Retrospective comparison of parent-reported genetics knowledge, empowerment, and familial uptake of cardiac screening between parents who received genetic counseling by a certified genetic counselor and those who did not: A single US academic medical center study.

Bicuspid aortic valve (BAV) is the most common congenital heart defect, which can cause severe cardiac complications. BAVs cluster in families and demonstrate high heritability. Cardiac screening for first-degree relatives of individuals with a BAV is recommended. This retrospective two-group study evaluated the impact of cardiovascular genetic counseling provided by a board-certified genetic counselor on parent-reported outcomes by comparing parental responses of those who received genetic counseling by a genetic counselor (GC group) for family history of BAV to those who did not (non-GC group). A retrospective chart review from May 2016 to June 2019 identified 133 pediatric patients with an isolated BAV. Parents of eligible probands were invited to complete an online survey assessing genetics knowledge, empowerment (Genomics Outcome Scale), and familial uptake of cardiac screening. Surveys were completed by 38/97 (39%) parents in the non-GC group and 20/36 (56%) parents in the GC group. The median genetics knowledge score was not significantly different between the two groups (GC group: 8, range 3-11 out of a maximum possible of 12; non-GC group: 7, range 2-11; p = .08). The mean empowerment score was not significantly different between the two groups (GC group: mean 24.6, SD 2.2; non-GC group: mean 23.2, SD 3.5; p = .06). The uptake of cardiac screening was significantly higher in the GC group with 39/59 (66%) total first-degree relatives reported as having been screened compared with 36/91 (40%) in the non-GC group (p = .002). Parent-reported outcomes in our study suggest that receiving genetic counseling by a board-certified genetic counselor significantly increased familial uptake of cardiac screening for first-degree relatives of pediatric patients with a BAV. Studies with larger sample sizes are needed to confirm the findings of this study; however, a referral to a genetic counselor should be considered for patients with a BAV.

Genetic counseling for congenital heart disease - Practice resource of the National Society of Genetic Counselors.

Congenital heart disease (CHD) is an indication which spans multiple specialties across various genetic counseling practices. This practice resource aims to provide guidance on key considerations when approaching counseling for this particular indication while recognizing the rapidly changing landscape of knowledge within this domain. This resource was developed with consensus from a diverse group of certified genetic counselors utilizing literature relevant for CHD genetic counseling practice and is aimed at supporting genetic counselors who encounter this indication in their practice both pre- and postnatally.

Impact of Genetic Testing for Cardiomyopathy on Emotional Well-Being and Family Dynamics: A Study of Parents and Adolescents.

BACKGROUND: Genetic testing is indicated for children with a personal or family history of hereditary cardiomyopathy to determine appropriate management and inform risk stratification for family members. The implications of a positive genetic result for children can potentially impact emotional well-being. Given the nuances of cardiomyopathy genetic testing for minors, this study aimed to understand how parents involve their children in the testing process and investigate the impact of genetic results on family dynamics. METHODS: A survey was distributed to participants recruited from the Children's Cardiomyopathy Foundation and 7 North American sites in the Pediatric Cardiomyopathy Registry. The survey explored adolescent and parent participants' emotions upon receiving their/their child's genetic results, parent-child result communication and its impact on family functionality, using the McMaster Family Assessment Device. RESULTS: One hundred sixty-two parents of minors and 48 adolescents who were offered genetic testing for a personal or family history of cardiomyopathy completed the survey. Parents whose child had cardiomyopathy were more likely to disclose positive diagnostic genetic results to their child (P=0.014). Parents with unaffected children and positive predictive testing results were more likely to experience negative emotions about the result (P≤0.001) but also had better family functioning scores than those with negative predictive results (P=0.019). Most adolescents preferred results communicated directly to the child, but parents were divided about whether their child's result should first be released to them or their child. CONCLUSIONS: These findings have important considerations for how providers structure genetic services for adolescents and facilitate discussion between parents and their children about results.

A Comprehensive Clinical Genetics Approach to Critical Congenital Heart Disease in Infancy.

