Uninformative Results Research Articles

Outcomes of retesting in patients with previously uninformative cancer genetics evaluations.

Advances in cancer genetics have increased germline pathogenic/likely pathogenic variant (PV/LPV) detection rates. More data is needed to inform which patients with previously uninformative results could benefit most from retesting, especially beyond breast/ovarian cancer populations. Here, we describe retesting outcomes and predictors of PV/LPVs in a cohort of patients unselected by cancer diagnosis. Retrospective chart reviews were conducted for patients at a cancer genetics clinic between 1998 and 2019 who underwent genetic testing (GT) on ≥ 2 dates with ≥ 1year between tests, with no PV/LPVs on first-line GT. Demographics, retesting indications, and GT details were reviewed to evaluate predictive factors of PV/LPV identification. 139 patients underwent retesting, of whom 24 (17.3%) had a PV/LPV, encompassing 15 genes. 14 PV/LPV carriers (58.3%) only returned for retesting after personal or familial history changes (typically new cancer diagnoses), while 10 (41.7%) retested due to updated GT availability. No specific GT method was most likely to identify PV/LPVs and no specific clinical factors were predictive of a PV/LPV. The identified PV/LPVs were consistent with patients' personal or family histories, but were discordant with the initial referral indication for GT. For 16 (66.7%) PV/LPV carriers, the genetic diagnosis changed clinical management. This study adds to the limited body of literature on retesting outcomes beyond first-line BRCA analysis alone and confirms the utility of multigene panel testing. Retesting certain affected individuals when updated GT is available could result in earlier PV/LPV identification, significantly impacting screening recommendations and potentially reducing cancer-related morbidity and mortality.

Development and validation in 500 female samples of a TP-PCR assay to identify AFF2 GCC expansions

Over 100 X-linked intellectual disability genes have been identified, with triplet repeat expansions at the FMR1 (FRAXA) and AFF2 (FRAXE) genes being the causative agent in two of them. The absence of FRAXE pathognomonic features hampers early recognition, delaying testing and molecular confirmation. Hence, our laboratory uses a multiplex PCR-based strategy to genotype both FRAXA and FRAXE. However, AFF2 expansions are missed giving rise to an uninformative result in around 20% of female samples. To rule out undetected expansions and confirm homozygosity Southern blot analysis is performed being labour- and resource-intensive. The aim of this study is to develop a timely and economic triplet-primed amplification (TP-PCR) screening strategy to size the AFF2 GCC repeat and accurately assess homozygosity as well as pinpoint multiplex-PCR false negatives in female samples. In order to achieve this, validation was performed in a cohort of 500 females with a previous uninformative FRAXE PCR result. Interestingly, the presence of a T > C SNP (rs868949662), contiguous to the GCC repetitive tract, allows triplet primer binding in two additional repeats, increasing the discrimination power of the TP-PCR assay in heterozygous and homozygous samples. Twelve alleles outside the normal range were recognized: eight intermediate and four premutated, which seems relevant considering the rarity of the AFF2 expansions. All genotypes are concordant with that obtained by Southern blotting, confirming this as a strict, reproducible and low-cost homozygosity screening strategy that enables the identification of small expanded alleles missed by the routine multiplex-PCR due to allele dropout. Overall, this assay is capable of spotting multiplex-PCR false negatives besides identifying alleles up to > 80 GCC repeats. Furthermore, the occurrence of intermediate repeat sizes with unexpected frequency, introduces new areas of clinical research in this cohort in understanding these less explored AFF2 repeat sizes and newly associated phenotypes.

Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families.

(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for BRCA1/2 were tested with a panel of 41 genes associated with BC risk. The frequency of pathogenic variants (PVs) was related to the clinical characteristics of BC. (3) Results: We detected a PV rate of 13.5% (excluding two cases each of BRCA1 and MUTYH). Among the 95 assessed cases, 17 PVs were identified in 16 ICs, as follows: BRCA1 (n = 2), CHEK2 (n = 3), ATM (n = 5), MUTYH (n = 2), TP53 (n = 2), BRIP1 (n = 1), CASP8 (n = 1), and MSH2 (n = 1). We also identified a novel loss-of-function variant in CASP8, a candidate gene for increased BC risk. There was no evidence that the clinical characteristics of BC might be related to a higher chance of identifying a PV. (4) Conclusions: In our cohort, which was enriched with families with a high number of BC cases, a high proportion of mutations in ATM and CHEK2 were identified. The clinical characteristics of BC associated with moderate-risk genes were different from those related to BRCA1/2 genes.

