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.

Orbital Dermoid Cysts in Monozygotic Twins

“…Additionally, limbal dermoids can be associated with the oculo-auriculo-vertebral syndrome, which suggests there may be a genetic etiology for those lesions. 9 Further work is needed to understand the genetic and environmental factors that lead to the development of orbital dermoid cysts. Our case of monozygotic twins with identical orbital dermoid cysts emphasizes the importance of evaluating the family members of a patient in whom an orbital dermoid cyst is diagnosed and hints at a possible underlying genetic etiology.…”

“…7 However, BRAF mutations are only found in 35% of conjunctival melanoma. 6,8,9 Patients with an unresectable or metastatic disease without BRAF mutations are typically treated with immune checkpoint inhibitors (ICIs). Immune checkpoint inhibitors have revolutionized the prognosis of patients with metastatic cutaneous melanoma.…”

“…10,11 The successful use of both single-agent and combination ICI has been demonstrated in the treatment of recurrent, locally advanced, and metastatic conjunctival melanoma. 9,[12][13][14][15][16] Immune checkpoint inhibitors have been shown to be successful in the management of unresectable locally advanced and metastatic conjunctival melanoma. 9,12 While these therapies have not yet been demonstrated in the neoadjuvant setting for conjunctival melanoma, they have been used for other tumor types, including cutaneous melanoma and non-small cell lung cancer 17,18 to reduce disease burden and increase the likelihood of complete surgical resection.…”

“…9,[12][13][14][15][16] Immune checkpoint inhibitors have been shown to be successful in the management of unresectable locally advanced and metastatic conjunctival melanoma. 9,12 While these therapies have not yet been demonstrated in the neoadjuvant setting for conjunctival melanoma, they have been used for other tumor types, including cutaneous melanoma and non-small cell lung cancer 17,18 to reduce disease burden and increase the likelihood of complete surgical resection. Here, we present our experience employing ICI in a patient with unresectable conjunctival melanoma involving the nasal cavity and lymph nodes which resulted in dramatic disease reduction and enabled tumor resection.…”

Happy 30th birthday to the European Journal of Human Genetics!

“…This rescued the effect of a frameshift variant found in trans and explained phenotypic variability in this pulmonary vascular disease. Carter et al report a heterozygous variant in PAX1 as causing oculoauriculo-vertebral syndrome [5]. With important implications for clinical testing.…”