A Novel Mutation in the Kringle IV Domain of LPA Gene Leading to Familial Cardiovascular Diseases

Background This study aims to investigate the clinical characterization and causative genetic defect of a four-generation Chinese Han family with cardiovascular diseases. Methods The combined use of next-generation sequencing and qPCR technique was performed to investigate genetic pathology of familial cardiovascular diseases. Results The clinical manifestations of the family members include coronaty artery disease, early-onset hypertension, lipoma, cerebral infarction and even unexplained sudden death, and a novel heterozygous deletion of 3-16 exon of LPA gene was identified to be causative for the symptoms in the family. Conclusions A novel deletion in the LPA gene was identified in a Chinese family associated with elevated Lp(a) levels and cardiovascular diseases, which expands the spectrum of the LPA mutation and its associated phenotypes.


Background
Coronary artery disease (CAD) has a wide range of clinical manifestations, from asymptomatic to stable coronary disease and acute coronary syndrome [1,2]. The elevated plasma concentration of lipoprotein(a) [Lp(a)] has a strong association with coronary heart disease [3][4]. Most laboratories around the world recognize elevated Lp(a) as plasma levels above 30 mg/dl [5]. Lp(a) consists of a single large apolipoprotein(a) [apo(a)] which is attached covalently to the apolipoprotein B moiety of a cholesterol-rich low-density lipoprotein (LDL) cholesterol particle [1]. The biological function of Lp(a) involves interfering with plasminogen activation and its atherogenic potential serving as a lipoprotein particle after receptor-mediated uptake [2]. LPA, the gene coding for apo(a), located on chromosome 6q25-6q26, explains more than 90% of the Lp(a) variance and it genetically determines the circulating Lp(a) level [2]. Lp(a) concentration has been reported to be largely determined by genetic variation within the LPA locus, including both SNVs (single nucleotide variants) and CNVs (copy number variations) [6]. LPA gene consists of ten homologous Kringle IV domains, Kringle IV types 1 and 3-10 occur only once in every apo(a) gene, while the copy number of Kringle IV type 2 is variable among individual, and this copy number variation which represents the size polymorphism of Lp(a) is of pathological significance [7]. It has been reported that genetic diversity at the LPA locus, including the SNPs rs10455872 and rs3798220, is associated with raised plasma concentrations of Lp(a) and incident cardiovascular disease [8]. In the present study, a novel genetic mutation in the Kringle IV domain of LPA gene was identified in a Chinese family which causes cardiovascular disease (CVD).

Methods
The proband (III:1) ( A novel heterozygous deletion of 3-16 exon of LPA gene was detected in the proband using next-generation sequencing (Table 1.). This copy number variation has not been reported in the related clinical cases, and the mutation is located in the Kringle IV area of LPA gene which has been reported to be associated with Lp(a) concentration in plasma [9]. So far, the frequency of this mutation is extremely low in the population genetic database and the mutation occurs in the Kringle IV region which plays an important role in functional activity of the protein. increased Lp(a) as an ASCVD risk enhancer for initiating or intensifying statin therapy [13]. Lp(a) value more than 30 mg/dl is strongly and independently associated with CVD complications in type 1 diabetic patients [14]. Studies suggest that Lp(a) levels more than 50 mg/dl is most pathogenic and supposed to signally increase CVD risk [15]. It has also been recommended to screen for elevated lipoprotein(a) concentration in patients with moderate or high-risk coronary heart disease, and available data increase priority for investigation of Lp(a) as a potential therapeutic target [16][17].
The present study expands the spectrum of the LPA mutation and its associated phenotypes. The

Consent for publication
An informed written consent for publication of the participants clinical details was obtained from each of the participants.

Availability of data and materials
The datasets used and analysed during the current study available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests. Project (14401970300). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors' contributions
YL, XZ, YW drafted the manuscript. FG, XY, TZ recruited, acquired, analyzed and interpreted the data.
TZ and XY supervised the management of the study and approved the manuscript. All authors read and approved the final manuscript.  Copy number graph of NGS carried out on proband (III:I).