Oculoauricular syndrome, sometimes referred to as Schorderet-Munier-Franceschetti syndrome, is an autosomal recessive disorder characterized by ocular anomalies (microphthalmia, cataract, ocular coloboma, anterior segment dysgenesis, and early onset retinal dystrophy) and external ear anomalies (lobule aplasia and abnormal external ear appearance with typical hearing). In some cases, additional features have been reported, most commonly orodental anomalies. Eye and ear anomalies with oculoauricular syndrome are apparent at birth/in infancy. The HMX1 gene (NKX5-3) is part of the NKL subclass of ANTP homeobox genes on 4p16.1. It has a highly conserved 60 amino acid homeodomain. HMX1 is involved in DNA binding. Gene targets include EPHA6, which is a gene implicated in retinal axon guidance (Marcelli et al. 2014, PMID: 24945320).
Three families have been reported in the literature with both the eye and ear phenotype. A consanguineous family with oculoauricular syndrome was first described by Franseschetti & Valerio in 1945. In 2008 Schorderet et al. (PMID: 18423520) reported additional information and family members for the original family and provided the first report of a homozygous HMX1 frameshift variant as the putative cause of disease. In this case, ERG evaluation of the proband revealed progressive rod-cone dystrophy. Since then, 2 additional consanguineous families with oculoauricular syndrome with homozygous HMX1 variants have been reported (Gillespie et al. 2015, PMID: 25574057; Abdel-Salam et al. 2018, PMID: 29140751). In addition, a 4th family, with two affected siblings, both with a homozygous nonsense variant, was identified (PMID: 35946463). In this curation, 4 probands, one from each family reported in the literature, were curated.
This gene-disease relationship is supported by zebrafish, mouse, and human expression data as well as morpholino and zinc-finger-nuclease knockdown/rescue studies in zebrafish (Schorderet et al. 2008, PMID: 18423520; Boisset et al. 2012, PMID: 23068565). Functional alternation studies indicate that an HMX1 mutant failed to activate transcription of reporter constructs (Gillespie et al. 2015, PMID: 25574057). In addition, the Dumbo mouse (dmbo), created in a forward mutagenesis screen, with large/protruding ears and microphthalmia, was found to have a nonsense variant in exon 1 of HMX1 (Munroe et al.2009, PMID: 19379485).
In summary, there is a definitive association between HMX1 and oculoauricular syndrome. This has been demonstrated multiple times over several years with experimental and genetic evidence.
This classification was approved by the ClinGen Retina gene Curation expert panel on May 6, 2021 (SOP Version 8).
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