De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly

Kuhlen, Michaela; Hönscheid, Andrea; Loizou, Loizos; Nabhani, Schafiq; Fischer, Ute; Stepensky, Polina; Schaper, Jörg; Klapper, Wolfram; Siepermann, Meinolf; Schuster, Friedhelm R.; Meisel, Roland

doi:10.1016/j.clim.2015.10.008

Cited by 33 publications

(18 citation statements)

References 11 publications

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“…The misspliced product predicts an in‐frame deletion of amino acids 434–475. In the literature, patients with heterozygous variations in IVS10 of PIK3R1 (according to our nomenclature: IVS11 c.1425+1G>T, IVS11 c.1425+1G>C, and IVS11 c.1425+1G>A) were previously described . It was shown that these variations lead to splicing from exon 9 to exon 11 (according to our nomenclature: exon 10 to exon 12) .…”

Section: Summary Of Clinical and Immunologic Findings Of P1 And P2mentioning

confidence: 93%

Activated PI3Kδ syndrome type 2: Two patients, a novel mutation, and review of the literature

Olbrich

Lorenz

Daball

et al. 2016

Pediatric Allergy Immunology

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Section: Summary Of Clinical and Immunologic Findings Of P1 And P2mentioning

confidence: 93%

Activated PI3Kδ syndrome type 2: Two patients, a novel mutation, and review of the literature

Olbrich

Lorenz

Daball

et al. 2016

Pediatric Allergy Immunology

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“…Subsequently, a number of additional studies have identified APDS patients with mutations in PIK3CD 5, 7, 64–69 or PIK3R1 6, 70–73. Patients with GOF mutations in either of these genes appear to largely phenocopy each other, despite the fact that p85α is ubiquitously expressed and can pair with p110α and p110β in addition to p110δ.…”

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 99%

PI3Kδ and primary immunodeficiencies

et al. 2016

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Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS) or p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

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“…Whole-exome sequencing (WES) of parent-child trios has become a popular strategy to identify causative genetic variants in children with rare diseases [4,10,21]. However, it has not been routinely implemented in pediatric oncology as yet.…”

Section: Introductionmentioning

confidence: 99%

Genetic predisposition in children with cancer – affected families' acceptance of Trio-WES

et al. 2017

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A considerable percentage of childhood cancers are due to cancer predisposition syndromes (CPS). The ratio of CPSs caused by inherited versus de novo germline mutations and the risk of recurrence in other children are unknown. We initiated a prospective study performing whole-exome sequencing (WES) of parent-child trios in children newly diagnosed with cancer. We initially aimed to determine the interest in and acceptance of trio WES among affected families and to systematically collect demographic, medical, and family history data to analyze whether these point to an underlying CPS. Between January 2015 and December 2016, 83 (88.3%) of 94 families participated; only 11 (11.7%) refused to participate. Five (6.0%) children presented with congenital malignancies and three (3.6%) with tumors with a high likelihood of an underlying CPS. Two (2.5%) families showed malignancies in family members < 18 years, 11 (13.8%) showed relatives < 45 years with cancer, 37 (46.3%) had a positive cancer history, and 14 (17.5%) families had > 1 relative with cancer.Conclusions: Genetic testing in pediatric oncology is of great interest to the families, and the vast majority opts for investigation into potentially underlying CPSs. Trio sequencing provides unique insights into CPS in pediatric cancers and is increasingly becoming a common approach in modern oncology, and thus, trio sequencing needs also to be integrated routinely into the practice of pediatric oncology.

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De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly

Cited by 33 publications

References 11 publications

Activated PI3Kδ syndrome type 2: Two patients, a novel mutation, and review of the literature

Activated PI3Kδ syndrome type 2: Two patients, a novel mutation, and review of the literature

PI3Kδ and primary immunodeficiencies

Genetic predisposition in children with cancer – affected families' acceptance of Trio-WES

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