1. A novelPAX1null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency
- Author
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Francesca Gensini, Gabriele Lorenzo Capone, Elisa Contini, Alessandro Barilaro, Berardino Porfirio, Anna Laura Putignano, Roberta Sestini, Irene Paganini, Laura Papi, Irene Giotti, and Annabella Marozza
- Subjects
0301 basic medicine ,Genetics ,Severe combined immunodeficiency ,Mutation ,Hearing loss ,media_common.quotation_subject ,Point mutation ,Nonsense ,Aplasia ,Biology ,medicine.disease ,medicine.disease_cause ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine ,Missense mutation ,medicine.symptom ,030217 neurology & neurosurgery ,Genetics (clinical) ,Exome sequencing ,media_common - 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.
- Published
- 2017