Cascade screening of a Pakistani consanguineous familial hypercholesterolemia cohort : identification of seven new homozygous patients

Ain, Quratul (author), Šikonja, Jaka (author), Sadiq, Fouzia (author), Shafi, Saeed (author), Kafol, Jan (author), Gorjanc, Tevž (author), Šuštar, Urša (author), Kovač, Jernej (author), Iqbal Khan, Mohammad (author), Ajmal, Muhammad (author), Grošelj, Urh (author)

Background and aims: Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels from birth, significantly increasing the risk of premature cardiac events and mortality. In Pakistan, despite the potential burden of FH, comprehensive studies evaluating its genetic characteristics, cascade screening significance, and lipoprotein (a) [Lp(a)] levels remain scarce. Understanding these factors is crucial for effective diagnosis, risk assessment, and management of FH in the Pakistani population. Methods: After the identification of index case with clinical homozygous FH, characterized by high LDL-C and high Lp(a) levels together with a positive personal and family history of cardiovascular disease, a cascade screening of 66 relatives from a consanguineous family was performed. Blood samples were obtained from all subjects for biochemical and genetic analysis. Simon Broome criteria was applied on children for clinical FH diagnosis. Dutch Lipid Clinic Network scores were calculated for individuals aged ≥16 years. Genetic screening was performed using next-generation sequencing to analyse all coding regions and exon-intron borders of the following genes: ALMS1, APOA1, APOB, APOA5, APOC2, APOC3, APOE, ABCA1, ABCG5, ABCG8, CREB3L3, GPIHBP1, LDLR, LDLRAP1, LIPA, LMF1, LPL, and PCSK9. The identified variants were confirmed using Sanger sequencing. Results: Cascade screening identified seven homozygous and 25 heterozygous FH patients with pathogenic variant in the LDLR gene (NM_000527.5: c.2416dupG: p. Val806GlyfsTer11). Additionally, heterozygous variants of uncertain significance were identified in 4 other subjects. Conclusion: This study underscores the high effectiveness of cascade screening in consanguineous families and societies that could lead to early detection and prevention.

• Language: English
• Keywords: cardiovascular disease, cascade screening, consanguineous, familial hypercholesterolemia, homozygous
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: 7 str.
• Numbering: Vol. 402, art. 119118
• PID: 20.500.12556/RUL-167797
• UDC: 616.4-053.2
• ISSN on article: 1879-1484
• DOI: 10.1016/j.atherosclerosis.2025.119118
• COBISS.SI-ID: 228355075
• Publication date in RUL: 12.03.2025

Record is a part of a journal

• Title: Atherosclerosis
• Shortened title: Atherosclerosis
• Publisher: Elsevier
• ISSN: 1879-1484
• COBISS.SI-ID: 6621247

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: kaskadno presejanje, krvno sorodstvo, družinska hiperholesterolemija, homozigot