OBJECTIVE: To investigate the frequency of genetic diagnoses among infants with critical congenital heart disease (CHD) using a comprehensive cardiovascular genetics approach and to identify genotype-phenotype correlations. STUDY DESIGN: A retrospective chart review of patients evaluated by cardiovascular genetics in a pediatric cardiac intensive care unit from 2010 to 2015 was performed. Infants with CHD who were <1 month of age were included. CHD was classified using structured phenotype definitions. Cardiac and noncardiac phenotypes were tested for associations with abnormal genetic testing using χ1 and Fisher exact tests. RESULTS: Genetic evaluation was completed in 293 infants with CHD, of whom 213 had isolated congenital heart disease (iCHD) and 80 had multiple congenital anomalies. Overall, the yield of abnormal genetic testing was 26%. The multiple congenital anomalies cohort had a greater yield of genetic testing (39%) than the iCHD cohort (20%) (OR 2.7). Using a non-hierarchical CHD classification and excluding 22q11.2 deletion and common aneuploidies, right ventricular obstructive defects were associated with abnormal genetic testing (P = .0005). Extracardiac features associated with abnormal genetic testing included ear, nose, and throat (P = .003) and brain (P = .0001) abnormalities. A diagnosis of small for gestational age or intrauterine growth retardation also was associated with abnormal genetic testing (P = .0061), as was presence of dysmorphic features (P = .0033, OR 3.5). Infants without dysmorphia with iCHD or multiple congenital anomalies had similar frequencies of abnormal genetic testing. CONCLUSIONS: The present study provides evidence to support a comprehensive cardiovascular genetics approach in evaluating infants with critical CHD while also identifying important genotype-phenotype considerations.

Comparison of Evolution of Aortic Root Dilation and Ghent Criteria in Preadolescents and Adolescents with and without Marfan Syndrome.

OBJECTIVE: To determine whether the Ghent Criteria (2010) can be reliably used in evaluating preadolescents and adolescents for Marfan syndrome by comparing aortic growth, systemic scores, and anthropometric features in individuals with and without Marfan syndrome. STUDY DESIGN: A retrospective chart review was completed for patients less than 15 years of age referred for Marfan syndrome. Comparisons were made between the first and last visit. Paired t tests were used to compare Ghent systemic scores. Wilcoxon rank-sum test were used to compare age, aortic root z scores, height z scores, and body mass index z scores. Recursive partitioning was used to identify combinations of factors to distinguish Marfan syndrome. RESULTS: In total, 53 individuals met inclusion criteria (29 Marfan syndrome and 24 non-Marfan syndrome). Ghent systemic score increased in the Marfan syndrome group and declined in the non-Marfan syndrome. The non-Marfan syndrome group did not develop progressive aortic root dilation with age. Individuals with Marfan syndrome had higher median height z scores than non-Marfan syndrome, with no difference in median body mass index z score between groups. A combination of aortic root z score above 0.95 and Ghent systemic score above 3 was highly indicative of a Marfan syndrome diagnosis in children less than 15 years of age. CONCLUSION: The Ghent criteria (2010) can be used to reliably exclude a diagnosis of Marfan syndrome in individuals less than 15 years of age. Genetic testing should be used as an aide in confirming or excluding the diagnosis of Marfan syndrome in individuals with an aortic root z score above 0.95 in combination with a Ghent systemic score above 3 at initial visit.

Cantu syndrome: A longitudinal review of vascular findings in three individuals.

Cantu syndrome is a rare autosomal dominant disorder caused by missense variants in ABCC9 and KCNJ8. It is characterized by hypertrichosis, neonatal macrosomia, coarse facial features, and skeletal anomalies. Reported cardiovascular anomalies include cardiomegaly, structural defects, collateral vessels, and rare report of arteriovenous malformation (AVM). Arterial dilation is reported in a few individuals including one with surgical intervention for a thoracic aortic aneurysm. The natural history of this aortopathy including the rate of progression or risk for dissection is unknown and longitudinal patient data is unavailable. We present data from vascular imaging in three individuals with genetically confirmed Cantu syndrome over 3 to 14 years of follow-up. All patients had generally stable aortic dilation, which did not reach the surgical threshold, including one individual followed closely through pregnancy. In adulthood, one individual had a maximum ascending aortic measurement of 4.2 cm. Two pediatric patients had aortic root or ascending z-scores of approximately +3. A large asymptomatic pelvic AVM was identified in one individual on head-pelvis MRI. While the data reported in these individuals is reassuring regarding the risk for progressive disease, further data from additional individuals with Cantu syndrome is needed to best inform screening recommendations, improve understanding of dissection risk, and guide management.

Highly Sensitive Blocker Displacement Amplification and Droplet Digital PCR Reveal Low-Level Parental FOXF1 Somatic Mosaicism in Families with Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins.

