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A novel PAX1 null homozygous mutation in autosomal recessive otofaciocervical syndrome associated with severe combined immunodeficiency
Author(s) -
Paganini I.,
Sestini R.,
Capone G.L.,
Putignano A.L.,
Contini E.,
Giotti I.,
Gensini F.,
Marozza A.,
Barilaro A.,
Porfirio B.,
Papi L.
Publication year - 2017
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.13085
Subject(s) - missense mutation , nonsense mutation , genetics , biology , exome sequencing , mutation , severe combined immunodeficiency , consanguinity , compound heterozygosity , gene
Otofaciocervical syndrome ( OFCS ) 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 OFCS 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 2 children, showing features of OFCS , expired from severe combined immunodeficiency ( SCID ). To date, the co‐occurrence of OFCS and SCID has never been reported. We found a nonsense homozygous mutation in PAX1 gene in the 2 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 SCID . This report provides evidence that bi‐allelic null PAX1 mutations may lead to a multi‐system autosomal recessive disorders, where SCID might represent the main feature.