Hereditary cancer testing in an ethnically diverse U.S. population.

10579 Background: The clinical utility of hereditary cancer multigene testing is well-established. Most testing has been performed in the White European population, with a relative shortage of data in other ethnic groups. Evaluation of hereditary cancer variants within diverse ethnic populations is important to drive accurate variant interpretation. This study aims to review the outcomes of hereditary cancer testing in an ethnically diverse U.S. population. Methods: We conducted a retrospective analysis of 8,888 test results from a 31-gene hereditary cancer test using next-generation sequencing with copy number variant analysis. Results were separated into seven categories based on the ethnicity selected on the test requisition: African American (AA), Asian (A), Ashkenazi Jewish (AJ), Hispanic (H), White (W), Other (O), and Unknown (U). O was used for any handwritten ethnicity or if multiple ethnicities were selected and U if no ethnicity was chosen. We quantified the number of negative, positive (pathogenic or likely pathogenic (P/LP) variant) and variant of uncertain significant (VUS) results for each ethnic group. We tallied the gene and variant for each result with a positive, negative or VUS. We used a Fisher's Exact test and Bonferroni-adjusted p-values to account for multiple hypothesis testing. Results: Of the 8,888 orders reviewed, 45% were non-White ethnic groups. The P/LP variant rate was lower for AA (4%, p=2e-04) compared to W (9%). The VUS rate was higher for O, AA and A (48%, 56%, and 57%; p=0.0045, 3.1e-17 and 4.8e-06, respectively), compared to 38% in W. Lower negative rates were found in A and AA (37% and 40%; p=0.00024 and 9.4e-10, respectively), and trending lower in O (46%, p=0.0097), compared to 58% for W. The VUS rate for H is 41% (p value = 0.095). Conclusions: Our results suggest that non-Whites may be at a disadvantage when it comes to hereditary cancer multigene testing due to the higher rate of VUS results. The inverse correlation between the overall rates of VUS and negative results when comparing these populations suggests there may be limited variant information for the non-White population in medical literature and available databases. This underrepresentation may make it more difficult to accurately characterize a variant. Despite the small sample size, these findings are consistent with previous publications; however, gene specific outcomes could not be evaluated. This finding suggests that providers could give these patients uninformative results more often, which has potential to impact screening protocols for these families. More research is needed to understand the impact of variant classification across ethnicities to decrease health disparities.

Factors associated with test failure in pregnant women undergoing cell-free DNA-based testing for fetal trisomy.

To investigate the factors associated with cell-free DNA test failure, and the optimal subsequent management of these pregnancies. This was a retrospective study of 27,363 singleton pregnancies undergoing cell-free DNA testing. Women with cell-free DNA test failure were divided into a high-risk group and a low-risk group according to their indications. The subsequent management and pregnancy outcomes of these women were followed up. The rate of cell-free DNA test failure at the first sampling was 1.49%, and 78.4% of failures were due to a low fetal fraction. Of the 66 women who refused any subsequent management, an adverse pregnancy outcome was seen in 5 cases, all belonging to the high-risk group. Of the 13 low-risk women who chose second-trimester maternal serum screening, all obtained a low-risk maternal serum screening result and an unaffected pregnancy outcome. A redraw was chosen by 171 women, which yielded a result in 75.4% and their pregnancy outcomes were unaffected; 42 women had an uninformative result again and received an amniocentesis. As 158 women had an amniocentesis after the first sampling, this procedure was offered in 200 cases altogether. Abnormal genetic testing results were shown in six (3%, 6/200) cases, all in the high-risk group. High-risk pregnant women with cell-free DNA test failure are at increased risk of adverse pregnancy outcomes. A second sampling for cell-free DNA test or maternal serum screening might be suggested to low-risk women. Invasive prenatal diagnosis should be offered to the high-risk patients, especially those with a second cell-free DNA test failure.

