Case 1

A 12-year-old female presented to the aortopathy clinic for evaluation for Ehlers–Danlos syndrome type III (EDS) (OMIM 130020) because she had DTC genetic testing and the raw data report revealed a single-nucleotide polymorphism (SNP) in the COL3A1 gene (Supplementary Table 1). The patient’s mother created her own database that used an internal algorithm to interpret her family’s raw data.

The patient’s echocardiogram and electrocardiogram (ECG) were normal. On her clinical evaluation, she did not meet clinical criteria for any types of EDS. The family requested a second opinion regarding the COL3A1 variant and were referred to medical genetics, who agreed that the patient did not meet clinical criteria for EDS. An Ehlers–Danlos, metabolic, and mitochondrial gene panel was ordered, and the reportedly pathogenic SNP in COL3A1 was not detected on clinical testing.

The patient’s family continues to seek evaluations for concerns of EDS despite normal evaluations with genetics and cardiology, and negative genetic testing. The patient has seen several specialists for EDS-related concerns, including seven cardiologists, two gynecologists, an ophthalmologist, a gastroenterologist, and six emergency room physicians for concerns of syncope. Four other relatives have undergone evaluations by a geneticist for EDS, the results of which the patient’s mother would not share.

Case 2

A 36-year-old male with idiopathic recurrent myocarditis was referred for genetic counseling after he shared an interpretation report of his DTC raw genetic data with his general cardiologist. The report indicated the patient carried a SNP that corresponded to a pathogenic variant in MYBPC3 (NM_000256.3:p.Asp770Asn; rs36211723), a gene associated with hypertrophic cardiomyopathy (HCM) (Supplementary Table 1).

The patient arrived eager to understand how this variant could be related to his myocarditis, unaware of its association with HCM. Review of clinical cardiovascular notes, imaging, and family history were not suggestive of a diagnosis of HCM. Clinical genetic testing of the MYBPC3 gene was sent. Pretest counseling included discussion of the possibility that the MYBPC3 variant may not be clinically confirmed and that, because he did not carry a diagnosis of HCM, his insurance may not cover the cost of the clinical genetic testing. The patient expressed that he was “crossing his fingers” that the variant was a false positive. The MYBPC3 variant was not detected in clinical genetic testing and the patient was relieved. Ongoing cardiac screening for HCM (in patient or his family) was not recommended.

Case 3

A healthy 22-year-old male referred himself to the HCM clinic for an evaluation after discovering the same MYBPC3 SNP as case 2 (NM_000256.3:p.Asp770Asn; rs36211723) (Supplementary Table 1) in his raw genetic data obtained from DTC genetic testing. During the clinical intake, the patient had significant anxiety about this result: he had taken medical leave from his PhD program after learning of his results “to focus on [my] HCM and risk of sudden death.” He was an avid cyclist, but gave it up after learning that vigorous exercise is not recommended for people with HCM. He had looked into joining a support group, but did not feel ready to discuss the possibility of myectomy or transplant “yet.”

In the appointment, the patient described that he was not surprised by the results; he attributed his history of palpitations during childhood and his father’s left ventricular hypertrophy (LVH) to HCM. After reviewing the patient’s echocardiogram and ECG and his father’s records, the cardiologist assessed that there was no clinical evidence for HCM in the patient or his father. Confirmatory testing of the DTC results confirmed that this SNP was not detected. In calling the patient with these results, he was emotional and relieved. This patient was released from screening for HCM.

Case 4

An 18-year-old female died suddenly while running. Her autopsy was inconclusive. Prior to her death, the proband and her father had submitted DTC samples, and this prompted him to research the raw data. The raw data interpretation identified multiple SNPs classified as pathogenic for arrhythmogenic right ventricular cardiomyopathy (ARVC) (Supplementary Table 1). Therefore, the proband’s 15-year-old sister was screened for ARVC, and cardiac magnetic resonance imaging (cMRI) showed an aneurysm in the apex of the RV. An implantable cardioverter defibrillator (ICD) was placed for primary prevention. Clinical genetic testing later revealed that the sister did not carry the PKP2 variant found on DTC testing. Concerned, the cardiologist referred the family to a specialty center. Upon expert evaluation, the sister’s cMRI was found to be normal and she did not meet diagnostic criteria for ARVC. The remaining autopsy sample was obtained and clinical genetic testing for arrhythmia and cardiomyopathy genes, including PKP2, did not identify the variant found by the DTC genetic testing company. Given that the benefits of an ICD in an asymptomatic individual do not outweigh risks of the device, the sister’s device was explanted. The family remains concerned and confused about the cause of their daughter’s death, and of their surviving daughter’s risk.