Disclosure of cardiac variants of uncertain significance results in an exome cohort.

This study examined the impact of disclosing subclassifications of genetic variants of uncertain significance (VUS) on behavioral intentions. We studied return of VUS results to 79 individuals with a cardiomyopathy-associated VUS, subclassified into VUS-high or VUS-low. Primary outcomes were perceived risk (absolute and comparative), perceived severity, perceived value of information, self-efficacy, decision regret, and behavioral intentions to share results and change behaviors. There was no significant difference between the 2 subclasses in overall behavioral intentions (t = 0.023, P = .982) and each of the individual items on the behavioral intentions scale; absolute (t = -1.138, P = .259) or comparative (t = -0.463, P = .645) risk perceptions; perceived value of information (t = 0.582, P = .563) and self-efficacy (t = -0.733, P = .466). Decision regret was significantly different (t = 2.148, P = .035), with VUS-low (mean = 17.24, SD = 16.08) reporting greater regret. Combining the subclasses, perceived value of information was the strongest predictor of behavioral intentions (ß = 0.524, P < .001). Participants generally understood the meaning of a genetic VUS result classification and reported satisfaction with result disclosure. No differences in behavioral intentions were found, but differences in decision regret suggest participants distinguish subclasses of VUS results. The perceived value of VUS may motivate recipients to pursue health-related behaviors.

Defining personal utility in genomics: A Delphi study.

BACKGROUND: Individual genome sequencing results are valued by patients in ways distinct from clinical utility. Such outcomes have been described as components of "personal utility," a concept that broadly encompasses patient-endorsed benefits, that is operationally defined as non-clinical outcomes. No empirical delineation of these outcomes has been reported. AIM: To address this gap, we administered a Delphi survey to adult participants in a National Institute of Health (NIH) clinical exome study to extract the most highly endorsed outcomes constituting personal utility. MATERIALS AND METHODS: Forty research participants responded to a Delphi survey to rate 35 items identified by a systematic literature review of personal utility. RESULTS: Two rounds of ranking resulted in 24 items that represented 14 distinct elements of personal utility. Elements most highly endorsed by participants were: increased self-knowledge, knowledge of "the condition," altruism, and anticipated coping. DISCUSSION: Our findings represent the first systematic effort to delineate elements of personal utility that may be used to anticipate participant expectation and inform genetic counseling prior to sequencing. The 24 items reported need to be studied further in additional clinical genome sequencing studies to assess generalizability in other populations. Further research will help to understand motivations and to predict the meaning and use of results.

PUGS: A novel scale to assess perceptions of uncertainties in genome sequencing.

Expectations of results from genome sequencing by end users are influenced by perceptions of uncertainty. This study aimed to assess uncertainties about sequencing by developing, evaluating, and implementing a novel scale. The Perceptions of Uncertainties in Genome Sequencing (PUGS) scale comprised ten items to assess uncertainties within three domains: clinical, affective, and evaluative. Participants (n=535) from the ClinSeq® NIH sequencing study completed a baseline survey that included the PUGS; responses (mean = 3.4/5, SD=0.58) suggested modest perceptions of certainty. A confirmatory factor analysis identified factor loadings that led to elimination of two items. A revised eight-item PUGS scale was used to test correlations with perceived ambiguity (r = -0.303, p < 0.001), attitudinal ambivalence (r = -0.111, p = 0.011), and ambiguity aversion (r = -0.093, p = 0.033). Results support nomological validity. A correlation with the MICRA uncertainty subscale was found among 175 cohort participants who had received results (r = -0.335, p < 0.001). Convergent and discriminant validity were also satisfied in a second sample of 208 parents from the HudsonAlpha CSER Project who completed the PUGS (mean = 3.4/5, SD = 0.72), and configural invariance was supported across the two datasets. As such, the PUGS is a promising scale for evaluating perceived uncertainties in genome sequencing, which can inform interventions to help patients form realistic expectations of these uncertainties.

Myocardial fat overgrowth in Proteus syndrome.