Detection of low-level somatic mosaicism [alternate allele fraction (AAF) ≤ 10%] in parents of affected individuals with the apparent de novo pathogenic variants enables more accurate estimate of recurrence risk. To date, only a few systematic analyses of low-level parental somatic mosaicism have been performed. Herein, highly sensitive blocker displacement amplification, droplet digital PCR, quantitative PCR, long-range PCR, and array comparative genomic hybridization were applied in families with alveolar capillary dysplasia with misalignment of pulmonary veins. We screened 18 unrelated families with the FOXF1 variant previously determined to be apparent de novo (n = 14), of unknown parental origin (n = 1), or inherited from a parent suspected to be somatic and/or germline mosaic (n = 3). We identified four (22%) families with FOXF1 parental somatic mosaic single-nucleotide variants (n = 3) and copy number variant deletion (n = 1) detected in parental blood samples and an AAF ranging between 0.03% and 19%. In one family, mosaic allele ratio in tissues originating from three germ layers ranged between <0.03% and 0.65%. Because the ratio of parental somatic mosaicism have significant implications for the recurrence risk, this study further implies the importance of a systematic screening of parental samples for low-level and very-low-level (AAF ≤ 1%) somatic mosaicism using methods that are more sensitive than those routinely applied in diagnostics.

Investigation of de novo variation in pediatric cardiomyopathy.

Pediatric cardiomyopathies can be caused by variants in genes encoding the sarcomere and cytoskeleton in cardiomyocytes. Variants are typically inherited in an autosomal dominant manner with variable expressivity. De novo variants have been reported, however their overall frequency is largely unknown. We sought to determine the rate of de novo, pathogenic and likely pathogenic (P/LP) variants in children with a diagnosis of hypertrophic, dilated, or restrictive cardiomyopathy (HCM, DCM, or RCM), and to compare disease outcomes between individuals with and without a de novo variant. A retrospective record review identified 126 individuals with HCM (55%), DCM (37%), or RCM (8%) ≤18 years of age who had genetic testing. Overall, 50 (40%) had positive genetic testing and 18% of P/LP variants occurred de novo. The rate of de novo variation in those with RCM (80%) was higher than in those with HCM (9%) or DCM (20%). There was evidence of germline mosaicism in one family with RCM. Individuals with de novo variants were more likely than those without to have a history of arrhythmia (p = .049), sudden cardiac arrest (p = .024), hospitalization (p = .041), and cardiac transplantation (p = .030). The likelihood of de novo variation and impact on family risk and screening should be integrated into genetic counseling.

Left ventricular outflow tract obstruction: Uptake of familial cardiac screening and parental knowledge from a single tertiary care center.

Left ventricular outflow tract obstruction (LVOTO) malformations exhibit higher heritability than other cardiac lesions and cardiac screening is encouraged for first-degree relatives. This study sought to determine the uptake of familial cardiac screening in families with an infant with an LVOTO and assess parental knowledge regarding genetics and heritability of LVOTO. A chart review of the period 2010-2015 identified 69 families who received genetic counseling regarding a diagnosis of LVOTO in an infant. Surveys assessing familial cardiac screening and parental knowledge were completed by a parent in 24 families (completion rate of 35%). Forty percent (36/89) of all at-risk first-degree family members completed cardiac screening. The presence of additional congenital malformations in the affected infant was the only significant factor reducing the uptake of familial cardiac screening (p = 0.003). The reported uptake of screening for subsequent at-risk pregnancies was 11/12 (92%) compared to 25/77 (32%) of living at-risk relatives. Survey respondents answered seven knowledge questions with an average score of 5.2 and all correctly identified that LVOTO can run in families. Uptake of familial cardiac screening is occurring in less than half of at-risk individuals, despite parents demonstrating basic knowledge and receiving genetic counseling. Follow-up counseling in the outpatient setting to review familial screening recommendations should be considered to increase uptake and optimize outcomes.

Prevalence of Noonan spectrum disorders in a pediatric population with valvar pulmonary stenosis.

