Cardiomyopathy_Paediatric

Gene: RRAGC

Green List (high evidence)

PMID:37057673 reports three patients with de novo missense variants (p.Thr90Asn, p.Pro118Leu, p.Trp115Arg). Patient one presented with ASD, VSD, global restrictive biventricular dysfunction, dilation of the right atrium, pachygyria and polymicrogyria. Patient two presented with motor developmental delay, cardiac failure (dilatation of left ventricle), septo-optic dysplasia (Bilateral cataracts & optic nerve hypoplasia) and liver dysfunction. Patient three presented with fetal hydrops, right ventricular enlargement, tricuspid valve insufficiency, severe DCM, cavum septum pellucidum and bilateral subependymal cysts. All three patients died due to cardiac failure.

Functional studies in fibroblasts from patient one, and transfection studies in HEK293 cells suggested constitutive over-activation of the mTORC1 pathway.

This publication also references PMID: 33057194, which aimed to identify de novo variants in a cohort of patients with a developmental disorder. A de novo RRAGC variant (p.Trp115Arg) was identified with no clinical details provided in the study, however it was later ascertained that this individual suffered from cardiomyopathy.

PMID: 27234373 reports a patient who was diagnosed with fetal cardiomegaly at 30 weeks gestation, who also presented with fetal hydrops. Postnatal echocardiography revealed severe biventricular and biatrial chamber enlargement, severe systolic, a small apical ventricular septal defect, and a moderate secundum atrial septal defect. Mild facial dysmorphism and bilateral cataracts were also identified. Died at 22 months of age with multisystem organ failure due to severe, end-stage heart failure. A de novo missense variant was identified (p.Ser75Tyr), and in vitro functional studies demonstrated activation of mTORC1 signaling.

Note that reported variants are recurring.

Created: 4 May 2023, 3:51 a.m. | Last Modified: 4 May 2023, 3:51 a.m.

Panel Version: 0.157

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Dilated cardiomyopathy (MONDO:0005021), RRAGC-related

Publications

• PMID:37057673
• 27234373
• 33057194

Red List (low evidence)

Functional studies support impact of variant on protein function rather than gene-disease association per se.

Created: 25 Aug 2020, 3:29 a.m. | Last Modified: 25 Aug 2020, 3:29 a.m.

Panel Version: 0.3

I don't know

PMID: 29367541 - 1 de novo patient (missense) w/ paediatric cardiomyopathy

PMID: 27234373 - same de novo missense as above, functional studies show a GOF mechanism

MIssense variant is absent from the population (gnomAD) and in a highly constrained region (Decipher)
Sources: Literature

Created: 25 Aug 2020, 12:37 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Pediatric Dilated Cardiomyopathy

Publications

• PMID: 29367541
• 27234373

Mode of pathogenicity
Other