Genetic counselors' utilization of ChatGPT in professional practice: A cross-sectional study.

PURPOSE: The precision medicine era has seen increased utilization of artificial intelligence (AI) in the field of genetics. We sought to explore the ways that genetic counselors (GCs) currently use the publicly accessible AI tool Chat Generative Pre-trained Transformer (ChatGPT) in their work. METHODS: GCs in North America were surveyed about how ChatGPT is used in different aspects of their work. Descriptive statistics were reported through frequencies and means. RESULTS: Of 118 GCs who completed the survey, 33.8% (40) reported using ChatGPT in their work; 47.5% (19) use it in clinical practice, 35% (14) use it in education, and 32.5% (13) use it in research. Most GCs (62.7%; 74) felt that it saves time on administrative tasks but the majority (82.2%; 97) felt that a paramount challenge was the risk of obtaining incorrect information. The majority of GCs not using ChatGPT (58.9%; 46) felt it was not necessary for their work. CONCLUSION: A considerable number of GCs in the field are using ChatGPT in different ways, but it is primarily helpful with tasks that involve writing. It has potential to streamline workflow issues encountered in clinical genetics, but practitioners need to be informed and uniformly trained about its limitations.

Exploring the evolving roles of clinical geneticists and genetic counselors in the era of genomic medicine.

The increased utilization of clinical genomic sequencing in the past decade has ushered in the era of genomic medicine, requiring genetics providers to acquire new skills and adapt their practices. The change in workplace responsibilities of clinical/medical geneticists (CMGs) and genetic counselors (GCs) in North America, due to the evolution of genetic testing, has not been studied. We surveyed CMGs (n = 80) and GCs (n = 127) with experience in general/pediatric genetics to describe their current practice of clinical tasks and the change in regularity of performing these tasks over the past 5-10 years. Currently, complementarity of responsibilities between CMGs and GCs clearly exists but providers who have been in the field for longer have noted role changes. Trends indicate that fewer experienced CMGs perform physical exams and select genetic tests than before and fewer experienced GCs complete requisitions and write result letters. The frequency of CMGs and GCs who investigate genetic test results, however, has increased. This study provides insight into the changing landscape of clinical genetics practice. Our findings suggest that the roles and responsibilities of CMGs and GCs have shifted in the past decade.

Assessing management practices for variants of uncertain significance among genetic counselors in pediatrics.

Increased utilization of genomic sequencing in pediatric medicine has increased the detection of variants of uncertain significance (VUS). Periodic VUS reinterpretation can clarify clinical significance and increase diagnostic yield, highlighting the importance of systematic VUS tracking and reinterpretation. There are currently no standardized guidelines or established best practices for VUS management, and our understanding of how genetic counselors (GCs) track and manage VUS results for pediatric patients is limited. In this exploratory study, GCs in pediatric clinics in North America were surveyed about their VUS management practices. A total of 124 responses were included in the analysis. The majority (n = 115, 92.7%) of GCs reported that VUS management workflows were at the discretion of each individual provider in their workplace. Approximately half (n = 65, 52%) kept track of patient VUS results over time, and GCs with lower patient volumes were more likely to do so (p = 0.04). While 95% (n = 114) of GCs had requested VUS reinterpretation at least once, only 5% (n = 6) requested it routinely. Most (n = 80, 86%) GCs notified patients when a VUS was reclassified, although methods of recontact differed when the reclassification was an upgrade versus a downgrade. GCs who asked patients to stay in touch through periodic recontact or follow-up appointments were more likely to request VUS reinterpretation (p = 0.01). The most frequently reported barriers to requesting reinterpretation regularly were patients being lost to follow-up (n = 39, 33.1%), insufficient bandwidth (n = 27, 22.9%), and lack of standardized guidelines (n = 25, 21.2%). GCs had consistent overall practices around VUS management around investigation, disclosure, reinterpretation, and recontact, but specific methods used differed and were at the discretion of each provider. These results showcase the current landscape of VUS management workflows in pediatrics and the challenges associated with adopting more uniform practices. The study findings can help inform future strategies to develop standardized guidelines surrounding VUS management.