Proteus syndrome (PS) is a rare, mosaic disorder with asymmetric and distorting overgrowth of the skeletal system, skin, and adipose tissues. Cardiac abnormalities are rare in this syndrome and only two prior cases have been reported. Many patients with PS followed at our institution underwent transthoracic echocardiograms for preoperative evaluation or as work-up for associated pulmonary disease. Some were noted to have prominent, focal echodense areas in the myocardium. We further investigated cardiac findings in a cohort of children and adult patients with PS. Patients with abnormal echocardiograms were referred for cardiac magnetic resonance imaging, Holter monitoring, and exercise treadmill testing. Twenty children and adults with PS, age 24 months to 50 years old, underwent transthoracic echocardiograms. Seven patients (35%) had focal bright echodense areas within the myocardium suggesting fatty infiltration. The majority of patients had significant involvement of the interventricular septum. The cardiac characteristics of all patients with fatty infiltration on transthoracic echocardiograms were compared to Proteus patients without these findings. There were no significant differences in chamber sizes, mass, systolic or diastolic function. No increased risk of conduction defects or arrhythmias was found. This study shows that abnormal fat overgrowth is a common finding in the myocardium in patients with Proteus syndrome; however, it is not associated with functional derangements or arrhythmias. Further evaluation of a larger number of Proteus patients is needed in order to determine the frequency and prognosis of cardiac involvement. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Determination of the allelic frequency in Smith-Lemli-Opitz syndrome by analysis of massively parallel sequencing data sets.

Data from massively parallel sequencing or 'Next Generation Sequencing' of the human exome has reached a critical mass in both public and private databases, in that these collections now allow researchers to critically evaluate population genetics in a manner that was not feasible a decade ago. The ability to determine pathogenic allele frequencies by evaluation of the full coding sequences and not merely a single nucleotide polymorphism (SNP) or series of SNPs will lead to more accurate estimations of incidence. For demonstrative purposes, we analyzed the causative gene for the disorder Smith-Lemli-Opitz Syndrome (SLOS), the 7-dehydrocholesterol reductase (DHCR7) gene and determined both the carrier frequency for DHCR7 mutations, and predicted an expected incidence of the disorder. Estimations of the incidence of SLOS have ranged widely from 1:10,000 to 1:70,000 while the carrier frequency has been reported as high as 1 in 30. Using four exome data sets with a total of 17,836 chromosomes, we ascertained a carrier frequency of pathogenic DHRC7 mutations of 1.01%, and predict a SLOS disease incidence of 1/39,215 conceptions. This approach highlights yet another valuable aspect of the exome sequencing databases, to inform clinical and health policy decisions related to genetic counseling, prenatal testing and newborn screening.

Guidelines for investigating causality of sequence variants in human disease.

The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

Parental attitudes, values, and beliefs toward the return of results from exome sequencing in children.

Exome sequencing is being offered for children with undiagnosed conditions to identify a primary (causative) variant. Parental preferences for learning secondary (incidental) variants are largely unexplored. Our objective was to characterize values and beliefs that shape parents' preferences for learning their children's sequencing results. We conducted semi-structured interviews with 25 parents of 13 minor probands with a variety of rare genetic conditions. Parents were asked to discuss their preferences to receive four types of results from exome sequencing. Many parents preferred to receive all types of results. Parents had the most positive attitudes toward learning about variants that predispose to disorders treatable or preventable in childhood. They had reservations about learning about predispositions for untreatable adult-onset conditions and carrier status for recessive conditions. Parents described their success in coping with their child's condition as evidence for an ability to manage any additional negative health information. They felt responsible for learning about secondary variants, desiring a gain in control over their child's health. Our findings suggest that investigators should incorporate parents' perceptions of the value in receiving secondary variant information about their children when designing studies employing exome sequencing.

Hyperphagia among patients with Bardet-Biedl syndrome.

BACKGROUND: The importance of hyperphagia as a cause for energy imbalance in humans with Bardet-Biedl syndrome (BBS) has not been established. We therefore compared hyperphagic symptoms in patients with BBS vs. controls. METHODS: We studied 13 patients with BBS and 23 non-syndromic controls with similar age, sex and body mass index (BMI) z-score. A 13-item hyperphagia questionnaire was completed by patients' parents/guardians. RESULTS: Total hyperphagia questionnaire score was higher in BBS than controls (27.6 ± 9.0 vs. 19.1 ± 7.9, P = 0.005). Behaviour and drive subscales were higher for BBS than controls (12.5 ± 4.1 vs. 7.8 ± 3.2, P = 0.001, and 11.2 ± 4.1 vs. 8.3 ± 3.8, P = 0.04, respectively); severity was not significantly different between groups (3.8 ± 1.5 vs. 3.0 ± 1.3, P = 0.072). After adjustment for demographic variables and BMI z-score, total and behaviour subscale scores remained significantly different between groups, suggesting food-seeking activity, rather than preoccupation with food may be the main hyperphagic feature among patients with BBS. CONCLUSION: Appetite dysregulation may contribute to obesity in BBS.

Effects of informed consent for individual genome sequencing on relevant knowledge.

Increasing availability of individual genomic information suggests that patients will need knowledge about genome sequencing to make informed decisions, but prior research is limited. In this study, we examined genome sequencing knowledge before and after informed consent among 311 participants enrolled in the ClinSeq™ sequencing study. An exploratory factor analysis of knowledge items yielded two factors (sequencing limitations knowledge; sequencing benefits knowledge). In multivariable analysis, high pre-consent sequencing limitations knowledge scores were significantly related to education [odds ratio (OR): 8.7, 95% confidence interval (CI): 2.45-31.10 for post-graduate education, and OR: 3.9; 95% CI: 1.05, 14.61 for college degree compared with less than college degree] and race/ethnicity (OR: 2.4, 95% CI: 1.09, 5.38 for non-Hispanic Whites compared with other racial/ethnic groups). Mean values increased significantly between pre- and post-consent for the sequencing limitations knowledge subscale (6.9-7.7, p < 0.0001) and sequencing benefits knowledge subscale (7.0-7.5, p < 0.0001); increase in knowledge did not differ by sociodemographic characteristics. This study highlights gaps in genome sequencing knowledge and underscores the need to target educational efforts toward participants with less education or from minority racial/ethnic groups. The informed consent process improved genome sequencing knowledge. Future studies could examine how genome sequencing knowledge influences informed decision making.

What you can learn from one gene: GLI3.

The study of patients with rare multiple congenital anomaly syndromes can provide illuminating insights into normal development and the pathogenesis of congenital anomalies. The GLI3 gene is a particularly good example as it illuminates the phenomena of pleiotropy, phenocopies, syndrome families, and evolutionary conservation of pathogenesis, and raises questions about how diagnoses are conceptualised. These topics are reviewed in turn, in the context of the clinical and biological data derived from patients with mutations in GLI3 and experimental work in model systems.

Mapping phenotypes to language: a proposal to organize and standardize the clinical descriptions of malformations.

Recent developments in molecular biology have markedly speeded the processes involved in determining the molecular etiology of human Mendelian disorders. Nowhere are these changes more evident than in the field that is variously termed molecular dysmorphology, human morphogenesis, or human developmental biology. In contrast to the rapid changes in molecular genetics analysis, the processes and approaches of the clinical component of molecular dysmorphology have not changed substantially, and clinical analysis is therefore becoming relatively slower than molecular discovery. If clinical discovery is to maintain its deserved position at the forefront of human genetics research, new methods must be developed to acquire, archive, and analyze these data. The limitations of current phenotyping, specifically, the limitations of the collection and archiving of clinical data in medical journal case reports and case series manuscripts are demonstrated. Several provocative approaches that have been proposed to advance the field of clinical analysis are reviewed. Lastly, a specific proposal for a system of clinical analysis and archiving of data on human pleiotropic developmental anomaly syndromes is proposed to address these limitations.

Psychiatric and neuropsychological characterization of Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS) is a rare, single-gene, malformation syndrome that includes central polydactyly, hypothalamic hamartoma, bifid epiglottis, endocrine dysfunction, and other anomalies. The syndrome has variable clinical manifestations and is inherited in an autosomal dominant pattern. We sought to determine whether psychiatric disorders and/or neuropsychological impairment were characteristic of PHS. We prospectively conducted systematic neuropsychiatric evaluations with 19 PHS subjects ranging in age from 7 to 75 years. The evaluation included detailed clinical interviews, clinician-rated and self-report instruments, and a battery of neuropsychological tests. Seven of 14 adult PHS subjects met diagnostic criteria for at least one DSM-IV Axis I disorder. Three additional subjects demonstrated developmental delays and/or neuropsychological deficits on formal neuropsychological testing. However, we found no characteristic psychiatric phenotype associated with PHS, and the frequency of each of the diagnoses observed in these subjects was not different from that expected in this size sample. The overall frequency of psychiatric findings among all patients with PHS cannot be compared to point prevalence estimates of psychiatric disease in the general population because of biased ascertainment. This limitation is inherent to the study of behavioral phenotypes in rare disorders. The general issue of psychiatric evaluation of rare genetic syndromes is discussed in light of this negative result.

Mutation analysis of the MKKS gene in McKusick-Kaufman syndrome and selected Bardet-Biedl syndrome patients.

McKusick-Kaufman syndrome comprises hydrometrocolpos, polydactyly, and congenital heart defects and overlaps with Bardet-Biedl syndrome, comprising retinitis pigmentosa, polydactyly, obesity, mental retardation, and renal and genital anomalies. Bardet-Biedl syndrome is genetically heterogeneous with three cloned genes ( BBS2, BBS4, and MKKS) and at least three other known loci ( BBS1, BBS3, and BBS5). Both McKusick-Kaufman syndrome and Bardet-Biedl syndrome are inherited in an autosomal recessive pattern, and both syndromes are caused by mutations in the MKKS gene. However, mutations in MKKS are found in only 4%-11% of unselected Bardet-Biedl syndrome patients. We hypothesized that an analysis of patients with atypical Bardet-Biedl syndrome and McKusick-Kaufman syndrome (Group I; 15 probands) and patients with Bardet-Biedl syndrome who had linkage results inconsistent with linkage to the other loci (Group II; 12 probands) could increase the MKKS mutation yield. Both mutant alleles were identified in only two families in Group II. Single (heterozygous) sequence variations were found in three Group I families and in two Group II families. Combining these results with previously published data showed that only one mutant allele was detected in nearly half of all patients screened to date, suggesting that unusual mutational mechanisms or patterns of inheritance may be involved. However, sequencing of the BBS2 gene in these patients did not provide any evidence of digenic or "triallelic" inheritance. The frequency of detected mutations in MKKS in Group II patients was 24%, i.e., six times higher than the published rate for unselected BBS patients, suggesting that small-scale linkage analyses may be useful in suitable families.

Scanning for telomeric deletions and duplications and uniparental disomy using genetic markers in 120 children with malformations.

We screened 120 children with sporadic multiple congenital anomalies and either growth or mental retardation for uniparental disomy (UPD) or subtelomeric deletions. The screening used short tandem repeat polymorphisms (STRP) from the subtelomeric regions of 41 chromosome arms. Uninformative marker results were reanalyzed by using the next available marker on that chromosome arm. In total, approximately 25,000 genotypes were generated and analyzed for this study. Subtelomeric deletions of 1 Mb in size were excluded for 27 of 40 chromosome arms. Among the 120 subjects none was found to have UPD, but five subjects (4%, 95% confidence interval 1-9%) were found to have a deletion or duplication of one or more chromosome arms. We conclude that UPD is not a frequent cause of undiagnosed multiple congenital anomaly syndrome. In addition, we determined that 9p and 7q harbor chromosome length variations in the normal population. We conclude that subtelomeric marker analysis is effective for the detection of subtelomeric duplications and deletions, although it is labor intensive. Given a detection rate that is similar to prior studies and the large workload imposed by STRPs, we conclude that STRPs are an effective, but impractical, approach to the determination of segmental aneusomy given current technology.

Parental attitudes toward a diagnosis in children with unidentified multiple congenital anomaly syndromes.

One of the most common and unsatisfying situations encountered in medical genetics clinics is the child with multiple congenital anomalies (MCAs) suggestive of an underlying syndrome for whom it is not possible to make a definitive diagnosis. We undertook a qualitative, descriptive study to learn more about the ways in which the lack of a diagnosis affects parental coping and adjustment to their child's special needs. Semistructured interviews were conducted with 29 parents of 16 children born with an unidentified MCA syndrome. Interviews were based on a small number of open-ended questions, with follow-up probing, asking about parents' experiences with seeking a diagnosis, obtaining treatment and special services, explaining their child's problems to others, reproductive decision making, and support group participation. Transcripts of interviews were analyzed to identify the principal themes surrounding parents' beliefs about the significance of diagnostic information. The parents in this study had been aware of their child's anomalies for 2-23 years, and all had sought multiple evaluations to find a diagnosis. A majority of parents were still interested in identifying their child's syndrome, but most felt that their interest in a diagnosis had diminished over time, and some felt that there were benefits in not having this information. We identified six areas where parents claimed a diagnosis would have impact: labels, causes, prognosis, treatment, acceptance, and social support. Significant issues included obtaining special education services, anticipating the child's future and potential medical complications, life expectancy, recurrence risks, finding sources of social support, and ensuring that the child was receiving appropriate treatment. We conclude that the significance of diagnostic information is complex and varies for different parents. Providers should explore the underlying issues associated with a parental quest for a diagnosis in order to identify and address specific concerns. Published 2001 Wiley-Liss, Inc.