Prevalence and Clinical Consequences of Multiple Pathogenic Variants in Dilated Cardiomyopathy.

Autor:	Stroeks SLVM; Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands.; KU Leuven, Cardiovascular Sciences, Belgium (S.L.V.M.S., E.A.V.J., S.R.B.H.)., Lunde IG; Genetics, Harvard Medical School, Boston, MA (I.G.L., H.W., J.G.).; Diagnostics and Technology, Akershus University Hospital, Oslo, Norway (I.G.L.)., Hellebrekers DMEI; Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.)., Claes GRF; Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.)., Wakimoto H; Genetics, Harvard Medical School, Boston, MA (I.G.L., H.W., J.G.)., Gorham J; Genetics, Harvard Medical School, Boston, MA (I.G.L., H.W., J.G.)., Krapels IPC; Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.)., Vanhoutte EK, van den Wijngaard A; Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.)., Henkens MTHM, Raafs AG; Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands., Sikking MA; Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands., Broers JLV; Genetics and Cell Biology (J.L.V.B., M.N.), Maastricht University, Maastricht, Netherlands., Nabben M; Genetics and Cell Biology (J.L.V.B., M.N.), Maastricht University, Maastricht, Netherlands., Jones EAV; Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands.; KU Leuven, Cardiovascular Sciences, Belgium (S.L.V.M.S., E.A.V.J., S.R.B.H.)., Heymans SRB; KU Leuven, Cardiovascular Sciences, Belgium (S.L.V.M.S., E.A.V.J., S.R.B.H.)., Brunner HG; Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.).; Radboud University Medical Center, Human Genetics, Nijmegen, the Netherlands (H.G.B.)., Verdonschot JAJ; Cardiovascular Research Institute Maastricht (CARIM); S.L.V.M.S., T.H.M.H., A.G.R., M.A.S., E.A.V.J., S.R.B.H., J.A.J.V.), Maastricht University, Maastricht, Netherlands.; Clinical Genetics, Maastricht University Medical Center, the Netherlands (D.M.E.I.H., G.R.F.C., I.P.C.K., E.P.K., A.v.d.W., H.G.B., J.A.J.V.).
Jazyk:	angličtina
Zdroj:	Circulation. Genomic and precision medicine [Circ Genom Precis Med] 2023 Apr; Vol. 16 (2), pp. e003788. Date of Electronic Publication: 2023 Mar 27.
DOI:	10.1161/CIRCGEN.122.003788
Abstrakt:	Background: Dilated cardiomyopathy (DCM) was considered a monogenetic disease that can be caused by over 60 genes. Evidence suggests that the combination of multiple pathogenic variants leads to greater disease severity and earlier onset. So far, not much is known about the prevalence and disease course of multiple pathogenic variants in patients with DCM. To gain insight into these knowledge gaps, we (1) systematically collected clinical information from a well-characterized DCM cohort and (2) created a mouse model. Methods: Complete cardiac phenotyping and genotyping was performed in 685 patients with consecutive DCM. Compound heterozygous digenic (LMNA [lamin]/titin deletion A-band) with monogenic (LMNA/wild-type) and wild-type/wild-type mice were created and phenotypically followed over time. Results: One hundred thirty-one likely pathogenic/pathogenic (LP/P) variants in robust DCM-associated genes were found in 685 patients with DCM (19.1%) genotyped for the robust genes. Three of the 131 patients had a second LP/P variant (2.3%). These 3 patients had a comparable disease onset, disease severity, and clinical course to patients with DCM with one LP/P. The LMNA/Titin deletion A-band mice had no functional differences compared with the LMNA/wild-type mice after 40 weeks of follow-up, although RNA-sequencing suggests increased cardiac stress and sarcomere insufficiency in the LMNA/Titin deletion A-band mice. Conclusions: In this study population, 2.3% of patients with DCM with one LP/P also have a second LP/P in a different gene. Although the second LP/P does not seem to influence the disease course of DCM in patients and mice, the finding of a second LP/P can be of importance to their relatives.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu