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Roberts JL , Buckley RH , Luo B , Pei JM , Lapidus A , Peri S , Wei Q , Shin J , Parrott RE , Dunbrack RL , Testa JR , Zhong XP , Wiest DL
CD45-deficient severe combined immunodeficiency caused by uniparental disomy
Proceedings of the National Academy of Sciences of the United States of America. 2012 Jun;109(26) :10456-10461
PMID: WOS:000306291400074    PMCID: PMC3387083   
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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.
Roberts, Joseph L. Buckley, Rebecca H. Luo, Biao Pei, Jianming Lapidus, Alla Peri, Suraj Wei, Qiong Shin, Jinwook Parrott, Roberta E. Dunbrack, Roland L., Jr. Testa, Joseph R. Zhong, Xiao-Ping Wiest, David L. Institute of Personalized Medicine at Fox Chase Cancer Center[AI047605, AI042951]; National Institutes of Health Challenge[RC1 HL099617]; [P30-DK-50306]; [P01CA06927] We thank Drs. Arvil Burks, Dietmar Kappes, and Maureen Murphy for critical review of the manuscript, and Dr. Haydar Frangoul of Vanderbilt University for referral of the patient. This work was supported in part by the Institute of Personalized Medicine at Fox Chase Cancer Center through Grants AI047605 and AI042951; National Institutes of Health Challenge Grant RC1 HL099617 and Core Grant P01CA06927; Center Grant P30-DK-50306; and an appropriation from the Commonwealth of Pennsylvania. 38 Natl acad sciences Washington 972qe Ence je, 1988, american journal of human genetics, v42, p217