Potential barriers to reverse cascade screening combined with universal cholesterol screening for paediatric familial hypercholesterolemia: focus on second-degree relatives of a proband

Aim: Familial hypercholesterolaemia (FH), an autosomal-dominant disorder, requires early diagnosis to prevent atherosclerosis in children and coronary artery disease (CAD) in their parents. This study aimed to evaluate the effectiveness and barriers of reverse cascade screening (RCS) combined with universal cholesterol screening (UCS) for paediatric FH. Methods: We performed RCS combined with UCS for paediatric FH between January 2018 and July 2023. Family pedigree was evaluated in second-degree relatives, using a child with a genetic diagnosis of FH as the proband. Based on the 2022 Japan Atherosclerosis Society clinical guidelines, cases with suspected FH were classified into four categories: “Definite”, “Probable”, “Possible”, or “Unlikely”. Those who did not complete the diagnostic process were evaluated based on the reasons, including challenges such as “Untested lipids in children”, “Bereavement”, “CAD with unspecified details”, “Dyslipidaemia with unspecified low-density lipoprotein cholesterol (LDL-C) levels”, and “No information on CAD or dyslipidaemia”. Results: Of 252 patients suspected of having FH, 94 completed the diagnostic process. Among them, 49 were classified as “Definite” FH cases, predominantly among first-degree relatives. In contrast, 158 patients did not complete the diagnostic process, with the most common barriers being “Dyslipidaemia with unspecified LDL-C levels” and “No information on CAD or dyslipidaemia”, particularly among second-degree relatives. Conclusion: RCS combined with UCS for paediatric FH using genetic testing is effective for the early diagnosis of FH in asymptomatic cases. However, addressing barriers that hinder FH diagnosis, such as difficulties in approaching second-degree relatives, is critical for improving diagnosis rates.