A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency

Abstract

Otofaciocervical syndrome is a rare disorder characterized by facial anomalies, cup-shaped low-set ears, preauricular fistulas, hearing loss, branchial defects, skeletal anomalies, and mild intellectual disability. Autosomal dominant cases are caused by deletions or point mutations of EYA1. A single family with an autosomal recessive form of otofaciocervical syndrome and a homozygous missense mutation in PAX1 gene has been described.

We report whole exome sequencing of 4 members of a consanguineous family in which two children, showing features of otofaciocervical syndrome, expired from severe combined immunodeficiency. To date, the co-occurrence of otofaciocervical syndrome and severe combined immunodeficiency has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the two affected children. In mice, Pax1 is required for the formation of specific skeletal structures as well as for the development of a fully functional thymus. The mouse model strongly supports the hypothesis that PAX1 depletion in our patients caused thymus aplasia responsible for severe combined immunodeficiency.

This report provides evidence that bi-allelic null PAX1 mutations may lead to a multi-system autosomal recessive disorders, where severe combined immunodeficiency might represent the main feature.

Graphical Abstract

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