Delineation of a KDM2B-related neurodevelopmental disorder and its associated DNA methylation signature.

PURPOSE: Pathogenic variants in genes involved in the epigenetic machinery are an emerging cause of neurodevelopment disorders (NDDs). Lysine-demethylase 2B (KDM2B) encodes an epigenetic regulator and mouse models suggest an important role during development. We set out to determine whether KDM2B variants are associated with NDD. METHODS: Through international collaborations, we collected data on individuals with heterozygous KDM2B variants. We applied methylation arrays on peripheral blood DNA samples to determine a KDM2B associated epigenetic signature. RESULTS: We recruited a total of 27 individuals with heterozygous variants in KDM2B. We present evidence, including a shared epigenetic signature, to support a pathogenic classification of 15 KDM2B variants and identify the CxxC domain as a mutational hotspot. Both loss-of-function and CxxC-domain missense variants present with a specific subepisignature. Moreover, the KDM2B episignature was identified in the context of a dual molecular diagnosis in multiple individuals. Our efforts resulted in a cohort of 21 individuals with heterozygous (likely) pathogenic variants. Individuals in this cohort present with developmental delay and/or intellectual disability; autism; attention deficit disorder/attention deficit hyperactivity disorder; congenital organ anomalies mainly of the heart, eyes, and urogenital system; and subtle facial dysmorphism. CONCLUSION: Pathogenic heterozygous variants in KDM2B are associated with NDD and a specific epigenetic signature detectable in peripheral blood.

Future Frontiers: Exploration of practices, challenges, and educational needs of genetic counselors in emerging subspecialties.

The augmented use of genomic testing across different medical subspecialties has led to increased involvement of genetic counselors (GCs) in specialized areas of medicine. However, the lack of educational infrastructure required for changing scholastic needs of GCs entering new subspecialties lends to the burden of self-directed learning and inconsistent knowledge. We conducted a cross-sectional study surveying GCs with experience in the emerging genetic subspecialties of Immunology, Dermatology, Endocrinology, and Pulmonology (abbreviated as "IDEP") on current practices, clinical challenges, and educational strategies undertaken while working in these settings. We compared knowledge and confidence in skills related to IDEP patient care between GCs who do (experienced cohort) and do not (control cohort) practice in these settings to assess their comfort with working in subspecialties. Participants were recruited from the National Society of Genetic Counselors membership. A total of 304 GCs (178 experienced and 126 control) completed the survey. Most GCs in the experienced cohort saw IDEP patients by themselves (n = 104; 58.4%) or with a geneticist (n = 97; 54.4%) and almost all (n = 176; 99%) cited GeneReviews as a primary informational source for IDEP genetics but half (n = 91; 51.1%) agreed that a dedicated online course would be the best way to learn about a specific subspecialty. The experienced cohort scored higher on confidence in all skills (p < 0.001, z = 7.32) and knowledge (p < 0.001, z = 5.68) related to IDEP genetics than the control cohort. Previous exposure to IDEP through graduate school coursework and rotations positively correlated with better self-confidence in skills (p = 0.02, z = -2.19; p < 0.001, z = -5.25) and genetic knowledge (p = 0.03, z = -2.09; p < 0.001, z = -2.81) related to IDEP patient care. Years of experience working as a GC did not correlate with better confidence in skills (p = 0.53) or better IDEP genetic knowledge (p = 0.15). Our findings show that provision of opportunities for increased exposure to subspecialties could help maximize GCs' ability to work in emerging niche fields.

