Despite successive advancement of genome editing technology with zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs), the recent breakthrough in the field has been related to clustered regularly interspaced short palindromic repeats/associated proteins (CRISPR/Cas). The high efficiency and convenience of CRIPSR/Cas systems dramatically accelerate pre- and clinical experimentations of dyslipidemia and atherosclerosis. In this chapter, we review the latest state of genome editing in translational research of dyslipidemia and atherosclerosis. We highlight recent progress in therapeutic development for familial dyslipidemia by genome editing. We point to the challenges in maximizing efficacy and minimizing safety issues related to the once-and-done therapy focusing on CRISPR/Cas systems. We give an outlook on the potential gene targets prioritized by large-scale genetic studies of cardiovascular diseases and genome editing in precision medicine of dyslipidemia and atherosclerosis. 

Genome Editing in Dyslipidemia and Atherosclerosis.

Additional file 1: Supplementary Table 1. Variants with an allele frequency of ≥1% found in the three patients. Supplementary Figure 1. Illustration showing that c.247_249+1del (in accordance with Human Genome Variation Society (HGVS) recommendations) may be alternatively described as c.246_249del. Exon 2 sequence is shown in upper case letters whereas intron 2 sequence is shown in lower case. The canonical 5’ splice site gt dinucleotide is highlighted in bold and blue. The deleted four nucleotides in each nomenclature version are barred. Supplementary Figure 2. SpliceAI predictions for the 55 LPL frameshift coding variants reported to date. Supplementary Figure 3. SpliceAI-predicted impact of the LPL c.899_921dup variant on splicing. (a) SpliceAI predictions. (b) Explanation of the predicted results in the context of the wild-type LPL exon 6 and flanking intronic sequences. Exon 6 sequence is shown in upper case letters whereas intronic sequence is shown in lower case. The physiological obligate acceptor and donor dinucleotides (ag and gt) are highlighted in blue. The 23-bp duplicated sequence is highlighted in red. The LPL c.899_921dup variant was predicted to activate an upstream cryptic donor splice site (highlighted in blue and underlined). The use of this cryptic donor splice site would result in a transcript lacking the last 149 (not divisible by 3) nucleotides (barred) of exon 6. Supplementary Figure 4. SpliceAI-predicted impact of the LPL c.1160_1161insT variant on splicing. (a) SpliceAI predictions. (b) Explanation of the predicted results in the context of the wild-type LPL exon 8 and flanking intronic sequences. Exon 8 sequence is shown in upper case letters whereas intronic sequence is shown in lower case. The physiological obligate splice site acceptor and donor dinucleotides (ag and gt) are highlighted in blue. The LPL c.1160_1161insT variant was predicted to activate a downstream cryptic acceptor splice site (highlighted in red). The use of this cryptic acceptor splice site would result in a transcript lacking the first 47 (not divisible by 3) nucleotides of exon 8. 

Additional file 1 of Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date

Lipoprotein lipase (LPL) is the rate-limiting enzyme for triglyceride hydrolysis. Homozygous or compound heterozygous LPL variants cause autosomal recessive familial chylomicronemia syndrome (FCS), whereas simple heterozygous LPL variants are associated with hypertriglyceridemia (HTG) and HTG-related disorders. LPL frameshift coding sequence variants usually cause complete functional loss of the affected allele, thereby allowing exploration of the impact of different levels of LPL function in human disease.All exons and flanking intronic regions of LPL were Sanger sequenced in patients with HTG-related acute pancreatitis (HTG-AP) or HTG-AP in pregnancy. Previously reported LPL frameshift coding sequence variants were collated from the Human Gene Mutation Database and through PubMed keyword searching. Original reports were manually evaluated for the following information: zygosity status of the variant, plasma LPL activity of the variant carrier, disease referred for genetic analysis, patient's age at genetic analysis, and patient's disease history. SpliceAI was employed to predict the potential impact of collated variants on splicing.Two novel rare variants were identified, and 53 known LPL frameshift coding sequence variants were collated. Of the 51 variants informative for zygosity, 30 were simple heterozygotes, 12 were homozygotes, and 9 were compound heterozygotes. Careful evaluation of the 55 variants with respect to their clinical and genetic data generated several interesting findings. First, we conclude that 6-7% residual LPL function could significantly delay the age of onset of FCS and reduce the prevalence of FCS-associated syndromes. Second, whereas a large majority of LPL frameshift coding sequence variants completely disrupt gene function through their "frameshift" nature, a small fraction of these variants may act wholly or partly as "in-frame" variants, leading to the generation of protein products with some residual LPL function. Third, we identified two candidate LPL frameshift coding sequence variants that may retain residual function based on genotype-phenotype correlation or SpliceAI-predicted data.This study reported two novel LPL variants and yielded new insights into the genotype-phenotype relationship as it pertains to LPL frameshift coding sequence variants. 

Frameshift coding sequence variants in the LPL gene: identification of two novel events and exploration of the genotype–phenotype relationship for variants reported to date

Whole exome sequencing for non-selective pediatric patients with hyperlipidemia

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Whole exome sequencing for non-selective pediatric patients with hyperlipidemia