FAM20C

Inheritance Pattern: AR

Disease ID:MONDO:0009821

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0009821

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0009821

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009821

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0009821

Submitter: ClinGen

FAM20C was first reported in relation to autosomal recessive Raine syndrome in 2007 (Simpson et al., PMID 27862258). Raine syndrome is also known as osteosclerotic bone dysplasia, lethal, and as osteomalacia, sclerosing, with cerebral calcification. Prenatal features have been identified as early as the first trimester, including FGR, cerebral alterations (large choroid plexuses, echogenic appearance of brain, intracerebral calcifications), brain structural defects (cortical dysplasia, cerebellar hypoplasia, gliosis, ocular defects, corpus callosum and hypophysis dysgenesis), bone sclerosis (usually long bones and skull), and a distinctive craniofacial phenotype (ocular proptosis and nasal hypoplasia with choanal atresia/stenosis and a flat facial profile). Raine syndrome was initially associated with death shortly after birth or in early infancy; the perinatal lethal phenotype includes severe craniofacial anomalies, respiratory distress, and severe choanal atresia. A non-lethal FAM20C-associated Raine syndrome phenotype was identified in 2009 (19250384), presenting with a variable neonatal phenotype, attenuated craniofacial anomalies, and age-related features including hypophosphatemic rickets, amelogenesis imperfecta, deformative brain defects, and functional neurological defects. The mechanism of pathogenicity appears to be loss of function of the FAM20C protein kinase activity. FAM20C is a protein kinase that phosphorylates secreted phosphoproteins and acts on substrates with known roles in regulating biomineralization. It has ubiquitous expression, especially in mineralized tissues. Lethality is associated with absence or significant impairment of kinase activity, while non-lethality is associated with nonsense or truncated proteins with missense variants that maintain the kinase domain. Pathogenic variants have been identified in all exons. All splicing variants are lethal, and pathogenic variants associated with lethal versus non-lethal Raine are situated close to functional protein regions such as catalytic, dimerization and glycosylation sites. Family variants are common; this curation includes affected probands with four different homozygous variants (24039075, 32833257) and two distinct compound heterozygous variants (32093234). This gene-disease relationship is supported by experimental evidence (mouse model, rescue in non-human model organisms, expression data, functional expression in non-patient cells, biochemical function evidence, protein interaction evidence, expression-level data; PMIDs: 22732358, 22615579, 22900076, 28926103, 32093234, 24982027). The protein sequence of FAM20C is well conserved across species, including mice. FAM20C null mice exhibit perinatal lethality, severe hypophosphatemia, stunted growth, neurological abnormalities, reduced bone density, amelogenesis imperfecta, and craniofacial anomalies including flat facial profile. Global deletions of FAM20C in mice resulted in skeletal defects and progressive development of intracerebral brain calcifications. Expression of the Fam20c transgene fully rescued skeletal defects in conditional knockout mice. In summary, there is definitive evidence to support this gene-disease relationship, with substantial replication over time. Only FAM20C has been associated with Raine syndrome. No convincing contradictory evidence has emerged. This classification was approved by the ClinGen Prenatal GCEP on the meeting date 6/25/2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0009821

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009821

Submitter: G2P