Successful Genetic Screening and Creating Awareness of Familial Hypercholesterolemia and Other Heritable Dyslipidemias in the Netherlands

Abstract

The genetic screening program for familial hypercholesterolemia (FH) in the Netherlands, which was embraced by the Dutch Ministry of Health from 1994 to 2014, has led to twenty years of identification of at least 1500 FH cases per year. Although funding by the government was terminated in 2014, the approach had proven its effectiveness and had built the foundation for the development of more sophisticated diagnostic tools, clinical collaborations, and new molecular-based treatments for FH patients. As such, the community was driven to continue the program, insurance companies were convinced to collaborate, and multiple approaches were launched to find new index cases with FH. Additionally, the screening was extended, now also including other heritable dyslipidemias. For this purpose, a diagnostic next-generation sequencing (NGS) panel was developed, which not only comprised the culprit LDLR, APOB, and PCSK9 genes, but also 24 other genes that are causally associated with genetic dyslipidemias. Moreover, the NGS technique enabled further optimization by including pharmacogenomic genes in the panel. Using such a panel, more patients that are prone to cardiovascular diseases are being identified nowadays and receive more personalized treatment. Moreover, the NGS output teaches us more and more about the dyslipidemic landscape that is less straightforward than we originally thought. Still, continuous progress is being made that underlines the strength of genetics in dyslipidemia, such as discovery of alternative genomic pathogenic mechanisms of disease development and polygenic contribution.

Cascade screening for familial hypercholesterolemia should be organized at a national level

“…The Norwegian cascade screening program could serve as a model for countries with a similar healthcare system. After the government-supported cascade screening program in the Netherlands was terminated, a Dutch nonprofit organization has been established as a national coordinating body for cascade screening [26 ▪▪ ]. In the Czech Republic, a network of regional and national centres has been established [37].…”

“…Whereas >4000 patients in total were diagnosed with FH per year when the national screening program was running, <500 patients have been diagnosed per year after the program was terminated and FH was diagnosed as part of ordinary healthcare [24]. Moreover, considering patients diagnosed by cascade screening only, more than 1500 patients were diagnosed per year when the Dutch national program was running and only 360 patients were diagnosed in 2015, 2 years after the program was terminated [26 ▪▪ ].…”

From the patient to the population: Use of genomics for population screening

“…Traditional methods to identify cases with HBOC, LS, and FH include genetic testing for patients meeting clinical, ethnicity or family-history based criteria ( Hampel et al, 2008 ; Schofield et al, 2014 ; Klančar et al, 2015 ; Tognetto et al, 2017 ; Groselj et al, 2018 ; Gupta et al, 2019 ; Daly et al, 2020 ; Kunnackal John et al, 2021 ; Zuurbier et al, 2021 ). However, these targeted approaches have been found to miss a substantial proportion of individuals who harbor pathogenic variants.…”

Avaliação do perfil de microRNAs exossomais em portadores de hipercolesterolemia familial

“…A grande maioria dos casos tem o padrão de herança autossômica dominante com 90% de penetrância (MEHTA et al, 2016;SINGH;BITTNER, 2015). O diagnóstico genético é muito importante na HF, pois pacientes com antecedentes genéticos para HF apresentam risco consideravelmente maior de DAC, em comparação com aqueles com causa idiopática ou secundária para HF, e podem ser tratados de forma mais rigorosa (KHERA et al, 2016;ZUURBIER;DEFESCHE;WIEGMAN, 2021).…”

“…Variantes no gene da LDLRAP1 levam a produção de proteína com a perda de função causando o aumento do LDL-c (BRAUTBAR et al, 2015;FALUDI et al, 2017). Além disso, mutações nos genes ABCG5 e ABCG8 que codificam proteínas transportadoras da família ABC (ATP binding cassete) causam sitosterolemia, uma outra forma de HF recessiva, caracterizada pelo aumento plasmático das concentrações de esteróis de plantas, como sitosterol e campesterol, provenientes da dieta (LAMIQUIZ-MONEO et al, 2017;ZUURBIER;DEFESCHE;WIEGMAN, 2021).…”