Towards a General Methodology of Bridging Ideological Spaces

Bridging ideological spaces is an important, but relatively troubled branch of the scaling literature. The most common bridging procedure, joint-scaling, ignores structural differences between groups resulting in uninformative results. Alternatively, dimensional-mapping addresses this issue by using transformation rather than merging. However, current implementations cannot bridge multi-dimensional spaces nor estimate ideal points non-parametrically. Furthermore, these methods require shared individuals between the two groups. To address these major issues, we introduce a generalized methodology for dimensional-mapping that enables both non-parametric and multi-dimensional ideal point estimation using either real or ''synthetic anchors.'' Synthetic anchors remove the stringent anchor assumption and are generated by transferring a small number of individuals from one group to the other and, when used appropriately, do not distort the ideological space. We demonstrate the utility of our methodology on two sets of voter-politician data from the United States and Japan by comparing its performance with existing approaches. Our results suggest that not only does our method make less stringent assumptions and is more widely applicable than existing techniques, but our approach also generates bridged ideal point estimates comparable to those generated by other methods.

Advanced cancer patient preferences for receiving molecular profiling results.

This study aimed to discern preferences for receiving somatic molecular profiling (MP) results in cancer patients who have given consent to undergo testing. We conducted a mixed-methods study to explore patients' views on which MP results they would like to receive and why. Advanced cancer patients (n = 1299) completed questionnaires after giving consent to participate in a parent genomics study and undergoing MP. A subset of patients (n = 20) participated in qualitative interviews. Almost all (96%) participants were interested in receiving results which would direct cancer treatment (ie, were actionable). A smaller majority wanted to access results which were not actionable (64%) or were variants of unknown significance (60%). Most (86%) were interested in finding out about germline findings, though not as a priority. Themes identified in interview data were: (a) Cancer is the focus; (b) Trust in clinicians; and (c) Respect for a right not to know. The majority of advanced cancer patients undergoing MP prioritised results which would lead to treatment options. They trusted their oncologists to help them navigate the results return process. While there was interest in knowing about other results, this was a lesser priority. Nevertheless, given high levels of interest in receiving all results, ethical aspects of not providing uninformative results requires further research, including a consideration of patient rationales for desiring this information and what health professionals can and should do to support patients in the absence of meaningful information being available.

Detection of maternal X chromosome abnormalities using single nucleotide polymorphism–based noninvasive prenatal testing

Maternal X chromosome abnormalities may cause discordant results between noninvasive prenatal screening tests and diagnostic evaluation of the fetus/newborn, leading to unnecessary invasive testing. Women with X chromosome abnormalities are at increased risk for reproductive, pregnancy, or other health complications, which may be reduced or ameliorated by early diagnosis, monitoring, and intervention. This study aimed to validate a single nucleotide polymorphism-based noninvasive prenatal test to identify X chromosome abnormalities of maternal origin. All tests unable to evaluate fetal risk for aneuploidy because of uninformative algorithm results were eligible for inclusion. Two groups of cases were prospectively identified: Group A (n=106) where a maternal X chromosome abnormality was suspected and Group B (control group, n=107) where a fetal chromosome abnormality involving chromosome 13, 18, 21, or X was suspected but did not meet criteria for reporting. Maternal DNA was isolated from the plasma-depleted cellular pellet and sent to a reference laboratory for blinded analysis using chromosomal microarray. A chromosome abnormality involving chromosomes 13, 18, 21, or X was reported by the reference laboratory if ≥5 Mb in size and present in ≥20% of the DNA. A maternal X chromosome abnormality was suspected in 1/1305 tests (149/194,385; 0.08%). In Group A, a maternal X chromosome abnormality was confirmed in 100/106 cases (94.3% positive predictive value, 1-sided 97.5% confidence interval, 88.1%-100.0%). Turner syndrome was the most commonly suspected maternal abnormality (58/106, 54.7%), with confirmation of mosaic or nonmosaic 45,X by microarray in 38/58 (65.5%) cases. Noninvasive prenatal screening tests suspected the presence of maternal 47,XXX with or without mosaicism in 40/106 (37.7%) cases, confirmed by microarray in 38/40 (95.0%). In Group B (n=107), no maternal microarray abnormalities were reported, providing a negative predictive value of 100% (1-sided 97.5% confidence interval, 96.6%-100.0%). When noninvasive prenatal testing suspected a maternal X chromosome abnormality, maternal microarray confirmed an X chromosome abnormality with 94.3% positive predictive value. Of the maternal X chromosome abnormalities detected by array, >50% were 45,X. When fetal chromosome abnormalities involving chromosomes 13, 18, 21, or X were suspected, no maternal chromosome abnormalities were reported, yielding a negative predictive value of 100%. Women with maternal X abnormalities suspected with noninvasive prenatal testing may be at increased risk for reproductive and health complications; early evaluation and treatment may prevent long-term consequences or disability.

