Communicating Unexpected Genetic Information with Family Members: A Multimethod Study of Secondary Findings Recipients

Background: Medically-actionable secondary genomic findings (SF) can be life- preserving or life-prolonging for recipients but this benefit can only extend to family members if this information is shared with relatives. How SF recipients communicate this important genetic information with relatives, barriers and facilitators to this process, and SF recipients’ lived experiences in communicating about their results over time remain largely unknown. Family communication is required for relatives of SF recipients to access cascade testing and the potential benefits of enhanced screening and management. Applying behavioral and implementation science theories and providing rich and deep descriptions of SF recipients’ lived experiences in sharing their results with relatives may lay the foundation for the development of future studies of interventions to optimize this process. Objective: The purpose of this study was to describe SF recipients’ lived experience of sharing their results with family members and characterize self-reported determinants of this process. Methods: This multimethod study was conducted in two Phases. In Phase 1, existing data from interviews of SF recipients was analyzed to characterize self-reported determinants of family communication. The COM-B (Michie et al., 2014) was employed as the theoretical framework for the thematic analysis of existing data to describe SF recipients’ capability, opportunity, and motivation to share their results with their relatives. A novel interview guide based on this analysis was also developed in Phase 1. In Phase 2 purposive sampling to emphasize diversity of family communication experiences was employed to conduct novel phenomenological interviews (Moustakas, 2011) with SF recipients to develop a deeper understanding of their lived experiences of sharing their results with their relatives over time. These data were also thematically analyzed and coded to describe textural and structural elements of the described lived experiences. A second coder, bracketing, and member-checking were employed to enhance trustworthiness of the data. Results: A codebook mapped to the COM-B constructs of Capability, Opportunity, and Motivation was developed to analyze existing interview transcripts from 40 participants in Phase 1 of the study. Over a quarter of participants (n=13) demonstrated poor or uncertain knowledge (Capability) of their SF. Interpersonal and social factors affecting family communication (Social Opportunity) were described by 32 participants and over half of participants (n=22) described emotional closeness as a facilitator of family communication. Physical proximity and frequency of contact (Physical Opportunity) were also cited as determinants of family communication. Participants commonly discussed a desire to help relatives as a Reflective Motivator of family communication, and many also described worry or concern about how relatives might react to their sharing their SF (Automatic Motivation). Purposive sampling was used to assemble a cohort of 11 Phase 2 participants, and analysis of the novel phenomenologic interviews that characterized this Phase extended and deepened some Phase 1 findings. Two major themes emerged from analysis of Phase 2 data: 1) the experience of family communication of SF is one that engenders personal reflection and emotional responses, and 2) family communication of SF is strongly influenced by existing family dynamics. For Phase 2 participants the essential experience of sharing their SF with relatives was analogous to giving each family member an important and valuable gift; sharing SF information was a personal and loving act, and they were very invested in, and affected by, how relatives received it. Discussion: This study’s theory-informed approach demonstrated key ways family communication of SF parallels what is known about how families communicate about genetic information generally and suggests some possible differences that may form intervention development for this understudied population. SF recipients may lack both knowledge of the medical implications of their findings and a shared familial understanding of how family health history may be related to their finding. As well, while SF recipients may be motivated to share their findings with relatives to improve their care, they are tasked with sharing unexpected medical information within complex existing family systems. The interplay of these factors suggests that interventions designed to optimize family communication of SF may need to address both gaps in knowledge and understanding as well as communication strategies employed in family systems

Molecular Analysis Expands the Spectrum of Phenotypes Associated with GLI3 Mutations

A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral-facial-digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype-phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral-facial-digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype-phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.</p> <p>Methods</p> <p>Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the <it>EVC/EVC2 </it>locus. The results did not exclude linkage, so samples were sequenced for mutations.</p> <p>Results</p> <p>We identified a c.1868T>C mutation in <it>EVC</it>, which predicts p.L623P, and was homozygous in affected individuals.</p> <p>Conclusion</p> <p>We conclude that this <it>EVC </it>mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. <it>EVC </it>mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.</p

