{"doi":"10.1172/jci.insight.186862","title":"Quantitative hypermorphic FAM111A alleles cause autosomal recessive Kenny-Caffey syndrome type 2 and osteocraniostenosis","abstract":"Kenny-Caffey syndrome (KCS) is a rare genetic disorder characterized by extreme short stature, cortical thickening and medullary stenosis of tubular bones, facial dysmorphism, abnormal T cell function, and hypoparathyroidism. Biallelic loss-of-function variants in TBCE cause autosomal recessive type 1 KCS (KCS1). By contrast, heterozygous missense variants in a restricted region of the FAM111A gene have been identified in autosomal dominant type 2 KCS (KCS2) and a more severe lethal phenotype, osteocraniostenosis (OCS); these variants have recently been shown to confer a gain of function. In this study, we describe 2 unrelated children with KCS and OCS who were homozygous for different FAM111A variant alleles that result in replacement of the same residue, Tyr414 (c.1241A>G, p.Y414C and c.1240T>A, p.Y414N), in the mature FAM111A protein. Their heterozygous relatives are asymptomatic. Functional studies of recombinant FAM111AY414C demonstrated normal dimerization and a mild gain-of-function effect. This study provides evidence that both biallelic and monoallelic variants of FAM111A with varying degrees of activation can lead to dominant or recessive KCS2 and OCS.","journal":"JCI Insight","year":2025,"id":540325,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":814569,"name":"Niels Mailand","orcid":"0000-0002-6623-709X","position":1,"is_corresponding":false},{"id":1428454,"name":"Emma Ewing","orcid":null,"position":2,"is_corresponding":false},{"id":1428125,"name":"Saskia Hoffmann","orcid":"0000-0003-4835-0504","position":3,"is_corresponding":false},{"id":68516,"name":"Richard Caswell","orcid":"0000-0003-0713-4602","position":4,"is_corresponding":false},{"id":1168198,"name":"Lewis Pang","orcid":null,"position":5,"is_corresponding":false},{"id":668379,"name":"Jacqueline Eason","orcid":"0000-0002-8711-8671","position":6,"is_corresponding":false},{"id":1428126,"name":"Ying Dou","orcid":"0000-0001-9037-6420","position":7,"is_corresponding":false},{"id":260224,"name":"Kathleen E. Sullivan","orcid":"0000-0003-4018-1646","position":8,"is_corresponding":false},{"id":37445,"name":"Håkon Håkonarson","orcid":"0000-0003-2814-7461","position":9,"is_corresponding":false},{"id":289381,"name":"Michael A. Levine","orcid":"0000-0003-0036-7809","position":10,"is_corresponding":false},{"id":17377,"name":"Dong Li","orcid":"0000-0002-2265-6727","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:52:38.861025Z","pmid":"39932783","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}