Genetic architecture of left ventricular noncompaction in adults

Abstract

The genetic etiology and heritability of left ventricular noncompaction (LVNC) in adults is unclear. This study sought to assess the value of genetic testing in adults with LVNC. Adults diagnosed with LVNC while undergoing screening in the context of a family history of cardiomyopathy were excluded. Clinical data for 35 unrelated patients diagnosed with LVNC at ≥18 years of age were retrospectively analyzed. Left ventricular (LV) dysfunction, electrocardiogram (ECG) abnormalities, cardiac malformations or syndromic features were identified in 25 patients; 10 patients had isolated LVNC in the absence of cardiac dysfunction or syndromic features. Exome sequencing was performed, and analysis using commercial panels targeted 193 nuclear and mitochondrial genes. Nucleotide variants in coding regions or in intron-exon boundaries with predicted impacts on splicing were assessed. Fifty-four rare variants were identified in 35 nuclear genes. Across all 35 LVNC patients, the clinically meaningful genetic diagnostic yield was 9% (3/35), with heterozygous likely pathogenic or pathogenic variants identified in the NKX2-5 and TBX5 genes encoding cardiac transcription factors. No pathogenic variants were identified in patients with isolated LVNC in the absence of cardiac dysfunction or syndromic features. In conclusion, the diagnostic yield of genetic testing in adult index patients with LVNC is low. Genetic testing is most beneficial in LVNC associated with other cardiac and syndromic features, in which it can facilitate correct diagnoses, and least useful in adults with only isolated LVNC without a family history. Cardiac transcription factors are important in the development of LVNC and should be included in genetic testing panels.

Keywords: Genetic testing; Genetics research.

Fig. 1. Echocardiogram and cardiac magnetic resonance imaging in LVNC.

Left ventricular non-compaction from a representative subject from the study, on a, 2D-transthoracic echocardiogram, b, 2D-transthoracic echocardiogram with colour Doppler flow, and c, cardiac magnetic resonance imaging. Red arrows indicate regions of non-compaction.

Fig. 2. Pedigrees for three families; two with loss of function variants in NKX2-5, and one with a loss of function variant in TBX5.

a CBT family; II:5 experienced a sudden cardiac death (SCD), III:1 has a small segment of posterior LVNC non-compaction, III:2 has a bicuspid aortic valve (BAV), b Sanger sequencing revealing de novo NKX2-5 variant in II:4, c BHS family, d 2-D transthoracic echocardiogram with colour Doppler flow from BHS proband II:4, and e BRP family; II:2 has LVNC and Holt-Oram syndrome (HOS), III:2 has HOS and increased left ventricular trabeculation/possible LVNC, III:3 has HOS, IV:2 has HOS. Grey symbol = increased left ventricular trabeculation/possible LVNC; +/− = heterozygous for variant; −/− = normal; arrow indicates proband.

Fig. 3. Family with mitochondrial variant in MT-TV gene.

a BKS family pedigree, b variant identified in whole-exome sequencing data, c Sanger sequencing revealing variant in tRNA-valine, d variant position in mitochondrial tRNA valine. III:1 has neurological and cardiac involvement (LVNC and hypertrophy), II:4 experienced stroke at 21 years of age, III:4 and III:5 have muscle weakness and had developmental delay, III:2 has epilepsy and has experienced unexplained syncopal events. Grey symbols = individuals who have shown features consistent with mitochondrial disease however have not received a diagnosis.

Fig. 4. Summary of key study findings illustrating the clinical settings where genetic testing may be useful in patients with LVNC.

LVNC Left Ventricular Noncompaction, LV left ventricular, LVEF left ventricular ejection fraction.