EDN1 – Auriculocondylar Syndrome

Auriculocondylar syndrome (ACS) is a rare craniofacial disorder marked by mandibular hypoplasia (micrognathia) and question-mark ears. Through whole-exome sequencing in a consanguineous family with two affected siblings and in two independent families with isolated question-mark ears, four probands were found to harbor EDN1 coding variants, including a homozygous c.249T>G (p.Tyr83Ter) truncating allele and missense changes in the mature peptide (PMID:24268655). Segregation of the stop mutation in the recessive family (two affected relatives) and vertical transmission of heterozygous stop and missense variants in dominant question-mark ear pedigrees support variable inheritance modes.

EDN1 acts via the EDNRA receptor to pattern the mandibular portion of the first pharyngeal arch in animal models, and loss of EDN1 function recapitulates mandibular hypoplasia, consistent with a haploinsufficiency mechanism. The identification of four EDN1-mutant probands across distinct families provides genetic evidence (Moderate) and, combined with concordant developmental studies in mouse and zebrafish, yields functional support (Moderate) for EDN1 as a causative gene in ACS. Additional deep-intronic and regulatory variants remain to be explored. Key Take-home: EDN1 sequencing should be considered in unexplained ACS or question-mark ear presentations.

References

• American journal of human genetics • 2013 • Mutations in endothelin 1 cause recessive auriculocondylar syndrome and dominant isolated question-mark ears. PMID:24268655

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