The spectrum of rare monogenic diseases in patients with premature coronary artery disease

[...]for most of these rare monogenic diseases besides FH, no clear clinical guidelines have been established for their differentiation and diagnosis in patients with premature CAD. [...]the underrecognition of rare genetic causes of premature CAD may hinder opportunities to improve patient outcomes through precision interventions. Most rare genetic diseases identified, except for autosomal dominant CAD caused by LRP6 mutation, currently have specific treatment strategies [Table 1]. [...]eight of the nine patients with positive diagnoses may benefit from WES through precision disease management. Multivariate logistic regression revealed that elevated LDL-C levels (defined as >3.4 mmol/L in the Chinese population) were significantly and independently associated with positive genetic diagnosis using WES after adjusting for sex, region of birth, and other cardiometabolic risk factors (odds ratio, 7.160; 95% confidence interval [CI], 1.430–35.843; P = 0.017) [Supplementary Table 10, http://links.lww.com/CM9/B879]. Patients (Age [years]/sex) CAD Gene cDNA change Protein change ACMG class Disease Precision managements Classical FH in premature CAD 41/F STEMI LDLR c.1448G>A p.Trp483* P FH Intensive cholesterol-reducing therapies (high-potency statins, ezetimibe, and PCSK9 inhibitors), cascade screening in first-degree relatives 39/M NSTEMI LDLR c.1529C>T p.Thr510Met LP FH 39/M UA LDLR c.1747C>T p.His583Tyr LP FH 35/M STEMI APOB c.10579C>T p.Arg3527Trp P FH 38/M UA APOB c.10579C>T p.Arg3527Trp P FH Other monogenic diseases in premature CAD 36/F UA ABCG5 c.1166G>A p.Arg389His P Sitostero lemia Dietary restriction on plant sterol; Ezetimibe 44/M AMI LRP6 c.1252T>C p.Tyr418His LP ADCAD2 NA 44/M CCS PLIN1 c.598+1G>T p.? LP FPLD4 Metreleptin[4] 41/M NSTEMI ABCC6 c.2542delA p.Met848fs P PXE Etidronate[5] †Complete information on the variants is provided in Supplementary Tables 5 and 6, http://links.lww.com/CM9/B879, and clinical information is provided in Supplementary Tables 11, http://links.lww.com/CM9/B879. *Premature stop codon. p.? a symbol used to indicate uncertainty about the effect of the splicing variant on the protein level.