Assessment of the beliefs, needs, and expectations for genetic counseling of patients with hypermobile Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome, hypermobility type (hEDS) is a heritable connective tissue disorder that currently does not have a known molecular etiology. Previous studies have explored the complex symptomology, clinical diagnosis, and psychological aspects of hEDS. Genetics providers currently aid in the diagnosis and management guidance of patients with hEDS, but there is limited data describing the needs and expectations of individuals with hEDS from a clinical genetics appointment. Our study sought to explore these items through the use of an online survey to assess participants' beliefs, needs and expectations (BNE) for genetic counseling as well as questions about demographics, hEDS symptoms, and current medical care. A total of 460 respondents with hEDS completed the survey. Most participants felt joint pain/weakness (n = 392; 88%) was one of the most disruptive symptoms of hEDS and 63% (n = 289) reported having psychiatric conditions. BNE scores were highest in two domains: expectations to have psychosocial concerns addressed during a genetic counseling appointment (mean score = 4.4/5; SD = 0.56) and desire for positive feelings after a genetic counseling session (mean score = 4.3/5; SD = 0.59). Participants who previously had genetic counseling felt less unsure about their diagnosis (p = 0.02) and had lower need for information about hEDS (p < 0.001). Majority of participants did not feel that their doctors were knowledgeable about hEDS (n = 269; 58%) and strongly supported a multidisciplinary approach to their care (n = 445; 97%). This research provides a framework for genetics providers and other healthcare professionals to assess the needs and expectations of patients with hEDS and consider re-structuring their appointment formats to service this population.

A novel homozygous variant in TRAPPC2L results in a neurodevelopmental disorder and disrupts TRAPP complex function.

BACKGROUND: Next-generation sequencing has facilitated the diagnosis of neurodevelopmental disorders with variable and non-specific clinical findings. Recently, a homozygous missense p.(Asp37Tyr) variant in TRAPPC2L, a core subunit of TRAPP complexes which function as tethering factors during membrane trafficking, was reported in two unrelated individuals with neurodevelopmental delay, post-infectious encephalopathy-associated developmental arrest, tetraplegia and accompanying rhabdomyolysis. METHODS: We performed whole genome sequencing on members of an Ashkenazi Jewish pedigree to identify the underlying genetic aetiology of global developmental delay/intellectual disability in three affected siblings. To assess the effect of the identified TRAPPC2L variant, we performed biochemical and cell biological functional studies on the TRAPPC2L protein. RESULTS: A rare homozygous predicted deleterious missense variant, p.(Ala2Gly), in TRAPPC2L was identified in the affected siblings and it segregated with the neurodevelopmental phenotype within the family. Using a yeast two-hybrid assay and in vitro binding, we demonstrate that the p.(Ala2Gly) variant, but not the p.(Asp37Tyr) variant, disrupted the interaction between TRAPPC2L and another core TRAPP protein, TRAPPC6a. Size exclusion chromatography suggested that this variant affects the assembly of TRAPP complexes. Employing two different membrane trafficking assays using fibroblasts from one of the affected siblings, we found a delay in traffic into and out of the Golgi. Similar to the p.(Asp37Tyr) variant, the p.(Ala2Gly) variant resulted in an increase in the levels of active RAB11. CONCLUSION: Our data fill in a gap in the knowledge of TRAPP architecture with TRAPPC2L interacting with TRAPPC6a, positioning it as a putative adaptor for other TRAPP subunits. Collectively, our findings support the pathogenicity of the TRAPPC2L p.(Ala2Gly) variant.

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.

PURPOSE: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. METHODS: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. RESULTS: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. CONCLUSION: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

COVID contingencies: Early epicenter experiences of different genetics clinics at a New York City institution inform emergency adaptation strategies.

The unique situational challenges of the COVID-19 pandemic have demanded creative modifications to the delivery of genetic services. Institutions across the country have adapted workflows to continue to provide quality care while minimizing the need for physical visits. As the first epicenter of the pandemic in the country, New York City healthcare workers and residents had to make rapid, unprecedented changes to their way of life. This article describes the workflow adaptations of genetic counselors across various clinical settings at New York Presbyterian/Columbia University Irving Medical Center, the largest provider of genetics care in New York City, during the height of the COVID-19 pandemic. The authors observe how the adaptations impacted clinical care and the genetic counselors. Our lived experience and account can provide guidance for others during the current and future pandemics.

Clinical genetic counselor experience in the adoption of telehealth in the United States and Canada during the COVID-19 pandemic.

