FAM111A – Osteocraniostenosis

Osteocraniostenosis (OCS) is a perinatally lethal skeletal dysplasia characterized by gracile bones, cloverleaf skull, hypoplastic spleen, and severe hypocalcemia secondary to hypoparathyroidism. Heterozygous gain-of-function variants in FAM111A underlie autosomal dominant OCS, while exceptionally, biallelic variants have been reported in a recessive form with similar lethal features.

Genetic evidence for FAM111A in OCS includes five unrelated probands with de novo heterozygous missense variants clustering in the C-terminal serine protease domain, particularly at residues Arg569 and Tyr414, consistent with a gain-of-function mechanism (PMID:23684011; PMID:32776417). Moreover, two unrelated children homozygous for p.Tyr414 substitutions exhibited OCS, and unaffected heterozygous relatives confirmed autosomal recessive inheritance in these cases (PMID:39932783).

Autosomal recessive segregation was demonstrated in a Turkish family with two affected siblings harboring compound heterozygous variants c.976T>A and c.1714_1716del, both presenting with early-onset hypocalcemia, dysmorphism, and skeletal dysplasia (PMID:34382758).

The variant spectrum comprises recurrent missense changes (e.g., c.1241A>G (p.Tyr414Cys)) and less common compound heterozygous alleles, all disrupting protease regulation. No loss-of-function null variants have been associated with dominant OCS, supporting a pathogenic gain-of-function model.

Functional studies revealed that patient-derived FAM111A mutants exhibit hyperactive protease activity, displacing DNA replication factors from chromatin and triggering caspase-dependent apoptosis, recapitulating the human phenotype at the cellular level (PMID:32776417; PMID:33369867).

A Fam111a knockout mouse exhibited normal serum calcium, parathyroid hormone, and bone architecture, indicating that disease arises from protease hyperactivity rather than haploinsufficiency (PMID:35715480).

Overall, multiple de novo and biallelic FAM111A variants in distinct pedigrees, coupled with consistent functional concordance, provide strong clinical validity for FAM111A in OCS. Genetic testing for FAM111A variants is clinically actionable and essential for prenatal diagnosis and management.

References

• American journal of human genetics • 2013 • FAM111A mutations result in hypoparathyroidism and impaired skeletal development. PMID:23684011
• JCI insight • 2025 • Quantitative hypermorphic FAM111A alleles cause autosomal recessive Kenny-Caffey syndrome type 2 and osteocraniostenosis. PMID:39932783
• Journal of clinical research in pediatric endocrinology • 2023 • Compound Heterozygous Variants in FAM111A Cause Autosomal Recessive Kenny-Caffey Syndrome Type 2. PMID:34382758
• EMBO reports • 2020 • FAM111 protease activity undermines cellular fitness and is amplified by gain-of-function mutations in human disease. PMID:32776417
• EMBO reports • 2021 • FAM111A induces nuclear dysfunction in disease and viral restriction. PMID:33369867
• Scientific reports • 2022 • FAM111A is dispensable for electrolyte homeostasis in mice. PMID:35715480

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