Mutations in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy

Abstract

ObjectiveUp to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. TRIM63 has been suggested as a candidate gene for the development of cardiomyopathies, although evidence for a causative role in HCM is limited. We sought to investigate the relationship between rare variants in TRIM63 and the development of HCM.MethodsTRIM63 was sequenced by next generation sequencing in 4867 index cases with a clinical diagnosis of HCM and in 3628 probands with other cardiomyopathies. Additionally, 3136 index cases with familial cardiovascular diseases other than cardiomyopathy (mainly channelopathies and aortic diseases) were used as controls.ResultsSixteen index cases with rare homozygous or compound heterozygous variants in TRIM63 (15 HCM and one restrictive cardiomyopathy) were included. No homozygous or compound heterozygous were identified in the control population. Familial evaluation showed that only homozygous and compound heterozygous had signs of disease, whereas all heterozygous family members were healthy. The mean age at diagnosis was 35 years (range 15–69). Fifty per cent of patients had concentric left ventricular hypertrophy (LVH) and 45% were asymptomatic at the moment of the first examination. Significant degrees of late gadolinium enhancement were detected in 80% of affected individuals, and 20% of patients had left ventricular (LV) systolic dysfunction. Fifty per cent had non-sustained ventricular tachycardia. Twenty per cent of patients suffered an adverse cerebrovascular event (20%).ConclusionTRIM63 appears to be an uncommon cause of HCM inherited in an autosomal-recessive manner and associated with concentric LVH and a high rate of LV dysfunction.

Genome-wide association study of cardiac troponin I in the general population

“…Both gene sets link the cTnI loci to cardiac structure. Finally, DEPICT prioritized several genes in the cTnI loci that were associated with heart development, structure and function, and with cardiovascular diseases: NRAP , which is located in the HABP2 locus, is involved in sarcomere assembly during cardiomyocyte development ( 48 ) and is associated with familial cardiomyopathies ( 49 ), and mutations in TRIM63 have been associated with left-ventricular dysfunction and hypertrophic cardiomyopathy ( 50 ). Likewise, SYNPO2L , which is located in the second most significant locus on chromosome 10, but further away from the index variant than VCL , is involved in sarcomeric signal transduction ( 51 ) and cardiac development ( 52 ).…”

Investigation of candidate genes and mechanisms underlying obesity associated type 2 diabetes mellitus using bioinformatics analysis and screening of small drug molecules

“…Matsha et al [ 170 ] and Ding et al [ 171 ] demonstrated that hsa-mir-1299 and hsa-mir-4530 were the miRNAs liable for progression of type 2 diabetes mellitus. Hall et al [ 172 ] and Salazar-Mendiguchía et al [ 173 ] reported that FLNC (filamin C) and TRIM63 were the genes involved in progression of cardio vascular disease, but these genes might be essential for development of obesity associated type 2 diabetes mellitus. Xiao et al [ 174 ], Stratigopoulos et al [ 175 ] and Zhou et al [ 176 ] noted that ATF4, CUX1 and ZBTB7A were the genes responsible for advancement of obesity.…”

Identification of biomarkers, pathways and potential therapeutic targets for heart failure using bioinformatics analysis

“…[109], FGF12 [110], AQP4 [111], LMOD2 [112], SELENBP1 [113], MB (myoglobin) [114], S100A1 [115], RYR2 [116], GPC5 [117], JARID2 [118], EGFR (epidermal growth factor receptor) [119], FUNDC1 [120], S1PR1 [121], EPAS1 [122] and OSBPL11 [123] genes are a potential biomarkers for the detection and prognosis of HF at an early age. A previous study reported that CALR (calreticulin) [124], BSCL2 [125], PKD1 [126], TMBIM1 [127], CHST15 [128], NAA10 [129], TCF3 [130], CNN1 [131], TAF1A [132], ACAD9 [133], KLHL24 [134], MYOM2 [135], TRIM63 [136] [210] are the key biomarkers in cardiac hypertrophy. Previous studies had shown that the expression of CLIC1 [211], ARPC1B [212], FLNA (filamin A) [213], HILPDA (hypoxia inducible lipid droplet associated) [214], RTN3 [215], G0S2 [216], CALU (calumenin) [ [239], NCOA2 [240], ZBTB16 [241], TFAM (transcription factor A, mitochondrial) [242], RASAL2 [243], NDUFB6 [244], HELZ2 [245] and CIITA (class II major histocompatibility complex transactivator) [246] were reported to be expressed in obesity, but these genes might be novel target for HF.…”