GRINL1A Complex Transcription Unit Containing GCOM1, MYZAP, and POLR2M Genes Associates with Fully Penetrant Recessive Dilated Cardiomyopathy

Abstract

Background: Familial dilated cardiomyopathy (DCM) is a monogenic disorder typically inherited in an autosomal dominant pattern. We have identified two Finnish families with familial cardiomyopathy that is not explained by a variant in any previously known cardiomyopathy gene. We describe the cardiac phenotype related to homozygous truncating GCOM1 variants. Methods and Results: This study included two probands and their relatives. All the participants are of Finnish ethnicity. Whole-exome sequencing was used to test the probands; bi-directional Sanger sequencing was used to identify the GCOM1 variants in probands' family members. Clinical evaluation was performed, medical records and death certificates were obtained. Immunohistochemical analysis of myocardial samples was conducted. A homozygous GCOM1 variant was identified altogether in six individuals, all considered to be affected. None of the nine heterozygous family members fulfilled any cardiomyopathy criteria. Heart failure was the leading clinical feature, and the patients may have had a tendency for atrial arrhythmias. Conclusions: This study demonstrates the significance of GCOM1 variants as a cause of human cardiomyopathy and highlights the importance of searching for new candidate genes when targeted gene panels do not yield a positive outcome.

Keywords: GCOM1; MYZAP; autosomal recessive; cardiomyopathy; dilated cardiomyopathy.

FIGURE 1

Four GRINL1A transcripts. Abbreviations: aa for amino acid, SEG for low complexity region; NDS for asparagine-linked glycosylation site; BRLZ for BRLZ leucine zipper; SP for signal peptide. The two GCOM1 variants are marked in red; Arg130* for GCOM1 c.388C > T, p.(Arg130*) and Lys384* for GCOM1 c.1150 A > T, p.(Lys384*) (Roginski et al., 2004; Seeger et al., 2010; Roginski et al., 2018).

FIGURE 2

Pedigrees of two families. Family one is affected with GCOM1 c.388C > T, p.(Arg130*) variant, Family 2 with GCOM1 c.1150 A > T, p.(Lys384). Circles represent women, squares men. Black symbols represent individuals who fulfil cardiomyopathy criteria. Grey symbol represents cardiomyopathy of other etiology. Arrow indicates proband. Genotypes: + / + homozygous and + / - heterozygous for the GCOM1 c.1150 A > T, p.(Lys384*); + / +* homozygous and +/ −* heterozygous the for GCOM1 c.388C > T, p.(Arg130*), − / − wild type allele. Clinical features are listed below the symbols; Age–age at the time of clinical examination or at the time of death, LVEDD left ventricular end-diastolic diameter (mm), LVEF left ventricular ejection fraction (%), pacemaker/cardiac transplant: + indicates yes,–indicates no, ToF Tetralogy of Fallot.

FIGURE 3

CMR images of the proband (Family 1, II.1), affected family member with homozygous GCOM1 p.(Arg130*) (Family 1, II.2), and affected family member with no familial mutation but DCM secondary to lymphocytic myocarditis (Family 1, II.4). Both homozygotes (II.1, II.2) presented mid-wall LGE in the septum (arrows) and subepicardial enhancement in the inferolateral areas (dashed arrow). The genotype negative patient (II.4) exhibited multifocal and patchy LGE involving several layers of the myocardium.

FIGURE 4

Histological samples. Myozap-staining of myocardial samples from homozygotes (Family 1: II.1 and Family 2: II.4, II.9, II.10) show clear loss of staining when compared to the wild type GCOM1 control samples. Controls with primary antibody omitted or substituted with rabbit non-immune IgG showed no staining (Data not shown).