Clinical Guideline for Preimplantation Genetic Testing in Inherited Cardiac Diseases

• DOI: 10.1161/circgen.123.004416
• Publication Date: 2024-03-22T09:00:48Z
• Authors: Job A.J. Verdonschot; Debby M.E.I. Hell...; Vanessa P.M. van ...; Malou Heijligers; Sonja de Munnik; Edith Coonen; Jos C.M.F. Dreesen; Arthur van den Wi...; Han G. Brunner; Masoud Zamani Esteki; Stephane R.B. Hey...; Christine E.M. de...; Aimée D.C. Paulussen
• Keywords: cardiomyopathies; Male; Heterozygote; Cardiac & Cardiovascular Systems; Heart Diseases; Clinical Decision-Making; heart disease; AMERICAN-COLLEGE; Human Genetics - Radboud University Medical Center - DCMN; DIAGNOSIS; heart transplantation; 03 medical and health sciences; 0302 clinical medicine; Humans; Brugada syndrome; Genetic Testing; Prospective Studies; Referral and Consultation; Preimplantation Diagnosis; Genetics & Heredity; Risk Management; Family Characteristics; Science & Technology; VENTRICULAR-ARRHYTHMIA; Genetic Diseases, Inborn; Arrhythmias, Cardiac; ASSOCIATION; American Heart Association; Original Articles; DILATED CARDIOMYOPATHY; CARRIERS; Cardiovascular System & Cardiology; Female; Cardiomyopathies; Life Sciences & Biomedicine

BACKGROUND: Preimplantation genetic testing (PGT) is a reproductive technology that selects embryos without (familial) genetic variants. PGT has been applied in inherited cardiac disease and is included in the latest American Heart Association/American College of Cardiology guidelines. However, guidelines selecting eligible couples who will have the strongest risk reduction most from PGT are lacking. We developed an objective decision model to select eligibility for PGT and compared its results with those from a multidisciplinary team.

METHODS: All couples with an inherited cardiac disease referred to the national PGT center were included. A multidisciplinary team approved or rejected the indication based on clinical and genetic information. We developed a decision model based on published risk prediction models and literature, to evaluate the severity of the cardiac phenotype and the penetrance of the familial variant in referred patients. The outcomes of the model and the multidisciplinary team were compared in a blinded fashion.

RESULTS: Eighty-three couples were referred for PGT (1997–2022), comprising 19 different genes for 8 different inherited cardiac diseases (cardiomyopathies and arrhythmias). Using our model and proposed cutoff values, a definitive decision was reached for 76 (92%) couples, aligning with 95% of the multidisciplinary team decisions. In a prospective cohort of 11 couples, we showed the clinical applicability of the model to select couples most eligible for PGT.

CONCLUSIONS: The number of PGT requests for inherited cardiac diseases increases rapidly, without the availability of specific guidelines. We propose a 2-step decision model that helps select couples with the highest risk reduction for cardiac disease in their offspring after PGT.