OBJECTIVE: To evaluate the prevalence of Noonan spectrum disorders (NSD) in a pediatric population with valvar pulmonary stenosis (vPS) and identify the clinical characteristics that differentiate those with NSD from those without NSD. DESIGN: A retrospective chart review of 204 patients diagnosed with vPS between 9/1/2012 and 12/1/2016 at a pediatric medical center was performed. The quantitative features of vPS, genetic diagnosis information, and phenotypic characteristics of Noonan syndrome were collected. Chi-square test, Fisher's exact test, t test, Wilcoxon rank-sum test, and ANOVA were used for comparisons among the groups. Logistic regression was used to test for the association between the clinical characteristics and the presence of NSD. RESULTS: Syndromic diagnoses were made in 10% of the children with vPS, with NSD accounting for 6%. Hypertrophic cardiomyopathy (P < .0001), short stature (P < .0001), developmental delay (P < .0001), ophthalmological abnormalities (P < .0001), pectus carinatum/excavatum (P = .01), neurological abnormalities (P = .022), and aortic stenosis (P = .031) were present more often in individuals with NSD compared to nonsyndromic vPS. A logistic regression analysis showed a 4.8-fold increase in odds for NSD for each additional characteristic (P < .0001). CONCLUSIONS: At least 6% of the children with vPS have an underlying NSD. Individuals with vPS and NSD were significantly more likely to have additional features known to be associated with NSD than those with vPS without NSD. We conclude that vPS in the presence of one or more significant characteristics should prompt referral for genetic evaluation as a guide to ascertain patients at risk for NSD while optimizing the use of clinical genetics evaluation and potential genetic testing.

Hypertrophic Cardiomyopathy Genotype Prediction Models in a Pediatric Population.

The Toronto Hypertrophic Cardiomyopathy (HCM) Genotype Score and Mayo HCM Genotype Predictor are risk assessment models developed to estimate a patient's likelihood of testing positive for a pathogenic variant causative of HCM. These models were developed from adult populations with HCM based on factors that have been associated with a positive genotype and have not been validated in external populations. The purpose of this study was to evaluate the overall predictive abilities of these models in a clinical pediatric HCM setting. A retrospective medical record review of 77 pediatric patients with gene panel testing for HCM between September 2005 and June 2015 was performed. Clinical and echocardiographic variables used in the developed models were collected and used to calculate scores for each patient. To evaluate model performance, the ability to discriminate between a carrier and non-carrier was assessed by area under the ROC curve (AUC) and overall calibration was evaluated by the Hosmer-Lemeshow goodness-of-fit statistic. Discrimination assessed by AUC was 0.72 (P < 0.001) for the Toronto model and 0.67 (P = 0.004) for the Mayo model. The Toronto model and the Mayo model showed P values of 0.36 and 0.82, respectively, for model calibration. Our findings suggest that these models are useful in predicting a positive genetic test result in a pediatric HCM setting. They may be used to aid healthcare providers in communicating risk and enhance patient decision-making regarding pursuit of genetic testing.

Genetic Testing in Pediatric Left Ventricular Noncompaction.

BACKGROUND: Left ventricular noncompaction (LVNC) can occur in isolation or can co-occur with a cardiomyopathy phenotype or cardiovascular malformation. The yield of cardiomyopathy gene panel testing in infants, children, and adolescents with a diagnosis of LVNC is unknown. By characterizing a pediatric population with LVNC, we sought to determine the yield of cardiomyopathy gene panel testing, distinguish the yield of testing for LVNC with or without co-occurring cardiac findings, and define additional factors influencing genetic testing yield. METHODS AND RESULTS: One hundred twenty-eight individuals diagnosed with LVNC at ≤21 years of age were identified, including 59% with idiopathic pathogenesis, 32% with familial disease, and 9% with a syndromic or metabolic diagnosis. Overall, 75 individuals had either cardiomyopathy gene panel (n=65) or known variant testing (n=10). The yield of cardiomyopathy gene panel testing was 9%. The severity of LVNC by imaging criteria was not associated with positive genetic testing, co-occurring cardiac features, pathogenesis, family history, or myocardial dysfunction. Individuals with isolated LVNC were significantly less likely to have a positive genetic testing result compared with those with LVNC and co-occurring cardiomyopathy (0% versus 12%, respectively; P<0.01). CONCLUSIONS: Genetic testing should be considered in individuals with cardiomyopathy co-occurring with LVNC. These data do not suggest an indication for cardiomyopathy gene panel testing in individuals with isolated LVNC in the absence of a family history of cardiomyopathy.

High burden of genetic conditions diagnosed in a cardiac neurodevelopmental clinic.

