Cerebellar and Pontocerebellar Hypoplasia
Gene: RFC4EnsemblGeneIds (GRCh38): ENSG00000163918
EnsemblGeneIds (GRCh37): ENSG00000163918
OMIM: 102577, Gene2Phenotype
RFC4 is in 5 panels
2 reviews
Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Morimoto-Ryu-Malicdan neuromuscular syndrome, MIM# 621010
Chirag Patel (Genetic Health Queensland)
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: LiteratureCreated: 5 Sep 2024, 5:05 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
RFC4-related multisystem disorder
Publications
- PMID: 39106866
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
-
- PMID: 39106866
- Panels with this gene
History Filter Activity
Entity classified by Genomics England curator
Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)Gene: rfc4 has been classified as Green List (High Evidence).
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
Entity classified by Genomics England curator
Chirag Patel (Genetic Health Queensland)Gene: rfc4 has been classified as Green List (High Evidence).
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 Cerebellar and Pontocerebellar Hypoplasia. 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