Exome and genome sequencing in adults with undiagnosed disease: a prospective cohort study

BackgroundExome and genome sequencing have been demonstrated to increase diagnostic yield in paediatric populations, improving treatment options and providing risk information for relatives. There are limited studies examining the clinical...

A comprehensive custom panel evaluation for routine hereditary cancer testing: improving the yield of germline mutation detection

BackgroundIn the context of our Regional Program of Hereditary Cancer, individuals fulfilling the criteria are tested for germline mutations to subsequently establish the clinical management. Our standard diagnostic approach focuses on sequencing a few classic high-risk genes, a method that frequently renders uninformative genetic results. This study aims to examine the improved yield offered by an On-Demand panel.MethodsWe designed an On-Demand panel for the analysis of 35-genes associated with inherited cancer susceptibility in a total of 128 cases of Hereditary Breast and Ovarian Cancer (HBOC) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC).ResultsEighteen deleterious mutations were detected, in both routinely (BRCA2, MLH1, MSH2, PMS2) and non-routinely (ATM, BLM, BRIP1, CHEK2, MUTYH) tested genes. The screening extended to 35 genes rendered by patients carrying several- up to 6-Variants of Unknown Significance (VUS). Moreover, we confirmed the splicing disruption at RNA level for a not previously reported BRIP1 splicing mutation. Using an On-Demand panel, we identified 18 pathogenic mutation carriers, seven of which would have gone unnoticed with traditional analysis.ConclusionsOur results reinforce the utility of NGS gene panels in the diagnostic routine to increase the performance of genetic testing, especially in individuals from families with overlapping cancer phenotypes.

Efficacy and safety of convalescent plasma for severe COVID-19 based on evidence in other severe respiratory viral infections: a systematic review and meta-analysis.

The safety and efficacy of convalescent plasma in severe coronavirus disease 2019 (COVID-19) remain uncertain. To support a guideline on COVID-19 management, we conducted a systematic review and meta-analysis of convalescent plasma in COVID-19 and other severe respiratory viral infections. In March 2020, we searched international and Chinese biomedical literature databases, clinical trial registries and prepublication sources for randomized controlled trials (RCTs) and nonrandomized studies comparing patients receiving and not receiving convalescent plasma. We included patients with acute coronavirus, influenza and Ebola virus infections. We conducted a meta-analysis using random-effects models and assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Of 1099 unique records, 6 studies were eligible, and none of these included patients with COVID-19. One nonrandomized study (n = 40) on convalescent plasma in severe acute respiratory syndrome coronavirus (SARS-CoV) provided uninformative results regarding mortality (relative risk [RR] 0.10, 95% confidence interval [CI] CI 0.01 to 1.70). Pooled estimates from 4 RCTs on influenza (n = 572) showed no convincing effects on deaths (4 RCTs, RR 0.94, 95% CI 0.49 to 1.81), complete recovery (2 RCTs, odds ratio 1.04, 95% CI 0.69 to 1.64) or length of stay (3 RCTs, mean difference -1.62, 95% CI -3.82 to 0.58, d). The quality of evidence was very low for all efficacy outcomes. Convalescent plasma caused few or no serious adverse events in influenza RCTs (RR 0.85, 95% CI 0.56 to 1.29, low-quality evidence). Studies of non-COVID-19 severe respiratory viral infections provide indirect, very low-quality evidence that raises the possibility that convalescent plasma has minimal or no benefit in the treatment of COVID-19 and low-quality evidence that it does not cause serious adverse events.

