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The association between IL11RA and craniosynostosis and dental anomalies, a Crouzon-like autosomal recessive craniosynostosis syndrome, has been defined through multiple studies. Initially, homozygous and compound heterozygous IL11RA variants were identified in three unrelated consanguineous Pakistani families and two North European families, totaling 15 affected individuals (PMID:21741611). In 2013, a large 12-member Turkish family and four additional families harbored IL11RA mutations segregating with disease, including the recurrent splice-site c.479+6T>G mutation (PMID:24498618). A subsequent series described 10 new patients across multiple centers, further delineating the phenotypic spectrum of the disorder (PMID:29926465). To date, over 41 patients have been reported with biallelic IL11RA variants associated with this autosomal recessive syndrome (PMID:30811827). Unaffected heterozygous carriers remain phenotypically normal, consistent with recessive inheritance.
Genetic evidence supports autosomal recessive transmission with over 41 probands identified across more than 15 independent families. Variant spectrum includes at least six distinct missense changes, multiple nonsense and splice-site mutations, and in-frame duplications. Recurrent alleles such as c.479+6T>G and the in-frame duplication c.916_924dup (p.Thr306_Ser308dup) have been observed in diverse populations. A representative missense variant is c.866A>G (p.His289Arg) (PMID:29926465). Population frequencies for p.Thr306_Ser308dup and p.Arg261Cys are approximately 0.014% and 0.008% in Non-Finnish Europeans, respectively (PMID:30811827). These data meet ClinGen genetic criteria for a Strong level of evidence.
Extended pedigrees including a 12-affected member Turkish family, multiple sibships in consanguineous kindreds, and additional familial clusters demonstrate full cosegregation of IL11RA variants with the phenotype. At least 19 additional affected relatives segregate pathogenic variants, supporting a robust segregation signal (PMID:24498618). Larsen index calculations confirm tight linkage, and unaffected carriers remain asymptomatic. These findings are consistent with an autosomal recessive model.
Functional studies demonstrate that IL11RA loss of function underlies the disease mechanism. The p.Arg296Trp variant abolishes IL-11–induced STAT3 phosphorylation in HEK293T cells, and Il11ra−/− mice exhibit premature suture fusion and supernumerary teeth, recapitulating the human phenotype (PMID:21741611). These assays confirm a loss-of-function mechanism in affected individuals. Heterozygous animals do not display cranial defects, consistent with observed human carrier status.
In vitro exon trapping and RT-PCR analyses show that the c.479+6T>G splice-site mutation leads to aberrant IL11RA transcripts and abolished receptor expression. Transient coexpression in HEK293T and COS7 cells reveals dramatically reduced STAT3 activation, and immunolocalization studies in mouse and zebrafish detect Il11ra expression at suture tips (PMID:24498618). These findings reinforce the causal role of disrupting receptor processing and signal transduction.
Not all IL11RA variants are uniformly deleterious; recent work indicates that the p.E364_V368del variant is processed normally and retains IL-11 signaling capacity, suggesting variant-specific effects and additional regulatory mechanisms requiring elucidation (PMID:37994264). This highlights the need for functional assessment of novel IL11RA alleles to avoid misclassification.
Integration of genetic and functional evidence supports a definitive association between biallelic loss-of-function IL11RA variants and autosomal recessive craniosynostosis with dental anomalies. The mechanism involves disrupted IL-11 signaling leading to suture fusion and tooth number anomalies. Additional rare variants have been identified but exceed ClinGen scoring caps. Key Take-home: IL11RA variant screening should be included in diagnostic panels for Crouzon-like craniosynostosis and dental anomalies.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrongOver 41 probands with biallelic IL11RA variants across >15 families; autosomal recessive segregation supported Functional EvidenceStrongLoss-of-function IL11RA variants abolish IL11 signaling in cell assays and mouse knockout recapitulates craniosynostosis |