Loss of Nexilin function leads to a recessive lethal fetal cardiomyopathy characterized by cardiomegaly and endocardial fibroelastosis

Abstract

The Nexilin F‐Actin Binding Protein (Nexilin) encoded by NEXN is a cardiac Z‐disc protein important for cardiac function and development in humans, zebrafish, and mice. Heterozygote variants in the human NEXN gene have been reported to cause dilated and hypertrophic cardiomyopathy. Homozygous variants in NEXN cause a lethal form of human fetal cardiomyopathy, only described in two patients before. In a Swedish, four‐generation, non‐consanguineous family comprising 42 individuals, one female had three consecutive pregnancies with intrauterine fetal deaths caused by a lethal form of dilated cardiomyopathy. Whole‐exome sequencing and variant analysis revealed that the affected fetuses were homozygous for a NEXN variant (NM_144573:c.1302del;p.(Ile435Serfs*3)). Moreover, autopsy and histology staining declared that they presented with cardiomegaly and endocardial fibroelastosis. Immunohistochemistry staining for Nexilin in the affected fetuses revealed reduced antibody staining and loss of striation in the heart, supporting loss of Nexilin function. Clinical examination of seven heterozygote carriers confirmed dilated cardiomyopathy (two individuals), other cardiac findings (three individuals), or no cardiac deviations (two individuals), indicating incomplete penetrance or age‐dependent expression of dilated cardiomyopathy. RNA sequencing spanning the variant in cDNA blood of heterozygote individuals revealed nonsense‐mediated mRNA decay of the mutated transcripts. In the current study, we present the first natural course of the recessively inherited lethal form of human fetal cardiomyopathy caused by loss of Nexilin function. The affected family had uneventful pregnancies until week 23–24, followed by fetal death at week 24–30, characterized by cardiomegaly and endocardial fibroelastosis.

NEXN Gene in Cardiomyopathies and Sudden Cardiac Deaths: Prevalence, Phenotypic Expression, and Prognosis

“…8 Furthermore, the homozygous p.(Glu528del) deletion has been identified in 2 siblings with severe DCM. 7 Recently, Johansson 15 reported on a fetus who died of severe DCM and who was homozygous for the p.(Ile435Serfs*3) variant. Along with previous reports, our results suggest that homozygous and heteroallelic NEXN variants are associated with a severe, early onset DCM phenotype.…”

Two genetic variants in NEXN and ABCC6 genes found in a patient with right coronary artery to right ventricle fistula combined with giant coronary aneurysm and patent ductus arteriosus

“…Additionally, it is suggested to lead to ASDs by inhibiting the cardiac key transcription factor GATA4 in mice and humans ( 13 ). Heterozygous variants of NEXN have previously been described in dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) patients at a mean age of 50 years ( 31 – 33 ). Our patient, who carried the NEXN-G100X truncated variant, was 6 years old and had cardiomegaly with a slightly reduced cardiac function (EF = 51%).…”

Structural and signaling proteins in the Z-disk and their role in cardiomyopathies

“…It is considered an essential component of this complex where it participates in the development and maintenance of cardiac T-tubules (Liu et al, 2020;Spinozzi et al, 2020). In addition, this protein is essential for cardiac function and development (Johansson et al, 2022), and is involved in cell adhesion and migration in various tissues including cardiac and skeletal muscle tissues (Wang et al, 2005). Other roles include maintaining the integrity of the Z-disks against the tension generated within the sarcomere (Lopes and Elliott, 2014).…”

“…Frontiers in Physiology frontiersin.org for the NEXN variant (p.Ile435SerfsTer3). Histology revealed cardiomegaly and endocardial fibroelastosis, with immunohistochemical staining using a polyclonal nexilin antibody showing loss of striation in the heart (Johansson et al, 2022).…”