Extending the PAX1 spectrum: a dominantly inherited variant causes oculo-auriculo-vertebral syndrome

Abstract

Oculo-auriculo-vertebral syndrome (OAVS) is a clinically heterogeneous disorder, with both genetic and environmental contributors. Multiple genes have been associated with OAVS and common molecular pathways, such as retinoic acid and the PAX-SIX-EYA-DACH (PSED) network, are being implicated in the disease pathophysiology. Biallelic homozygous nonsense or hypomorphic missense mutations in PAX1 cause otofaciocervical syndrome type 2 (OTFCS2), a similar but more severe multi-system disorder that can be accompanied by severe combined immunodeficiency due to thymic aplasia. Here we have identified a multi-generational family with mild features of OAVS segregating a heterozygous frameshift in PAX1. The four base duplication is expected to result in nonsense-mediated decay, and therefore cause a null allele. While there was full penetrance of the variant, expressivity of facial and ear features were variable. Our findings indicate there can be monoallelic and biallelic disorders associated with PAX1, and further implicate the PSED network in OAVS.

Fig. 1. Clinical and genetic characterization of family.

A Pedigree of OAVS features. B Facial features of affected family members with PAX1 variant. III.1 and III.2 display right hemifacial microsomia and microtia, whilst I.1 has subtle facial asymmetry. Misshapen right ears are present in all three individuals ranging from over-folded ear in I.1 to the lobule-type ear in III.2. C Sanger sequencing of PAX1c.1154_1157dup variant. Heterozygous duplication results in overlapping peaks from the frameshift variant site (orange). D PAX1c.1154_1157dup variant located in Exon 4 generates a premature truncation codon in the mRNA transcript (p.Tyr386*) and likely stimulates degradation of the transcript by nonsense-mediated decay (NMD); therefore no protein would be produced from this allele.