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Muscular dystrophy and myopathy_Paediatric v1.79 RFC4 Zornitza Stark Marked gene: RFC4 as ready
Muscular dystrophy and myopathy_Paediatric v1.79 RFC4 Zornitza Stark Gene: rfc4 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.79 RFC4 Zornitza Stark Phenotypes for gene: RFC4 were changed from Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010 to Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010
Muscular dystrophy and myopathy_Paediatric v1.79 RFC4 Zornitza Stark Phenotypes for gene: RFC4 were changed from RFC4-related multisystem disorder to Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010
Muscular dystrophy and myopathy_Paediatric v1.78 RFC4 Zornitza Stark reviewed gene: RFC4: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Muscular dystrophy and myopathy_Paediatric v1.70 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.70 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.69 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.69 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.69 RFC4 Chirag Patel Classified gene: RFC4 as Green List (high evidence)
Muscular dystrophy and myopathy_Paediatric v1.69 RFC4 Chirag Patel Gene: rfc4 has been classified as Green List (High Evidence).
Muscular dystrophy and myopathy_Paediatric v1.68 RFC4 Chirag Patel 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
Added comment: 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