Prospectus, February 4, 1982

WE WANT YOU FOR STUGO; News In Brief; More StuGo prospects; Letters To The Editor: She thinks StuGo should attend to other problems. Thanks to former president; Exercise your right to vote; Nautical look \u27in\u27 this spring; PC Happenings…: Improve thyself, AHT offers Sweetheart raffle, Go Western in Ski Club, Managing your money; Teleview to make debut in March; Need financial aid? Here\u27s how to get it; Teleview to make debut in March; Sheriff discusses overcrowding at jail; Increased enrollment results in overcrowding; Com Club sets election; \u27Snow\u27 chance of a heat wave: Surprise storm hits area for 3rd weekend in a row!; Sunday\u27s snow nearly sets record; Not end of candy business: Chris\u27 reopening; Low-cost trips, tours offered to college students; Keeping friends is series topic; Few in Illinois have tax problems; J. Geils is back; Storm postpones athletic events; College bowling tourney held at Arrowhead; Kinks\u27 latest gives what we want; Big Daddy: rockabilly party; Rick James leads new Punk Funk wave; Something crazy was expected, but...: Ozzy pays back Champaign; This week\u27s happenings: Clubs offer local talent; Abba\u27s new album adds to their success; Reviewer enjoys brass band; \u27Dragonriders\u27 series deals in Pem fantasy; Classifieds; \u27Roots\u27 begins Feb. 9; Euchre tourney begins tonight; Skating party is Feb. 8; Top boxing prospect appearing at Danville; PC track team places in two events; Cagers keep winning streak alive with Joliet victory; Makeever leads Cobras to victory; Lady Cobras suffer defeat; Today\u27s farmer from new era; Burnham establishes scholarship; Farm technology is tapering off; Wind and cold make bitter combinationhttps://spark.parkland.edu/prospectus_1982/1030/thumbnail.jp

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.</p> <p>Methods</p> <p>Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the <it>EVC/EVC2 </it>locus. The results did not exclude linkage, so samples were sequenced for mutations.</p> <p>Results</p> <p>We identified a c.1868T>C mutation in <it>EVC</it>, which predicts p.L623P, and was homozygous in affected individuals.</p> <p>Conclusion</p> <p>We conclude that this <it>EVC </it>mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. <it>EVC </it>mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.</p

NAA10 polyadenylation signal variants cause syndromic microphthalmia

Background A single variant in NAA10 (c.471+2T>A), the gene encoding N-acetyltransferase 10, has been associated with Lenz microphthalmia syndrome. In this study, we aimed to identify causative variants in families with syndromic X-linked microphthalmia.Methods Three families, including 15 affected individuals with syndromic X-linked microphthalmia, underwent analyses including linkage analysis, exome sequencing and targeted gene sequencing. The consequences of two identified variants in NAA10 were evaluated using quantitative PCR and RNAseq.Results Genetic linkage analysis in family 1 supported a candidate region on Xq27-q28, which included NAA10. Exome sequencing identified a hemizygous NAA10 polyadenylation signal (PAS) variant, chrX:153,195,397T>C, c.*43A>G, which segregated with the disease. Targeted sequencing of affected males from families 2 and 3 identified distinct NAA10 PAS variants, chrX:g.153,195,401T>C, c.*39A>G and chrX:g.153,195,400T>C, c.*40A>G. All three variants were absent from gnomAD. Quantitative PCR and RNAseq showed reduced NAA10 mRNA levels and abnormal 3′ UTRs in affected individuals. Targeted sequencing of NAA10 in 376 additional affected individuals failed to identify variants in the PAS.Conclusion These data show that PAS variants are the most common variant type in NAA10-associated syndromic microphthalmia, suggesting reduced RNA is the molecular mechanism by which these alterations cause microphthalmia/anophthalmia. We reviewed recognised variants in PAS associated with Mendelian disorders and identified only 23 others, indicating that NAA10 harbours more than 10% of all known PAS variants. We hypothesise that PAS in other genes harbour unrecognised pathogenic variants associated with Mendelian disorders. The systematic interrogation of PAS could improve genetic testing yi