The COVID-19 pandemic has significantly impacted the service delivery model (SDM) of clinical genetic counseling across the United States and Canada. A cross-sectional survey was distributed to 4,956 genetic counselors (GCs) from the American Board of Genetic Counselors and Canadian Association of Genetic Counselors mailing lists in August 2020 to assess the change in utilization of telehealth for clinical genetic counseling during the COVID-19 pandemic compared with prior to the pandemic. Data from 411 eligible clinical genetic counselors on GC attitudes and their experiences prior to and during the pandemic were collected and analyzed to explore the change in SDM, change in appointment characteristics, change in billing practices, GC perceived benefits and limitations of telehealth, and prediction of future trends in SDM in the post-pandemic era. The study showed the overall utilization of audiovisual and telephone encounters increased by 43.4% and 26.2%, respectively. The majority of respondents who provided audiovisual and telephone encounters reported increased patient volume compared with prior to the pandemic, with an average increase of 79.4% and 42.8%, respectively. There was an increase of 69.4% of GCs rendering genetic services from home offices. The percentage of participants who billed for telehealth services increased from 45.7% before the pandemic to 80.3% during the pandemic. The top GC perceived benefits of telehealth included safety for high-risk COVID patients (95.2%) and saved commute time for patients (94.7%). The top GC perceived limitations of telehealth included difficulty to conduct physician evaluation/coordinating with healthcare providers (HCP) (73.7%) and difficulty addressing non-English speaking patients (68.5%). Overall, 89.6% of GCs were satisfied with telehealth; however, 55.3% reported uncertainty whether the newly adopted SDM would continue after the pandemic subsides. Results from this study demonstrate the rapid adoption of telehealth for clinical genetic counseling services as a result of the COVID-19 pandemic, an increase in billing for these services, and support the feasibility of telehealth for genetic counseling as a longer term solution to reach patients who are geographically distant.

Bi-allelic missense disease-causing variants in RPL3L associate neonatal dilated cardiomyopathy with muscle-specific ribosome biogenesis.

Dilated cardiomyopathy (DCM) belongs to the most frequent forms of cardiomyopathy mainly characterized by cardiac dilatation and reduced systolic function. Although most cases of DCM are classified as sporadic, 20-30% of cases show a heritable pattern. Familial forms of DCM are genetically heterogeneous, and mutations in several genes have been identified that most commonly play a role in cytoskeleton and sarcomere-associated processes. Still, a large number of familial cases remain unsolved. Here, we report five individuals from three independent families who presented with severe dilated cardiomyopathy during the neonatal period. Using whole-exome sequencing (WES), we identified causative, compound heterozygous missense variants in RPL3L (ribosomal protein L3-like) in all the affected individuals. The identified variants co-segregated with the disease in each of the three families and were absent or very rare in the human population, in line with an autosomal recessive inheritance pattern. They are located within the conserved RPL3 domain of the protein and were classified as deleterious by several in silico prediction software applications. RPL3L is one of the four non-canonical riboprotein genes and it encodes the 60S ribosomal protein L3-like protein that is highly expressed only in cardiac and skeletal muscle. Three-dimensional homology modeling and in silico analysis of the affected residues in RPL3L indicate that the identified changes specifically alter the interaction of RPL3L with the RNA components of the 60S ribosomal subunit and thus destabilize its binding to the 60S subunit. In conclusion, we report that bi-allelic pathogenic variants in RPL3L are causative of an early-onset, severe neonatal form of dilated cardiomyopathy, and we show for the first time that cytoplasmic ribosomal proteins are involved in the pathogenesis of non-syndromic cardiomyopathies.

Examining the Psychosocial Impact of Genetic Testing for Cardiomyopathies.

Inherited cardiomyopathies, including hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), are the most common monogenic cause of cardiac disease and can rarely lead to sudden cardiac death (SCD). They are characterized by incomplete and age-dependent penetrance and are usually initially symptomatic in adulthood yet can present in childhood as well. Over 20 genes have been identified to cause HCM, and more than 40 genes are known to cause DCM. Genetic testing for these genes has been integrated into medical care; however, the psychological impact of genetic testing and the impact of the uncertainty that comes with receiving these results have not been well studied. This study surveyed 90 adult probands and relatives with a personal or family history of cardiomyopathy from a single hospital-based cardiac genetic program to determine the psychosocial impact of genetic testing for cardiomyopathies. Standardized psychological instruments including an adapted Multidimensional Impact of Cancer Risk Assessment (aMICRA), Impact of Event Scale (IES), and Satisfaction with Decision (SWD) scales were utilized. Patients with positive genetic test results had higher scores for intrusive thoughts, avoidance, and distress when compared to those with negative genetic test results and were also more likely to make or plan to make life changes because of the results of their genetic testing. Satisfaction with the decision to undergo genetic testing was similar regardless of genetic test results. The results of this study provide insight into the patient experience of genetic testing for cardiomyopathies and how these experiences are associated with genetic test results and cardiac history.

Phenotype-Driven Molecular Genetic Test Recommendation for Diagnosing Pediatric Rare Disorders.

Rare disease patients often endure prolonged diagnostic odysseys and may still remain undiagnosed for years. Selecting the appropriate genetic tests is crucial to lead to timely diagnosis. Phenotypic features offer great potential for aiding genomic diagnosis in rare disease cases. We see great promise in effective integration of phenotypic information into genetic test selection workflow. In this study, we present a phenotype-driven molecular genetic test recommendation (Phen2Test) for pediatric rare disease diagnosis. Phen2Test was constructed using frequency matrix of phecodes and demographic data from the EHR before ordering genetic tests, with the objective to streamline the selection of molecular genetic tests (whole-exome / whole-genome sequencing, or gene panels) for clinicians with minimum genetic training expertise. We developed and evaluated binary classifiers based on 1,005 individuals referred to genetic counselors for potential genetic evaluation. In the evaluation using the gold standard cohort, the model achieved strong performance with an AUROC of 0.82 and an AUPRC of 0.92. Furthermore, we tested the model on another silver standard cohort (n=6,458), achieving an overall AUROC of 0.72 and an AUPRC of 0.671. Phen2Test was adjusted to align with current clinical guidelines, showing superior performance with more recent data, demonstrating its potential for use within a learning healthcare system as a genomic medicine intervention that adapts to guideline updates. This study showcases the practical utility of phenotypic features in recommending molecular genetic tests with performance comparable to clinical geneticists. Phen2Test could assist clinicians with limited genetic training and knowledge to order appropriate genetic tests.

Heterozygous rare variants in NR2F2 cause a recognizable multiple congenital anomaly syndrome with developmental delays.

Nuclear receptor subfamily 2 group F member 2 (NR2F2 or COUP-TF2) encodes a transcription factor which is expressed at high levels during mammalian development. Rare heterozygous Mendelian variants in NR2F2 were initially identified in individuals with congenital heart disease (CHD), then subsequently in cohorts of congenital diaphragmatic hernia (CDH) and 46,XX ovotesticular disorders/differences of sexual development (DSD); however, the phenotypic spectrum associated with pathogenic variants in NR2F2 remains poorly characterized. Currently, less than 40 individuals with heterozygous pathogenic variants in NR2F2 have been reported. Here, we review the clinical and molecular details of 17 previously unreported individuals with rare heterozygous NR2F2 variants, the majority of which were de novo. Clinical features were variable, including intrauterine growth restriction (IUGR), CHD, CDH, genital anomalies, DSD, developmental delays, hypotonia, feeding difficulties, failure to thrive, congenital and acquired microcephaly, dysmorphic facial features, renal failure, hearing loss, strabismus, asplenia, and vascular malformations, thus expanding the phenotypic spectrum associated with NR2F2 variants. The variants seen were predicted loss of function, including a nonsense variant inherited from a mildly affected mosaic mother, missense and a large deletion including the NR2F2 gene. Our study presents evidence for rare, heterozygous NR2F2 variants causing a highly variable syndrome of congenital anomalies, commonly associated with heart defects, developmental delays/intellectual disability, dysmorphic features, feeding difficulties, hypotonia, and genital anomalies. Based on the new and previous cases, we provide clinical recommendations for evaluating individuals diagnosed with an NR2F2-associated disorder.

