Muscular dystrophy and myopathy_Paediatric

Gene: RFC4

Green List (high evidence)

RFC4 (replication factor C subunit 4)
EnsemblGeneIds (GRCh38): ENSG00000163918
EnsemblGeneIds (GRCh37): ENSG00000163918
OMIM: 102577, Gene2Phenotype
RFC4 is in 5 panels

2 reviews

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010

Chirag Patel (Genetic Health Queensland)

Green List (high evidence)

9 affected individuals (aged birth to 47yrs) from 8 unrelated families with a multisystem disorder. Clinical features included: muscle weakness/myopathy (9/9), motor incoordination/gait disturbance (8/8), delayed gross motor development (6/9), dysarthria (5/5), peripheral neuropathy (3/3 adults), bilateral sensorineural hearing impairment (6/9), decreased body weight (8/9), short stature (5/9), microcephaly (4/9), respiratory issues/insufficiency (6/9), cerebellar atrophy (4/9), pituitary hypoplasia (3/9).

WES or WGS identified biallelic loss-of-function variants in RFC4 (3 frameshift, 2 splice site, 1 single AA duplication, 2 single AA deletions, 2 missense), and almost all are likely to disrupt the C-terminal domain indispensable for Replication factor C (RFC) complex formation. All variants segregated with the disease.

The RFC complex (with 5 subunits) is central to process of regulation of DNA replication, and it loads proliferating cell nuclear antigen onto DNA to facilitate the recruitment of replication and repair proteins and enhance DNA polymerase processivity. RFC1 is associated with CANVAS but the contributions of RFC2-5 subunits on human Mendelian disorders is unknown.

Analysis of a previously determined cryo-EM structure of RFC bound to proliferating cell nuclear antigen suggested that the variants disrupt interactions within RFC4 and/or destabilize the RFC complex. Cellular studies using RFC4-deficient HeLa cells and primary fibroblasts demonstrated decreased RFC4 protein, compromised stability of the other RFC complex subunits, and perturbed RFC complex formation. Additionally, functional studies of the RFC4 variants affirmed diminished RFC complex formation, and cell cycle studies suggested perturbation of DNA replication and cell cycle progression.
Sources: Literature
Created: 5 Sep 2024, 5:05 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
RFC4-related multisystem disorder

Publications

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

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010
OMIM
102577
Clinvar variants
Variants in RFC4
Penetrance
None
Publications
Panels with this gene

History Filter Activity

15 Nov 2024, Gel status: 3

Entity classified by Genomics England curator

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Gene: rfc4 has been classified as Green List (High Evidence).

15 Nov 2024, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: RFC4 were changed from Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010 to Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010

15 Nov 2024, Gel status: 3

Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Phenotypes for gene: RFC4 were changed from RFC4-related multisystem disorder to Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010

5 Sep 2024, Gel status: 3

Entity classified by Genomics England curator

Chirag Patel (Genetic Health Queensland)

Gene: rfc4 has been classified as Green List (High Evidence).

5 Sep 2024, Gel status: 3

Entity classified by Genomics England curator

Chirag Patel (Genetic Health Queensland)

Gene: rfc4 has been classified as Green List (High Evidence).

5 Sep 2024, Gel status: 3

Entity classified by Genomics England curator

Chirag Patel (Genetic Health Queensland)

Gene: rfc4 has been classified as Green List (High Evidence).

5 Sep 2024, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Chirag Patel (Genetic Health Queensland)

gene: RFC4 was added gene: RFC4 was added to Muscular dystrophy and myopathy_Paediatric. Sources: Literature Mode of inheritance for gene: RFC4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RFC4 were set to PMID: 39106866 Phenotypes for gene: RFC4 were set to RFC4-related multisystem disorder Review for gene: RFC4 was set to GREEN gene: RFC4 was marked as current diagnostic