A novel donor site mutation in LMNA gene leading to severe form of Dilated Cardiomyopathy in a proband of a family from Bihar, India

Abstract

Background: Dilated Cardiomyopathy (DCM) is poorly understood in terms of their mechanistic pathways. It may lead to sudden cardiac death with a prevalence rate of 0.04%. The cause of DCM is still unknown and referred as Idiopathic Dilated Cardiomyopathy. There are many candidate genes associated with the DCM but most of the mutations are found in the LMNA and MYH7 genes. Aim: To report the clinical phenotype of a patient with novel mutation in the donor site region of LMNA gene. Methods: The proband underwent 2-D, M-Mode Echocardiography and ECG to confirm the diagnosis. 5ml Intravenous blood sample was collected and DNA was extracted using Phenol-chloroform method. The hot spot regions exon 23 of MYH7 gene, exon3 and exon 4 along with the intron3 of LMNA gene were sequenced using Sanger sequencing (ABI 3730xl). Polymorphisms 287bp I/D in intron 16 of ACE and 5bp I/D intron 3 of TNNT2 genes were also analyzed. The study was ethically approved by Institutional committee and informed written consent was taken from all participants. Results: The proband aged 45yrs diagnosed with DCM, showing severe symptoms such as dyspnea, palpitation, fatigue and pedal edema under NYHA III classification undergone echocardiography showing dilated LV with ejection fraction of 30%. Proband's mother died due to some heart disease but was not clinically confirmed for DCM and his sister had a suspicious death. A Novel donor splice site mutation G>C transversion in intron3 was found in LMNA gene and a synonymous mutation (C>T at codon 923) was found in MYH7 gene in the proband. ACE and TNNT2 polymorphisms showed a heterozygous (ID) and homozygous (II) genotypes respectively. Conclusion: As reported in previous studies, LMNA gene mutations are associated to the severe form of Dilated Cardiomyopathy. From the above results, it may be concluded that the severe form of the disease is due to the splice site mutation. Screening of the available family members is in progress.