Parents’ perceptions of personal utility of exome sequencing results

PurposeClinical genome or exome sequencing (GS/ES) provides a diagnosis for many individuals with suspected genetic disorders, but also yields negative or uncertain results for the majority. This study examines how parents of a child with an undiagnosed condition attribute personal utility to all types of ES results. MethodsReturn of 31 exome sequencing results was observed during clinic sessions, followed by semistructured interviews with parents one month later. Observations and interviews were recorded and transcribed. Data display matrices were used for content analysis and systematic comparisons of parents’ perceptions of utility. ResultsES results could not provide all the answers to parents’ questions, especially in cases of clinically uninformative results, but parents nonetheless attributed utility to the knowledge gained. Parents across all results categories used the genomic information to rule out possible causes, end or postpone the diagnostic odyssey, and shift focus to treatment and management of symptoms. ConclusionThis study suggests that parents value even uninformative ES results while expressing hope for future discoveries. As pediatric genetics moves toward GS/ES as a first-tier test, how parents perceive the personal utility of negative or uncertain results is an important topic for genetic counseling and further research.

Низкая фетальная фракция внеклеточной ДНК при проведении неинвазивного пренатального ДНК-скрининга: возможные причины, клиническое значение и тактические решения

Study Objective: To compare the rates of fetal chromosomal abnormalities (CA) detected during initial non-invasive prenatal DNA testing (NIPT) with the rates of CA found through repeat NIPT in patients with low fetal fraction or low quality of cell-free embryonic DNA. Study Design: This was a retrospective cohort study. Materials and Methods: Twenty-one thousand forty-two women who underwent NIPT in Russia between 2013 and 2018 were included in the study. The main group comprised 1,025 of the 1,044 patients with uninformative results (low fetal fraction result, making it impossible to assess the risk of CA), who consented to repeat NIPT. The control group was made up of 19,998 women who had informative results of initial NIPT. The exclusion group comprised women with low fetal fraction who declined repeat screening. The study method was targeted NIPT. Blood samples were taken from a vein and centrifuged to obtain plasma. Fetal cell-free DNA was analyzed by next-generation sequencing (NGS), a method patented by Natera for sequencing single nucleotide polymorphisms. Study Results: Initial NIPT was uninformative in 1,044 (5%) of the patients and repeat procedure yielded informative results in 821 (80.1%) out of 1,025 patients. Among the patients with informative results from the initial study, the rate of chromosomal aneuploidies was 2.4%. In the group of women with informative results from the repeat procedure, fetal CA were detected in 27 (3.3%) cases. In the subgroup of women with informative results only after a third NIPT, the prevalence of CA was 9.3% (seven out of 75 cases). The study showed that in women carrying fetuses with trisomy 18 or 13 or monosomy X, mean fetal fraction in the first trimester was significantly lower than normal. In the second trimester, significantly lower than normal fetal fraction was observed in women carrying fetuses with trisomy 18 or monosomy X. There was a statistically significant difference in fetal fraction levels between patients with body weight <50 kg and those with body weight 80-89 kg or above (р<0.05). Conclusion: The probability of detecting CA by repeat NIPT is significantly higher than in an initial procedure. If initial testing is not informative, it should be repeated. If the second procedure also fails to yield informative results, invasive prenatal diagnosis should be considered. Fetal fraction levels are lower in heavier women. Thus, other methods of prenatal diagnosis should be recommended for overweight and obese women. Keywords: non-invasive prenatal DNA testing, fetal fraction, prenatal diagnosis, Down syndrome.

Combining the use of a fetal fraction-based risk algorithm and probability of an informative redraw in noninvasive prenatal testing for fetal aneuploidy.

