Paternal uniparental isodisomy of chromosome 6 causing a complex syndrome including complete IFN‐γ receptor 1 deficiency

Prando, Carolina; Boisson–Dupuis, Stéphanie; Grant, Audrey V.; Kong, Xiao‐Fei; Bustamante, Jacinta; Feinberg, Jacqueline; Chapgier, Ariane; Rose, Y; Jannière, Lucile; Rizzardi, Elena; Zhang, Qiuping; Shanahan, Catherine M.; Viollet, Louis; Lyonnet, Stanislas; Abel, Laurent; Ruga, Ezia; Casanova, Jean‐Laurent

doi:10.1002/ajmg.a.33291

Cited by 23 publications

(10 citation statements)

References 72 publications

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“…Four autosomal recessive primary immunodeficiencies caused by UPD have been reported to date, including Chediak-Higashi syndrome (chromosome 1), cartilage hair hypoplasia (chromosome 9), perforin deficiency (chromosome 10), and IFN-g receptor 1 deficiency (chromosome 6). 20 The immunologic phenotype of the LCK-deficient patient reported here resembles that of lck 2/2 mice, with T-cell lymphopenia, low levels of CD4 and CD8 expression at the cell surface, and a lack of response to TCR activation. 17 Lck has been shown to play a key role in the initiation of TCR signaling after the recognition of MHC-peptide molecules.…”

Section: Discussionmentioning

confidence: 59%

Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency

Hauck

Randriamampita

Martin

et al. 2012

Journal of Allergy and Clinical Immunology

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Section: Discussionmentioning

confidence: 59%

Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency

Hauck

Randriamampita

Martin

et al. 2012

Journal of Allergy and Clinical Immunology

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“…Although UPD has been implicated in the development of a number of inherited syndromes, it is not widely considered as an inheritance mechanism and has only been described in isolated cases of five other primary immune-deficiency syndromes, including C4 deficiency (22), cartilage-hair hypoplasia without associated SCID (23), Chediak-Higashi syndrome (24), familial hemophagocytic lymphohistiocytosis (25), and IFN-γ receptor 1 deficiency (26). Disease in our patient was because of isodisomy of Chr 1, and of the 23 other reported cases of this type of UPD (27), only one was associated with immune deficiency (24).…”

Section: Discussionmentioning

confidence: 99%

CD45-deficient severe combined immunodeficiency caused by uniparental disomy

Roberts¹,

Buckley

Luo

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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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.

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“…Two genetic forms of AR complete IFN-γR1 deficiency have been described, with [46, 53, 84, 85] or without surface expression of the receptor [37, 46, 48, 50, 65, 66, 86–101] (Table 1). A case of paternal uniparental disomy of chromosome 6, including IFNGR1, has been described in a patient with mycobacterial infectious disease and a complex phenotype including neonatal hyperglycemia, neuromuscular disease, and dysmorphic features [88]. The cellular phenotype of AR complete IFN-γR1 deficiency is characterized by a lack of response to IFN-γ in vitro , in terms of IL-12p70 production by leukocytes, gamma-activating factor (GAF: STAT1 homodimers) DNA-binding activity in Epstein-Barr virus-transformed lymphoblastic (EBV-B) cell lines, or HLA-II induction in fibroblasts [14, 46, 65, 84, 102, 103].…”

Section: Ifn-γr1 Deficiencymentioning

confidence: 99%

Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

Bustamante

Boisson–Dupuis

Abel

et al. 2014

Seminars in Immunology

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591

655

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Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity.

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Paternal uniparental isodisomy of chromosome 6 causing a complex syndrome including complete IFN‐γ receptor 1 deficiency

Cited by 23 publications

References 72 publications

Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency

Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency

CD45-deficient severe combined immunodeficiency caused by uniparental disomy

Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

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