A novel biallelic loss-of-function variant in DAND5 causes heterotaxy syndrome.

The majority of heterotaxy cases do not obtain a molecular diagnosis, although pathogenic variants in more than 50 genes are known to cause heterotaxy. A heterozygous missense variant in DAND5, a nodal inhibitor, which functions in early development for establishment of right-left patterning, has been implicated in heterotaxy. Recently, the first case was reported of a DAND5 biallelic loss-of-function (LoF) variant in an individual with heterotaxy. Here, we describe a second unrelated individual with heterotaxy syndrome and a homozygous frameshift variant in DAND5 (NM_152654.2:c.197del [p.Leu66ArgfsTer22]). Using an in vitro assay, we demonstrate that the DAND5 c.197del variant is unable to inhibit nodal signaling when compared with the wild-type expression construct. This work strengthens the genetic and functional evidence for biallelic LoF variants in DAND5 causing an autosomal recessive heterotaxy syndrome.

Erratum: Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas.

[This corrects the article DOI: 10.1016/j.xhgg.2022.100107.].

Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas.

Esophageal atresias/tracheoesophageal fistulas (EA/TEF) are rare congenital anomalies caused by aberrant development of the foregut. Previous studies indicate that rare or de novo genetic variants significantly contribute to EA/TEF risk, and most individuals with EA/TEF do not have pathogenic genetic variants in established risk genes. To identify the genetic contributions to EA/TEF, we performed whole genome sequencing of 185 trios (probands and parents) with EA/TEF, including 59 isolated and 126 complex cases with additional congenital anomalies and/or neurodevelopmental disorders. There was a significant burden of protein-altering de novo coding variants in complex cases (p = 3.3 × 10-4), especially in genes that are intolerant of loss-of-function variants in the population. We performed simulation analysis of pathway enrichment based on background mutation rate and identified a number of pathways related to endocytosis and intracellular trafficking that as a group have a significant burden of protein-altering de novo variants. We assessed 18 variants for disease causality using CRISPR-Cas9 mutagenesis in Xenopus and confirmed 13 with tracheoesophageal phenotypes. Our results implicate disruption of endosome-mediated epithelial remodeling as a potential mechanism of foregut developmental defects. Our results suggest significant genetic heterogeneity of EA/TEF and may have implications for the mechanisms of other rare congenital anomalies.

Novel candidate genes in esophageal atresia/tracheoesophageal fistula identified by exome sequencing.

The various malformations of the aerodigestive tract collectively known as esophageal atresia/tracheoesophageal fistula (EA/TEF) constitute a rare group of birth defects of largely unknown etiology. Previous studies have identified a small number of rare genetic variants causing syndromes associated with EA/TEF. We performed a pilot exome sequencing study of 45 unrelated simplex trios (probands and parents) with EA/TEF. Thirteen had isolated and 32 had nonisolated EA/TEF; none had a family history of EA/TEF. We identified de novo variants in protein-coding regions, including 19 missense variants predicted to be deleterious (D-mis) and 3 likely gene-disrupting (LGD) variants. Consistent with previous studies of structural birth defects, there is a trend of increased burden of de novo D-mis in cases (1.57-fold increase over the background mutation rate), and the burden is greater in constrained genes (2.55-fold, p = 0.003). There is a frameshift de novo variant in EFTUD2, a known EA/TEF risk gene involved in mRNA splicing. Strikingly, 15 out of 19 de novo D-mis variants are located in genes that are putative target genes of EFTUD2 or SOX2 (another known EA/TEF gene), much greater than expected by chance (3.34-fold, p value = 7.20e-5). We estimated that 33% of patients can be attributed to de novo deleterious variants in known and novel genes. We identified APC2, AMER3, PCDH1, GTF3C1, POLR2B, RAB3GAP2, and ITSN1 as plausible candidate genes in the etiology of EA/TEF. We conclude that further genomic analysis to identify de novo variants will likely identify previously undescribed genetic causes of EA/TEF.

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.