Some women undergoing noninvasive prenatal testing (NIPT) do not receive an informative result due to low fetal fraction (FF). A proportion of these are at increased risk for fetal trisomy 13, 18, or triploidy, while others have no change from their prior risk. Women with an initial uninformative NIPT need to be counseled about any such change in their risk for fetal abnormality and also the probability that a redraw will be informative. To help in the decision making, we reviewed a dataset of single nucleotide polymorphism‐based NIPT with uninformative results where a redraw was received. Risk for trisomy 13, 18, or triploidy was evaluated using a fetal fraction‐based risk (FFBR) algorithm. Risk‐unchanged women were further analyzed using a regression model to determine the likelihood of an informative redraw. Of 2,644 women with an uninformative NIPT and a redraw, 1,147 (43.4%) were high risk for trisomy 13, 18, or triploidy. 1,497 (56.6%) were risk unchanged and, of these, 975 (65.1%) cases had an informative redraw (i.e., risks were available for 2,122 (80%) of those initially classified as uninformative). The regression model for the risk‐unchanged cases provided a new table for predicting an informative redraw. Likelihood of a successful redraw was significantly (p < .001) dependent on the initial FF, maternal weight, and time between blood draws. We conclude that the FFBR algorithm and the predictive model for an informative redraw provide complementary additions in the management of women presented with an initially uninformative SNP‐based NIPT due to low FF. We suggest approaches for the counseling and follow‐up testing for women with an initially uninformative NIPT.

Discussion on: Breast cancer risk assessment in patients who test negative for a hereditary cancer syndrome

DR. STEPHANIE VALENTE (Cleveland, Ohio): As we heard, the authors evaluated 88 patients with a strong family history of breast cancer who underwent genetic testing and were negative. They used the term “uninformed result” because physicians don’t know how to properly counsel or subsequently screen a patient with a strong family history and subsequent negative genetic results. The results of the study showed that there is a patient population at significant risk for developing breast cancer and that the uninformative result patient should be further explored to identify proper individualized high risk screening plan. Following the patients in this study long term to determine concordance between risk calculation and further development of breast cancer will be important. Breast cancer risk assessment in patients who test negative for a hereditary cancer syndromeThe American Journal of SurgeryVol. 219Issue 3PreviewThe majority of women who undergo genetic testing due to a significant family history of breast cancer will receive a negative result. Using three widely used risk assessment models, we calculated lifetime breast cancer risks of women who had undergone genetic testing and received a negative result. We found that over half of the women included in the study were considered to be high-risk for the development of breast cancer. Full-Text PDF

Breast cancer risk assessment in patients who test negative for a hereditary cancer syndrome

BackgroundThe majority of women who undergo genetic testing due to a significant family history of breast cancer will receive a negative result. The purpose of this study was to calculate the lifetime risk of breast cancer in women undergoing genetic counseling who received an uninformative genetic test result. MethodsA retrospective chart review of mutation-negative women presenting to a cancer risk assessment clinic was performed. Lifetime risks of breast cancer were calculated using the Claus, Gail, and Tyrer-Cuzick risk assessment models. ResultsApproximately half (51%) of the women were classified as high-risk by at least one risk assessment model. The Tyrer-Cuzick model identified the highest proportion (43.2%) of patients as high-risk. Four percent (n = 4) of the sample was considered high-risk by all three models. ConclusionsMore than half (51%) of women who underwent genetic counseling and received an uninformative negative genetic test result had a significantly elevated risk for the development of breast cancer. It is, therefore, imperative that women do not conclude that a negative genetic test result represents a lack of risk.

Result of Prospective Validation of the Trisomy Test® for the Detection of Chromosomal Trisomies.

Noninvasive prenatal testing (NIPT) is one of the most common prenatal screening tests used worldwide. Trisomy Test® belongs to NIPT tests based on low-coverage whole-genome sequencing. In our prospective study, 7279 samples of pregnant women collected during approximately two years were analyzed. In this cohort, 117 positive cases for trisomies 21, 18, and 13 were reported. An in-house designed bioinformatic pipeline and proprietary biostatistical approach was used for the detection of trisomies. The pooled sensitivity and specificity of our test reached 99.12% and 99.94%, respectively. The proportion of repeatedly uninformative results after repeated blood draws was 1.11%. Based on the presented results, we can confirm that the Trisomy Test® is fully comparable with other commercial NIPT tests available worldwide.

Health outcomes, utility and costs of returning incidental results from genomic sequencing in a Canadian cancer population: protocol for a mixed-methods randomised controlled trial

IntroductionGenomic sequencing has rapidly transitioned into clinical practice, improving diagnosis and treatment options for patients with hereditary disorders. However, large-scale implementation of genomic sequencing faces challenges, especially with regard to...

Hypertrophic cardiomyopathy genetic test reports: A qualitative study of patient understanding of uninformative genetic test results

Studies have shown that patients with hypertrophic cardiomyopathy (HCM) may misinterpret the meaning of uninformative genetic testing results to mean that a genetic etiology and family members' risk is ruled out. We hypothesized that poor comprehension of the laboratory genetic test report may contribute to this misunderstanding. We conducted a qualitative study to examine patient understanding of uninformative laboratory results and reports and elicit suggestions for an improved report. Fifteen participants with HCM were interviewed after undergoing genetic testing and receiving their report. While all patients read the report, most participants reported only partially reading it. Most reported not understanding the report at all or only partially understanding it because a provider explained it to them. Some participants said that the report was helpful for understanding their result, but there was evidence of misunderstanding; most participants stated that specific aspects of the report were unhelpful. While most of our participants communicated risk with relatives, none said that the report helped with the communication. Most participants did not recall or find the accompanying physician-directed result letter useful for their understanding or familial communication. Many participants expressed need for a supplemental report that illustrates a personalized clinical 'action plan' that could summarize clinical and familial implications of the result for the patient and their family. We conclude that laboratory reports and physician-directed result letters did not help participants understand their results or their familial implications. Our results suggest opportunities for research to explore the utility of a patient-directed result supplement to improve patient comprehension of genetic test results and outline clinical recommendations via a patient action plan.

Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study

Identification of chromosomal aneuploidies and copy number variants that are associated with fetal structural anomalies has substantial value. Although whole-exome sequencing (WES) has been applied to case series of a few selected prenatal cases, its value in routine clinical settings has not been prospectively assessed in a large unselected cohort of fetuses with structural anomalies. We therefore aimed to determine the incremental diagnostic yield (ie, the added value) of WES following uninformative results of standard investigations with karyotype testing and chromosomal microarray in an unselected cohort of sequential pregnancies showing fetal structural anomalies. In this prospective cohort study, the parents of fetuses who were found to have a structural anomaly in a prenatal ultrasound were screened for possible participation in the study. These participants were predominantly identified in or were referred to the Columbia University Carmen and John Thain Center for Prenatal Pediatrics (New York, NY, USA). Fetuses with confirmed aneuploidy or a causal pathogenic copy number variant were excluded from WES analyses. By use of WES of the fetuses and parents (parent-fetus trios), we identified genetic variants that indicated an underlying cause (diagnostic genetic variants) and genetic variants that met the criteria of bioinformatic signatures that had previously been described to be significantly enriched among diagnostic genetic variants. Between April 24, 2015, and April 19, 2017, 517 sequentially identified pregnant women found to have fetuses with a structural anomaly were screened for their eligibility for inclusion in our study. 71 (14%) couples declined testing, 87 (17%) trios were missing at least one DNA sample (from either parent or the fetus), 69 (13%) trios had a clinically relevant abnormal karyotype or chromosomal microarray finding, 51 (10%) couples did not consent to WES or withdrew consent, and five (1%) samples were not of good enough quality for analysis. DNA samples from 234 (45%) eligible trios were therefore used for analysis of the primary outcome. By use of trio sequence data, we identified diagnostic genetic variants in 24 (10%) families. Mutations with bioinformatic signatures that were indicative of pathogenicity but with insufficient evidence to be considered diagnostic were also evaluated; 46 (20%) of the 234 fetuses assessed were found to have such signatures. Our analysis of WES data in a prospective cohort of unselected fetuses with structural anomalies shows the value added by WES following the use of routine genetic tests. Our findings suggest that, in cases of fetal anomalies in which assessment with karyotype testing and chromosomal microarray fail to determine the underlying cause of a structural anomaly, WES can add clinically relevant information that could assist current management of a pregnancy. The unique challenges of WES-based prenatal diagnostics require analysis by a multidisciplinary team of perinatal practitioners and laboratory specialists. Institute for Genomic Medicine (Columbia University Irving Medical Center).