CD45-deficient severe combined immunodeficiency caused by uniparental disomy.

Journal Article (Journal Article)

Analysis of the molecular etiologies of SCID has led to important insights into the control of immune cell development. Most cases of SCID result from either X-linked or autosomal recessive inheritance of mutations in a known causative gene. However, in some cases, the molecular etiology remains unclear. To identify the cause of SCID in a patient known to lack the protein-tyrosine phosphatase CD45, we used SNP arrays and whole-exome sequencing. The patient's mother was heterozygous for an inactivating mutation in CD45 but the paternal alleles exhibited no detectable mutations. The patient exhibited a single CD45 mutation identical to the maternal allele. Patient SNP array analysis revealed no change in copy number but loss of heterozygosity for the entire length of chromosome 1 (Chr1), indicating that disease was caused by uniparental disomy (UPD) with isodisomy of the entire maternal Chr1 bearing the mutant CD45 allele. Nonlymphoid blood cells and other mesoderm- and ectoderm-derived tissues retained UPD of the entire maternal Chr1 in this patient, who had undergone successful bone marrow transplantation. Exome sequencing revealed mutations in seven additional genes bearing nonsynonymous SNPs predicted to have deleterious effects. These findings are unique in representing a reported case of SCID caused by UPD and suggest UPD should be considered in SCID and other recessive disorders, especially when the patient appears homozygous for an abnormal gene found in only one parent. Evaluation for alterations in other genes affected by UPD should also be considered in such cases.

Full Text

Duke Authors

Cited Authors

  • Roberts, JL; Buckley, RH; Luo, B; Pei, J; Lapidus, A; Peri, S; Wei, Q; Shin, J; Parrott, RE; Dunbrack, RL; Testa, JR; Zhong, X-P; Wiest, DL

Published Date

  • June 26, 2012

Published In

Volume / Issue

  • 109 / 26

Start / End Page

  • 10456 - 10461

PubMed ID

  • 22689986

Pubmed Central ID

  • PMC3387083

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1202249109


  • eng

Conference Location

  • United States