BACKGROUND: There is a known high prevalence of genetic and clinical syndrome diagnoses in the paediatric cardiac population. These disorders often have multisystem effects, which may have an important impact on neurodevelopmental outcomes. Taken together, these facts suggest that patients and families may benefit from consultation by genetic specialists in a cardiac neurodevelopmental clinic. OBJECTIVE: This study assessed the burden of genetic disorders and utility of genetics evaluation in a cardiac neurodevelopmental clinic. METHODS: A retrospective chart review was conducted of patients evaluated in a cardiac neurodevelopmental clinic from 6 December, 2011 to 16 April, 2013. All patients were seen by a cardiovascular geneticist with genetic counselling support. RESULTS: A total of 214 patients were included in this study; 64 of these patients had a pre-existing genetic or syndromic diagnosis. Following genetics evaluation, an additional 19 were given a new clinical or laboratory-confirmed genetic diagnosis including environmental such as teratogenic exposures, malformation associations, chromosomal disorders, and single-gene disorders. Genetic testing was recommended for 112 patients; radiological imaging to screen for congenital anomalies for 17 patients; subspecialist medical referrals for 73 patients; and non-genetic clinical laboratory testing for 14 patients. Syndrome-specific guidelines were available and followed for 25 patients with known diagnosis. American Academy of Pediatrics Red Book asplenia guideline recommendations were given for five heterotaxy patients, and family-based cardiac screening was recommended for 23 families affected by left ventricular outflow tract obstruction. CONCLUSION: Genetics involvement in a cardiac neurodevelopmental clinic is helpful in identifying new unifying diagnoses and providing syndrome-specific care, which may impact the patient's overall health status and neurodevelopmental outcome.

Aortopathy in the 7q11.23 microduplication syndrome.

The 7q11.23 microduplication syndrome, caused by the reciprocal duplication of the Williams-Beuren syndrome deletion region, is a genomic disorder with an emerging clinical phenotype. Dysmorphic features, congenital anomalies, hypotonia, developmental delay highlighted by variable speech delay, and autistic features are characteristic findings. Congenital heart defects, most commonly patent ductus arteriosus, have been reported in a minority of cases. Included in the duplicated region is elastin (ELN), implicated as the cause of supravalvar aortic stenosis in patients with Williams-Beuren syndrome. Here we present a series of eight pediatric patients and one adult with 7q11.23 microduplication syndrome, all of whom had aortic dilation, the opposite vascular phenotype of the typical supravalvar aortic stenosis found in Williams-Beuren syndrome. The ascending aorta was most commonly involved, while dilation was less frequently identified at the aortic root and sinotubular junction. The findings in these patients support a recommendation for cardiovascular surveillance in patients with 7q11.23 microduplication syndrome.

The Role of the Geneticist and Genetic Counselor in an ACHD Clinic.

There is a growing population of adults with congenital heart disease due to the advancements in surgical repair and medical management. At the same time, the understanding of the genetic basis of both syndromic and isolated congenital heart disease has grown tremendously and is being rapidly translated into changes in clinical care, resulting in an increasing need for incorporation of genetic expertise into the care of adult congenital heart disease patients. Here we review the importance of delivery of genetic information to the adult congenital heart disease population and highlight the shared and distinct roles of clinical geneticists and genetic counselors in provision of services. The adult congenital heart disease patient population has unique needs and clinical geneticists and genetic counselors can play an important role in the diagnostic evaluation and assessment of these patients to provide an accurate etiologic diagnosis and to counsel regarding genetic testing, recurrence risk, family screening, and prenatal diagnosis.

Media coverage of direct-to-consumer genetic testing.

Media coverage of Direct-to-Consumer (DTC) genetic testing shapes public perception of such testing. The purpose of this study was to determine and assess the themes presented by U.S. news media regarding DTC genetic testing. We performed a Lexis-Nexis search with the keywords "Direct-to-Consumer" and "genetic test" for news stories published from 2006-2009. The sample was coded on themes of genetic determinism, privacy, discrimination, validity, regulation, the Genetic Information Nondiscrimination Act (GINA), utility, and cost. Ninety-two news stories were included. Stories displayed moderate genetic determinism and were neutral about validity and utility. Stories indicated that insurance and employers were the most likely sources of discrimination, yet identified the physicians and DTC companies as groups most likely to violate privacy. Stories claimed lack of regulation would harm consumers, but most post-GINA stories did not discuss the law. The costs of tests were frequently included. The results of this study show a broad range of views toward DTC genetic testing and its potential impacts. The genetics community should be aware that the public has been exposed to multiple views of DTC genetic testing when discussing these tests.