Stakeholder views on secondary findings in whole-genome and whole-exome sequencing:a systematic review of quantitative and qualitative studies

Purpose: As whole-exome and whole-genome sequencing (WES/WGS) move into routine clinical practice, it is timely to review data that might inform the debate around secondary findings (SF) and the development of policies that maximize participant benefit. Methods: We systematically searched for qualitative and quantitative studies that explored stakeholder views on SF in WES/WGS. Framework analysis was undertaken to identify major themes. Results: 44 articles reporting the views of 11,566 stakeholders were included. Stakeholders were broadly supportive of returning ‘actionable’ findings, but definitions of actionability varied. Stakeholder views on SF disclosure exist along a spectrum: potential WES/WGS recipients’ views were largely influenced by a sense of rights, while views of genomics professionals were informed by a sense of professional responsibility. Experience of genetic illness and testing resulted in greater caution about SF, suggesting that truly informed decisions require an understanding of the implications and limitations of WES/WGS and possible findings. Conclusion: This review suggests that bidirectional interaction during consent might best facilitate informed decision-making about SF, and that dynamic forms of consent, allowing for changing preferences, should be considered. Research exploring views from wider perspectives and from recipients who have received SF is critical if evidence-based policies are to be achieved.</p

Defining ourselves:Personal bioinformation as a tool of narrative self-conception

Where ethical or regulatory questions arise about an individual’s interests in accessing bioinformation about herself (such as findings from screening or health research), the value of this information has traditionally been construed in terms of its clinical utility. It is increasingly argued, however, that the “personal utility” of findings should also be taken into account. This article characterizes one particular aspect of personal utility: that derived from the role of personal bioinformation in identity construction. The suggestion that some kinds of information are relevant to identity is not in itself new. However, the account outlined here seeks to advance the debate by proposing a conception of the relationship between bioinformation and identity that does not depend on essentialist assumptions and applies beyond the narrow genetic contexts in which identity is customarily invoked. The proposal is that the identity-value of personal bioinformation may be understood in terms of its instrumental role in the construction of our narrative identities, specifically that its value lies in helping us to develop self-narratives that support us in navigating our embodied existences. I argue that this narrative conception provides useful insights that are pertinent to the ethical governance of personal bioinformation. It illuminates a wider range of ethical considerations in relation to information access; it accounts for variations in the utility of different kinds of information; and it highlights that the context in which information is conveyed can be as important as whether it is disclosed at all. These arguments are illustrated using an example drawn from psychiatric neuroimaging research

Candidate gene/loci studies in cleft lip/palate and dental anomalies finds novel susceptibility genes for clefts

Purpose: We revisited 42 families with two or more cleft-affected siblings who participated in previous studies. Complete dental information was collected to test the hypothesis that dental anomalies are part of the cleft phenotype spectrum, and can provide new opportunities for identification of cleft susceptibility genes. Methods: Genotypes from 1489 single nucleotide polymorphism markers located in 150 candidate genes/loci were reanalyzed. Two sets of association analyses were carried out. First, we ran the analysis solely on the cleft status. Second, we assigned affection to any cleft or dental anomaly (tooth agenesis, supernumerary teeth, and microdontia) and repeated the analysis. Results: Significant over-transmission was seen for a single nucleotide polymorphism in ankyrin repeat and sterile alpha motif domain containing 6 (rs4742741, 9q22.33; P = 0.0004) when a dental anomaly phenotype was included in the analysis. Significant over-transmission was also seen for a single nucleotide polymorphism in ERBB2 (rs1810132, 17q21.1; P = 0.0006). In the clefts only data, the most significant result was also for ERBB2 (P = 0.0006). Other markers with suggestive P values included interferon regulatory factor 6 and 6q21q23 loci. In contrast to the above results, suggestive over-transmission of markers in GART, DPF3, and neurexin 3 were seen only when the dental anomaly phenotype was included in the analysis. Conclusions: These findings support the hypothesis that some loci may contribute to both clefts and congenital dental anomalies. Thus, including dental anomalies information in the genetics analysis of cleft lip and palate will provide new opportunities to map susceptibility loci for clefts. Copyright © American College of Medical Genetics

Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts

EEC syndrome is an autosomal dominant disorder with the cardinal signs of ectrodactyly, ectodermal dysplasia, and orofacial clefts. EEC syndrome has been linked to chromosome 3q27 and heterozygous p63 mutations were detected in unrelated EEC families. In addition, homozygous p63 null mice exhibit craniofacial abnormalities, limb truncations, and absence of epidermal appendages, such as hair follicles and tooth primordia. In this study, we screened 39 syndromic patients, including four with EEC syndrome, five with syndromes closely related to EEC syndrome, and 30 with other syndromic orofacial clefts and/or limb anomalies. We identified heterozygous p63 mutations in three unrelated cases of EEC syndrome, two Iowa white families and one sporadic case in a Filipino boy. One family is atypical for EEC and has features consistent with Hay-Wells syndrome. In this family, the mutation ablates a splice acceptor site and, in the other two, mutations produce amino acid substitutions, R280C and R304Q, which alter conserved DNA binding sites. Germline mosaicism was detected in the founder of the mutation in one case. These three cases show significant interfamilial and intrafamilial variability in expressivity. We also screened p63 in 62 patients with non-syndromic orofacial clefts, identifying an intronic single nucleotide polymorphism but finding no evidence of mutations that would explain even a subset of non-syndromic orofacial clefts. This study supports a common role for p63 in classical EEC syndrome, both familial and sporadic, but not in other related or non-syndromic forms of orofacial clefts

A genome-wide linkage scan for cleft lip and cleft palate identifies a novel locus on 8p11-23

Isolated or nonsyndromic cleft lip and palate (NS CLP) is a complex disorder resulting from multiple genetic and environmental factors. NS CLP has a birth prevalence of 1 per 500 in the Philippines where large families provide an opportunity for gene localization. Genotyping of 392 microsatellite repeat markers at 10 cM intervals over the genome was performed by the Center for Inherited Disease Research (CIDR) on 220 Filipino families with 567 affected and 1,109 unaffected family members genotyped. Among the most statistically significant results from analysis of the genome-wide scan data was a 20 cM region at 8p11-23 in which markers had LODs ≥1.0. This region on 8p11-23 has not been found in any previous genome wide scan nor does it contain any of the candidate genes widely studied in CLP. Fine mapping in 8p11-23 was done in the 220 families plus an additional 51 families, using SNP markers from 10 known genes (FGFR1, NRG1, FZD3, SLC8A1, PPP3CC, EPHX2, BNIP3L, EGR3, PPP2R2A, and NAT1) within the 20 cM region of 8p11-23. Linkage and association analyses of these SNPs yield suggestive results for markers in FGFR1 (recessive multipoint HLOD 1.07) and BAG4 (recessive multipoint HLOD 1.31). © 2007 Wiley-Liss, Inc

Genome scan, fine-mapping, and candidate gene analysis of non-syndromic cleft lip with or without cleft palate reveals phenotype-specific differences in linkage and association results

Objectives: Non-syndromic orofacial clefts, i.e. cleft lip (CL) and cleft palate (CP), are among the most common birth defects. The goal of this study was to identify genomic regions and genes for CL with or without CP (CL/P). Methods: We performed linkage analyses of a 10 cM genome scan in 820 multiplex CL/P families (6,565 individuals). Significant linkage results were followed by association analyses of 1,476 SNPs in candidate genes and regions, utilizing a weighted false discovery rate (wFDR) approach to control for multiple testing and incorporate the genome scan results. Results: Significant (multipoint HLOD ≥3.2) or genome-wide-significant (HLOD ≥4.02) linkage results were found for regions 1q32, 2p13, 3q27-28, 9q21, 12p11, 14q21-24 and 16q24. SNPs in IRF6 (1q32) and in or near FOXE1 (9q21) reached formal genome-wide wFDR-adjusted significance. Further, results were phenotype dependent in that the IRF6 region results were most significant for families in which affected individuals have CL alone, and the FOXE1 region results were most significant in families in which some or all of the affected individuals have CL with CP. Conclusions: These results highlight the importance of careful phenotypic delineation in large samples of families for genetic analyses of complex, heterogeneous traits such as CL/P