CD45-deficient severe combined immunodeficiency caused by uniparental disomy.
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.
Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA.
Joseph L
JL
Roberts
Rebecca H
RH
Buckley
Biao
B
Luo
Jianming
J
Pei
Alla
A
Lapidus
Suraj
S
Peri
Qiong
Q
Wei
Jinwook
J
Shin
Roberta E
RE
Parrott
Roland L
RL
Dunbrack
Joseph R
JR
Testa
Xiao-Ping
XP
Zhong
David L
DL
Wiest
D006579:Heterozygote; D006801:Humans; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology*; D019656:Loss of Heterozygosity; D020641:Polymorphism, Single Nucleotide; D016511:Severe Combined Immunodeficiency / Q000276:immunology*; D024182:Uniparental Disomy
D017493:Leukocyte Common Antigens