2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Biallelic missense <em>NEXN</em> variants lead to recessive severe neonatal cardiomyopathy

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This document discusses a case study of a patient with severe neonatal-onset dilated cardiomyopathy (DCM) due to compound heterozygous missense variants in the NEXN gene. The NEXN gene encodes the protein Nexilin, which plays a role in stabilizing the sarcomere in the myocardium. Previous studies have shown that heterozygous pathogenic loss-of-function NEXN variants are associated with adult-onset autosomal dominant DCM and hypertrophic cardiomyopathy. However, this case study presents a unique scenario where two missense variants in the NEXN gene were identified, resulting in a less severe autosomal recessive presentation of DCM at two months of age.<br /><br />The patient in the case study presented with symptoms of tachycardia, tachypnea, failure to thrive, hoarseness, and dyspnea. Further evaluation revealed dysmorphic features, including microcephaly and rotated ears. Chest X-ray and echocardiogram confirmed the diagnosis of DCM with severe left ventricle dilation and depressed biventricular function. The patient required extracorporeal membrane oxygenation (ECMO) until 102 days of life.<br /><br />The document also mentions that previous studies have identified different genetic etiologies for DCM, but only a small percentage of cases can be attributed to known causative genes. The NEXN gene is one of the 19 genes known to be causative in DCM, explaining only 20-35% of cases. The genetic basis of DCM is complex, with heterozygous NEXN loss-of-function variants causing adult-onset DCM and homozygous NEXN loss-of-function variants causing severe neonatal-onset DCM.<br /><br />Overall, this case study contributes to the understanding of the genetic basis of DCM and highlights the importance of considering compound heterozygous missense variants in the NEXN gene as a cause of neonatal-onset DCM.

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Presenting Author - Casey A. Thornton, PhD; Co-Author - Elizabeth A. Mizerik, MS, CGC; Co-Author - Dan R. Brooks, MD; Co-Author - Chaya N. Murali, MD; Co-Author - Christian M. Parobek, MD, PhD; Co-Author - Lorraine Potocki, MD; Co-Author - Pengfei Liu, PhD, FACMG; Co-Author - Nichole Owen, PhD, FACMG; Co-Author - Liesbeth Vossaert, PhD, FACMG;

Meta Tag

Clinical History

Congenital Anomaly

Exome sequencing

Genetic Testing

Identification of Disease Genes

Inheritance Patterns

Phenotype

Co-Author Elizabeth A. Mizerik, MS, CGC

Co-Author Dan R. Brooks, MD

Co-Author Chaya N. Murali, MD

Co-Author Christian M. Parobek, MD, PhD

Co-Author Lorraine Potocki, MD

Co-Author Pengfei Liu, PhD, FACMG

Co-Author Nichole Owen, PhD, FACMG

Co-Author Liesbeth Vossaert, PhD, FACMG

Presenting Author Casey A. Thornton, PhD

Keywords

neonatal-onset dilated cardiomyopathy

NEXN gene

compound heterozygous missense variants

Nexilin protein

adult-onset autosomal dominant DCM

hypertrophic cardiomyopathy

autosomal recessive presentation

extracorporeal membrane oxygenation

genetic etiologies

causative genes