A Point Mutation in PDGFRB Causes Autosomal-Dominant Penttinen Syndrome

Penttinen syndrome is a distinctive disorder characterized by a prematurely aged appearance with lipoatrophy, epidermal and dermal atrophy along with hypertrophic lesions that resemble scars, thin hair, proptosis, underdeveloped cheekbones, and marked acro-osteolysis. All individuals have been simplex cases. Exome sequencing of an affected individual identified a de novo c.1994T>C p.Val665Ala variant in PDGFRB, which encodes the platelet-derived growth factor receptor β. Three additional unrelated individuals with this condition were shown to have the identical variant in PDGFRB. Distinct mutations in PDGFRB have been shown to cause infantile myofibromatosis, idiopathic basal ganglia calcification, and an overgrowth disorder with dysmorphic facies and psychosis, none of which overlaps with the clinical findings in Penttinen syndrome. We evaluated the functional consequence of this causative variant on the PDGFRB signaling pathway by transfecting mutant and wild-type cDNA into HeLa cells, and transfection showed ligand-independent constitutive signaling through STAT3 and PLCγ. Penttinen syndrome is a clinically distinct genetic condition caused by a PDGFRB gain-of-function mutation that is associated with a specific and unusual perturbation of receptor function

An unusual cause for Coffin–Lowry syndrome: Three brothers with a novel microduplication in RPS6KA3

Coffin–Lowry syndrome (CLS) is a rare X‐linked disorder characterized by moderate to severe intellectual disability, hypotonia, craniofacial features, tapering digits, short stature, and skeletal deformities. Using whole exome sequencing and high‐resolution targeted comparative genomic hybridization array analysis, we identified a novel microduplication encompassing exons five through nine of RPS6KA3 in three full brothers. Each brother presented with intellectual disability and clinical and radiographic features consistent with CLS. qRT‐PCR analyses performed on mRNA from the peripheral blood of the three siblings revealed a marked reduction of RPS6KA3 levels suggesting a loss‐of‐function mechanism. PCR analysis of the patients’ cDNA detected a band greater than expected for an exon 4–10 amplicon, suggesting this was likely a direct duplication that lies between exons 4 through 10, which was later confirmed by Sanger sequencing. This microduplication is only the third intragenic duplication of RPS6KA3, and the second and smallest reported to date thought to cause CLS. Our study further supports the clinical utility of methods such as next‐generation sequencing and high‐resolution genomic arrays to detect small intragenic duplications. These methods, coupled with expression studies and cDNA structural analysis have the capacity to confirm the diagnosis of CLS in these rare cases

Safety and efficacy of low-dose sirolimus in the PIK3CA-Related Overgrowth Spectrum

Purpose PIK3CA-related overgrowth spectrum (PROS) encompasses a range of debilitating conditions defined by asymmetric overgrowth caused by mosaic activating PIK3CA variants. PIK3CA encodes the p110α catalytic subunit of phosphatidylinositol-3-kinase (PI3K), a critical transducer of growth factor signaling. As mTOR mediates the growth-promoting actions of PI3K, we hypothesized that the mTOR inhibitor sirolimus would slow pathological overgrowth. Methods Thirty-nine participants with PROS and progressive overgrowth were enrolled into open-label studies across three centers, and results were pooled. For the primary outcome, tissue volumes at affected and unaffected sites were measured by dual energy X-ray absorptiometry during 26 weeks of untreated run-in and 26 weeks of sirolimus therapy. Results Thirty participants completed the study. Sirolimus led to a change in mean percentage total tissue volume of –7.2% (SD 16.0, p = 0.04) at affected sites, but not at unaffected sites (+1.7%, SD 11.5, p = 0.48) (n = 23 evaluable). Twenty-eight of 39 (72%) participants had ≥1 adverse event related to sirolimus of which 37% were grade 3 or 4 in severity and 7/39 (18%) participants were withdrawn consequently. Conclusion This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS