refugees he received hundreds of written appeals from persecuted foreigners seeking asylum in France, many of whom were Jewish. In attending to their pleas for travel papers, residency permits and liberation from French internment camps, Grumbach used his network to employ all means possible to help them, even when popular opinion worked against him. [ABSTRACT FROM PUBLISHER]

The CAG repeats in the human Huntington's disease (HD) gene exhibit striking length-dependent intergenerational instability, typically small size increases or decreases of one to a few CAGs, but little variation in somatic tissues. In a subset of male transmissions, larger size increases occur to produce extreme HD alleles that display somatic instability and cause juvenile onset of the disorder. Initial efforts to reproduce these features in a mouse model transgenic for HD exon 1 with 48 CAG repeats revealed only mild intergenerational instability (∼2% of meioses). A similar pattern was obtained when this repeat was inserted into exon 1 of the mouse Hdh gene. However, lengthening the repeats in Hdh to 90 and 109 units produced a graded increase in the mutation frequency to >70%, with instability being more evident in female transmissions. No large jumps in CAG length were detected in either male or female transmissions. Instead, size changes were modest increases and decreases, with expansions typically emanating from males and contractions from females. Limited CAG variation in the somatic tissues gave way to marked mosaicism in liver and striatum for the longest repeats in older mice. These results indicate that gametogenesis is the primary source of inherited instability in the Hdh knock-in mouse, as it is in man, but that the underlying repeat length-dependent mechanism, which may or may not be related in the two species, operates at higher CAG numbers. Moreover, the large CAG repeat increases seen in a subset of male HD transmissions are not reproduced in the mouse, suggesting that these arise by a different fundamental mechanism than the small size fluctuations that are frequent during gametogenesis in both species. [ABSTRACT FROM AUTHOR]

On the Cover: This cover image is based on the Special Article Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene by Diane B. Zastrow et al., Pages 1569–1580. DOI: 10.1002/humu.23649. [ABSTRACT FROM AUTHOR]