Genetics and Clinical Features of Noncompaction Cardiomyopathy in the Fetal Population

Abstract

Objectives: Noncompaction Cardiomyopathy (NCCM) has been classified as primary genetic cardiomyopathy and has gained increasing clinical awareness; however, little is known about NCCM in the fetal population. We aimed to investigate the clinical characteristics and genetic spectrum of a fetal population with NCCM.Methods: We retrospectively reviewed all fetuses with a prenatal diagnosis of NCCM at a single center between October 2010 and December 2019. These cases were investigated for gestational age at diagnosis, gender, left or biventricular involvement, associated cardiac phenotypes, outcomes, and genetic testing data.Results: We identified 37 fetuses with NCCM out of 49,898 fetuses, indicating that the incidence of NCCM in the fetal population was 0.07%. Of the 37 fetuses, 26 were male, ten were female and one was of unknown gender. NCCM involvement biventricle is the most common (n = 16, 43%), followed by confined to the left ventricle (n = 14, 38%). Nineteen (51%) had additional congenital heart defects, with right-sided lesions being the most common (n = 14, 74%), followed by ventricular septal defects (n = 10, 53%). Hydrops fetalis was present in 12 cases (32%), of which four were atypical (pericardial effusion only). Sequencing analysis was performed at autopsy (n = 19) or postnatally (n = 1) on 20 fetuses. Of the 20 fetuses undergoing copy number variation sequencing and whole-exome sequencing, nine (47%) had positive genetic results, including one with a pathogenic copy number variant and eight with pathogenic/likely pathogenic variants. Non-sarcomere gene mutations accounted for the vast majority (n = 7). In contrast, sarcomere gene mutations occurred in only one case (TPM1), and no mutations were identified in the three most common sarcomere genes (MYH7, TTN, and MYBPC3) of pediatric and adult patients. Pathogenic/likely pathogenic variants were significantly more frequent in fetuses with congenital heart defects than those without congenital heart defects.Conclusions: Our data demonstrate that fetal NCCM is a unique entity. Compared with pediatric and adult NCCM, fetal NCCM is more prone to biventricle involvement, more likely to be complicated with congenital heart defects, and has a distinct genetic spectrum.

Molecular Approaches in Fetal Malformations, Dynamic Anomalies and Soft Markers: Diagnostic Rates and Challenges—Systematic Review of the Literature and Meta-Analysis

“…For the quantitative analysis, 40 articles [121, were secondarily excluded. Of these, three papers focused on fetal demises or stillbirths [256][257][258], three papers focused on information postmortem [242,250,254], three were case reports [238,246,252], five focused on a single specific phenotype [240,241,248,261,274], three presented inhomogeneity in inclusion criteria and chromosomal anomalies/CNV assessment [239,251,262], six included both fetuses and postnatal cases [244,249,253,259,260,269], three focused on candidate genes [243,247,263], three focused on recurrent phenotypes or previously described cohorts [245,255,272], five were excluded for the lack of inclusion or eligibility criteria [264,265,268,271,276], two were excluded for the higher a priori risk for consanguinity and recurrence [266,270], one because parents were tested for recessive disorders [267], two because they focused on gene panels [273,275], and one due to the postnatal diagnosis [121].…”

A Novel Homozygous PKP2 Variant in Severe Neonatal Non-compaction and Concomitant Ventricular Septal Defect: A Case Report

“…The prevalence of CHD in LVNC was 20-50% depending on recruitment criteria, with VSD being the most common associated CHD (27-35%), followed by Ebstein's anomaly, atrial septal defect, and transposition of great arteries (1,2,6,18,22). When focusing on severe perinatal-onset LVNC, the higher prevalence of VSD (37-62%) was observed (21)(22)(23) and that apical muscular subtype appeared to be an unusually frequent finding compared with the general low prevalence, 10-20% (17).…”

“…A recent study of a large cohort of LVNC in fetal population showed a positive genetic test at 47% (9/20) and that mutations of non-sarcomeric genes accounted for the vast majority, including de novo dominant mutations of KCNH2 and PRKAG2 genes and maternally inherited X-linked gene mutations of NONO , with the exception of one case harboring a de novo mutation of a sarcomeric gene, TPM1 ( 21 ). The authors proposed that LVNC in fetal population with intrauterine onset heart failure might represent a unique entity and had distinct genetic spectrum ( 3 ).…”

Diverse cardiac phenotypes among different carriers of the same MYH7 splicing variant allele (c.732+1G>A) from a family

“…WES was performed as previously described [ 7 – 9 ]. Briefly, gDNA was extracted, hybridized, and enriched for sequencing.…”