Paediatric or syndromic cardiomyopathy

Gene: NEXN

The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 26 Sep 2024, 3:01 p.m. | Last Modified: 26 Sep 2024, 3:01 p.m.

Panel Version: 5.12

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Green List (high evidence)

Comment on mode of inheritance: As reviewed by Hannah Robinson, there is sufficient evidence available for updating the MOI from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' in the next GMS update.

Created: 11 Jun 2024, 3:21 p.m. | Last Modified: 11 Jun 2024, 3:21 p.m.

Panel Version: 4.7

PMID:32058062 - One male foetus was reported with compound heterozygous NEXN variants (c.1756A > T & c.1909_1912del) and dilated cardiomyopathy.

PMID:33027564 - One case was identified with dilated and hypertrophic cardiomyopathy and with compound heterozygous NEXN variants (p.Arg216Ter & p.Lys536fs). However, it was not possible to determine the phase (whether cis or trans) on the basis of exome sequencing.

PMID:33949776 - One patient presented with fetal hydrops at 33  weeks gestation requiring emergency caesarian delivery. Postnatally she required ventilation and continuous inotropic support for left ventricle systolic dysfunction. She died after 2 weeks when therapy was withdrawn. Homozygous c.1174C > T (p.Arg392Ter) variant in the NEXN gene was identified in this patient.

PMID:35166435 - A female from a four-generation Swedish family comprising 42 individuals had three three consecutive pregnancies with intrauterine fetal deaths caused by a lethal form of dilated cardiomyopathy. Homozygous NEXN variant (c.1302del/ p.Ile435Serfs*3) was identified in these foetuses.

In addition to these peer reviewed cases, additional biallelic cases were reported in the following reports: 10.1016/j.jsha.2013.03.180 & 10.1016/j.gimo.2023.100620.

The phenotypes associated with monoallelic variants are already reported in OMIM. However, phenotypes associated with biallelic variants are not yet reported either in OMIM or in Gene2Phenotype.

Created: 11 Jun 2024, 3:19 p.m. | Last Modified: 11 Jun 2024, 3:19 p.m.

Panel Version: 4.6

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Publications

• 32058062
• 33027564
• 33949776
• 35166435

Multiple cases with biallelic NEXN variants presenting with severe, early-onset DCM, often presenting during the second or third trimesters of pregnancy. Neonatal presentations also reported.

Al‐Hassnan ZN, Almesned A, Tulbah S, Al‐Manea W, Al‐Fayyadh M. Identification of a novel homozygous NEXN gene mutation in recessively inherited dilated cardiomyopathy. Journal of the Saudi Heart Association 2013;25(2):171–172. DOI:10.1016/j.jsha.2013.03.180

Bruyndonckx L, Vogelzang JL, Bugiani M, Straver B, Kuipers IM, Onland W, et al. Childhood onset nexilin dilated cardiomyopathy: A heterozygous and a homozygous case. Am J Med Genet A. 2021;185(8):2464-2470. DOI: 10.1002/ajmg.a.62231

Johansson J, Frykholm C, Ericson K, Kazamia K, Lindberg A, Mulaiese N, et al. Loss of Nexilin function leads to a recessive lethal fetal cardiomyopathy characterized by cardiomegaly and endocardial fibroelastosis. Am J Med Genet A. 2022;188(6):1676-1687. DOI: 10.1002/ajmg.a.62685

Sparks T, Lianoglou B, Adami R, Pluym I, Holliman K, Duffy J, et al. Exome Sequencing for Prenatal Diagnosis in Nonimmune Hydrops Fetalis. N Engl J Med. 2020;383(18):1746-1756. doi:10.1056/NEJMoa2023643

Rinaldi B, Race V, Corveleyn A, Van Hoof E, Bauters M, Van Den Bogaert K, et al. Next-generation sequencing in prenatal setting: Some examples of unexpected variant association. European Journal of Medical Genetics. 2020; 63(5): 103875

Thornton C, Mizerik E, Brooks D, Murali C, Parobek C, Potocki L, et al. P573: Biallelic missense NEXN variants lead to recessive severe neonatal cardiomyopathy. Genetic in medicine open. 2023; 1(1): 100620. doi: https://doi.org/10.1016/j.gimo.2023.100620

Created: 7 May 2024, 8:29 a.m. | Last Modified: 7 May 2024, 8:29 a.m.

Panel Version: 4.3

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Publications

• 35166435
• 33949776
• 33027564
• 32058062

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Submitted on behalf of the GMS Cardiology specialist group. The group has agreed that this gene should be Green on this panel.

Created: 2 Dec 2019, 3:58 p.m. | Last Modified: 2 Dec 2019, 3:58 p.m.

Panel Version: 0.16

Green List (high evidence)

Cardiomyopathy, dilated, 1CC OMIM#613122; Cardiomyopathy, hypertrophic, 20 OMIM#613876

Created: 25 Mar 2019, 4:30 p.m.

HGMD: 31 variants assoc with DCM only 10 DM. Included in review of DCM genes: Dalin 2017 International Journal of Cardiology 228 (2017) 742748, Hershberger 2013 Nat Rev Cardiol 10:531. Generally AD adult onset but a poster presentation presented a homozyogous variant in paediatric onset DCM: Al-Hassnan J Saudi Heart Assoc 2013;25:113172

Created: 25 Mar 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Variants in this GENE are reported as part of current diagnostic practice