FAM20C – lethal osteosclerotic bone dysplasia (Raine syndrome)

FAM20C encodes a Golgi‐localized kinase essential for phosphorylation of secreted phosphoproteins involved in skeletal mineralization. Biallelic loss‐of‐function variants in FAM20C cause lethal osteosclerotic bone dysplasia, also known as Raine syndrome, an autosomal recessive disorder characterized by generalized osteosclerosis, intracranial calcifications, and distinctive craniofacial anomalies. The consistency of the phenotype across unrelated families and functional studies of mutant proteins support a definitive gene–disease relationship.

Raine syndrome is inherited in an autosomal recessive manner, with affected individuals harboring homozygous or compound heterozygous FAM20C variants. Over 21 probands have been reported in the literature, including sibships from consanguineous pedigrees demonstrating segregation of pathogenic alleles (PMID:20825432).

Case series and individual reports have identified a spectrum of variant classes, including missense substitutions (e.g., c.982C>T (p.Pro328Ser)), nonsense changes, frameshifts, splice-site mutations, and whole‐gene deletions. Recurrent pathogenic alleles have been observed in distinct populations, with no evidence of a single founder event.

Clinically, classic Raine syndrome presents with neonatal lethality due to pulmonary hypoplasia and respiratory compromise. Attenuated, non-lethal forms manifest with hypophosphatemic osteomalacia, amelogenesis imperfecta, variable neurodevelopmental delay, and survival into childhood or adulthood (PMID:24039075). Key features include generalized osteosclerosis (HP:0005789), cerebral calcification (HP:0002514), and craniofacial dysmorphism (HP:0000271).

Functional assays demonstrate that Raine‐associated FAM20C mutants exhibit markedly reduced kinase activity, impaired secretion, and failure to enhance DMP1 promoter activity, leading to dysregulated FGF23 expression and hypophosphatemia (PMID:25026495). Animal models and in vitro knockdown studies corroborate the role of FAM20C in phosphate homeostasis and bone mineralization.

While most historical cases were neonatal lethal, recent reports of non-lethal Raine syndrome underscore phenotypic variability. Nevertheless, all affected individuals share core mineralization defects, reinforcing the pathogenicity of FAM20C variants without substantive conflicting evidence.

Molecular testing for FAM20C variants is essential for diagnosing Raine syndrome, guiding prenatal counseling, and informing management of bone and dental complications. Early genetic confirmation enables multidisciplinary care, improves prognostic accuracy, and facilitates family planning.

References

• Clinical genetics • 2011 • Osteosclerotic bone dysplasia in siblings with a Fam20C mutation. PMID:20825432
• American journal of medical genetics. Part A • 2013 • Hereditary deletion of the entire FAM20C gene in a patient with Raine syndrome. PMID:24039075
• Bone • 2014 • Functional analysis of mutant FAM20C in Raine syndrome with FGF23-related hypophosphatemia. PMID:25026495

Evidence Based Scoring (AI generated)