FAM111A – Kenny-Caffey syndrome type 2

FAM111A pathogenic variants cause autosomal dominant Kenny-Caffey syndrome type 2, a rare skeletal dysplasia characterized by proportionate short stature, cortical thickening and medullary stenosis of tubular bones, delayed closure of the anterior fontanelle, hypoparathyroidism, ocular anomalies, and variable neurodevelopmental involvement.

Inheritance of KCS2 is autosomal dominant, with de novo heterozygous missense variants in FAM111A identified in sporadic cases. A recurrent c.1706G>A (p.Arg569His) hotspot was first reported in four unrelated Japanese patients ([PMID:23996431]) and has since been observed de novo in pediatric and adult presentations ([PMID:32765931]; [PMID:36686468]; [PMID:37122511]). A family with autosomal dominant father-to-daughter transmission further demonstrates heritability ([PMID:38591167]).

Genetic evidence encompasses at least 15 unrelated probands harboring FAM111A missense variants, including eight newly documented individuals from six families (seven with c.1706G>A (p.Arg569His); one with c.1531T>C (p.Tyr511His)) ([PMID:38591167]). A literature review identifies over 46 genetically confirmed KCS2 cases, with c.1706G>A accounting for 16/23 (70%) previously reported alleles ([PMID:37122511]).

Variant spectrum is dominated by missense changes clustering in the C-terminal serine protease domain of FAM111A. The hotspot allele c.1706G>A (p.Arg569His) recurs in both sporadic and familial presentations. Additional pathogenic variants include c.1531T>C (p.Tyr511His) and c.1685A>C (p.Tyr562Ser) in allelic osteocraniostenosis cases.

Functional assays corroborate a gain-of-function mechanism: patient-associated variants hyperactivate FAM111A proteolytic activity, inducing apoptosis-like nuclear defects in cell models ([PMID:32776417]; [PMID:33369867]); structural studies reveal dimerization-dependent activation of the protease domain ([PMID:38453899]), while Fam111a knockout mice display normal electrolyte homeostasis and bone morphology, excluding haploinsufficiency ([PMID:35715480]).

Collectively, the robust genetic and experimental concordance supports a definitive gene-disease relationship. FAM111A variant testing is clinically useful for diagnosis and management of KCS2 patients.

References

• Journal of bone and mineral research • 2014 • A recurrent de novo FAM111A mutation causes Kenny-Caffey syndrome type 2. PMID:23996431
• Journal of pediatric genetics • 2020 • Ophthalmologic Impairment and Intellectual Disability in a Girl Presenting Kenny-Caffey Syndrome Type 2. PMID:32765931
• Frontiers in endocrinology • 2022 • Case report: Late middle-aged features of FAM111A variant, Kenny-Caffey syndrome type 2-suggestive symptoms during a long follow-up. PMID:36686468
• World journal of clinical cases • 2023 • Clinical and genetic features of Kenny-Caffey syndrome type 2 with multiple electrolyte disturbances: A case report. PMID:37122511
• Molecular genetics & genomic medicine • 2024 • Further delineation of phenotype and genotype of Kenny-Caffey syndrome type 2 (phenotype and genotype of KCS type 2). PMID:38591167
• 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
• Nature communications • 2024 • Dimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes. PMID:38453899
• Scientific reports • 2022 • FAM111A is dispensable for electrolyte homeostasis in mice. PMID:35715480

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