The Importance of Genetic Counseling, DNA Diagnostics, and Cardiologic Family Screening in Left Ventricular Noncompaction Cardiomyopathy

Abstract

Background-Left ventricular (LV) noncompaction (LVNC) is a distinct cardiomyopathy featuring a thickened bilayeredLV wall consisting of a thick endocardial layer with prominent intertrabecular recesses with a thin, compact epicardial layer. Similar to hypertrophic and dilated cardiomyopathy, LVNC is genetically heterogeneous and was recently associated with mutations in sarcomere genes. To contribute to the genetic classification for LVNC, a systematic cardiological family study was performed in a cohort of 58 consecutively diagnosed and molecularly screened patients with isolated LVNC (49 adults and 9 children). Methods and Results-Combined molecular testing and cardiological family screening revealed that 67% of LVNC is genetic.Cardiological screening with electrocardiography and echocardiography of 194 relatives from 50 unrelated LVNC probands revealed familial cardiomyopathy in 32 families (64%), including LVNC, hypertrophic cardiomyopathy, and dilated cardiomyopathy. Sixty-three percent of the relatives newly diagnosed with cardiomyopathy were asymptomatic. Of 17 asymptomatic relatives with a mutation, 9 had noncompaction cardiomyopathy. Clinical Perspective on p 239Prevalence of LVNC, estimated from retrospective studies, ranges from 4.5 to 26 per 10 000 adult patients referred for echocardiography. 3-5 LVNC was diagnosed in 3.7% of patients with an LV ejection fraction Յ45%, suggesting that LVNC might not be a rare disorder in adults. 5 In pediatric series, LVNC is the most frequent cardiomyopathy after dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), comprising Ϸ9% of childhood cardiomyopathies. 6 Clinical features include heart failure, arrhythmias, and thromboembolic events. 3,7 Familial disease was estimated to occur in Ϸ18% to 50% of adults with isolated LVNC, mostly consistent with an autosomal dominant mode of inheritance. 3,8 -13 Intrafamilial phenotypic variability, including LVNC, HCM, and DCM, suggests that these cardio- and rare chromosomal defects and loci. [23][24][25][26][27][28][29][30] The present study investigates the heredity of LVNC, the spectrum of clinical features, and the genetic causes of LVNC by combining systematic cardiological family studies with extensive molecular analysis. Methods Study PopulationThe study comprised 58 unrelated patients with isolated LVNC; 53 were diagnosed consecutively from 2005 to 2008 in the cardiogenetics clinic of the Erasmus MC in Rotterdam and 5 in other tertiary referral centers in The Netherlands. All fulfilled the 4 echocardiographic diagnostic Jenni criteria: (1) excessively thickened LV myocardial wall with a 2-layered structure comprising a compact epicardial layer (C) and a noncompacted endocardial layer (NC) of prominent trabeculations and deep intertrabecular recesses; (2) maximal end-systolic ratio of noncompacted to compacted wall Ͼ2 measured at the parasternal short axis; (3) color Doppler evidence of deep perfused intertrabecular recesses; and (4) absence of coexisting Hoedemaekers et al Family Study of Noncompa...

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

“…9,12 This study confirms our previous results demonstrating that pathogenic variants in another sarcomeric protein gene, MYBPC3, can also lead to LVNC (OMIM number #615396, LVNC10). 9,13 MYBPC3 mutations in HCM lead to an altered primary contractile function.…”

“…Like HCM, LVNC is genetically heterogeneous. 9,12 Recently, LVNC was shown to be mainly caused by heterozygous variants in genes encoding sarcomeric Biallelic pathogenic MYBPC3 mutations in neonates MW Wessels et al 15 e Not clear whether these variants are in cis or in trans. f A third variant in MYH7 was found.…”

“…All coding regions and intron-exon boundaries of the MYBPC3 gene were analyzed by direct sequencing analysis as described. 9 In addition, MLPA analysis of the MYBPC3 gene was performed (SALSA MLPA kit P100, MRC Holland, Amsterdam, the Netherlands) to detect possible genomic rearrangements. (MYBPC3 exon numbering according to NG_007667.1, DNA variants were numbered according to reference sequence LRG_386 (identical to reference sequence NM_000256.3) using HGVS nomenclature (www.HGVS.org)).…”

The pathogenicity of genetic variants previously associated with left ventricular non‐compaction

“…Hoedemaekers et al. (2010) performed a family screening with both molecular and clinical examinations in 58 patients with LVNC and their 194 family members. This screening revealed that 67% (39/58 patients with LVNC) had a genetic background with these variants.…”

Genetik der angeborenen Herzfehler

“…Mittels genetischer Diagnostik lässt sich mit 35-40 % im Vergleich zu AHF ein deutlich höherer Prozentsatz an Mutationen bei den betroffenen Personen mit LVNC identifizieren [23,25,29]. Dies könnte, trotz der großen Vielfalt an unterschiedlichen Genen, an einem gemeinsamen Entstehungsmechanismus liegen, der auf unterschiedliche Art und Weise während der Entwicklung gestört wird.…”