ABSTRACT
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.
Subject(s)
Branchio-Oto-Renal Syndrome/genetics , Intellectual Disability/genetics , Mutation , Paired Box Transcription Factors/genetics , Severe Combined Immunodeficiency/genetics , Animals , Base Sequence , Branchio-Oto-Renal Syndrome/complications , Branchio-Oto-Renal Syndrome/immunology , Branchio-Oto-Renal Syndrome/pathology , Child , Consanguinity , Disease Models, Animal , Exome , Family , Female , Gene Expression , Genes, Recessive , Humans , Infant , Intellectual Disability/complications , Intellectual Disability/immunology , Intellectual Disability/pathology , Male , Mice , Morocco , Paired Box Transcription Factors/immunology , Pedigree , Severe Combined Immunodeficiency/complications , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/pathology , Thymus Gland/abnormalities , Thymus Gland/immunology , Thymus Gland/metabolismABSTRACT
A novel class I human leukocyte antigen allele HLA-A*24:309 is described.
Subject(s)
Alleles , Bone Marrow , HLA-A Antigens/genetics , Tissue Donors , Humans , Italy , MaleABSTRACT
A newly identified allele, named HLA-DRB1*13:154, differs from DRB1*13:13 by the single nucleotide substitution 227T-A at codon 47 in exon 2.
