Journal ArticleDOI
Beyond monogenetic rare variants: tackling the low rate of genetic diagnoses in predominantly antibody deficiency
TLDR
The clinical and immunological variability of PAD is defined, how genetic defects identified in PAD have given insight into B-cell immunobiology is considered, and recent technological advances in genomics and the challenges associated with identifying causal variants are addressed.Abstract:
Predominantly antibody deficiency (PAD) is the most prevalent form of primary immunodeficiency, and is characterized by broad clinical, immunological and genetic heterogeneity. Utilizing the current gold standard of whole exome sequencing for diagnosis, pathogenic gene variants are only identified in less than 20% of patients. While elucidation of the causal genes underlying PAD has provided many insights into the cellular and molecular mechanisms underpinning disease pathogenesis, many other genes may remain as yet undefined to enable definitive diagnosis, prognostic monitoring and targeted therapy of patients. Considering that many patients display a relatively late onset of disease presentation in their 2nd or 3rd decade of life, it is questionable whether a single genetic lesion underlies disease in all patients. Potentially, combined effects of other gene variants and/or non-genetic factors, including specific infections can drive disease presentation. In this review, we define (1) the clinical and immunological variability of PAD, (2) consider how genetic defects identified in PAD have given insight into B-cell immunobiology, (3) address recent technological advances in genomics and the challenges associated with identifying causal variants, and (4) discuss how functional validation of variants of unknown significance could potentially be translated into increased diagnostic rates, improved prognostic monitoring and personalized medicine for PAD patients. A multidisciplinary approach will be the key to curtailing the early mortality and high morbidity rates in this immune disorder.read more
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Clinical and immunologic phenotype associated with activated ă phosphoinositide 3-kinase delta syndrome 2: A cohort study
Elodie Elkaim,Bénédicte Neven,Julie Bruneau,Kanako Mitsui-Sekinaka,Aurélie Stanislas,Lucie Heurtier,Carrie L. Lucas,Helen F. Matthews,Marie-Céline Deau,Svetlana O. Sharapova,James Curtis,Janine Reichenbach,Catherine Glastre,David A. Parry,Gururaj Arumugakani,Elizabeth M. McDermott,Sara Sebnem Kilic,Motoi Yamashita,Despina Moshous,Hicham Lamrini,Burkhard Otremba,Andrew R. Gennery,Tanya I. Coulter,Isabella Quinti,Jean-Louis Stephan,Vassilios Lougaris,Nicholas Brodszki,Vincent Barlogis,Takaki Asano,Lionel Galicier,David Boutboul,Shigeaki Nonoyama,Andrew J. Cant,Kohsuke Imai,Capucine Picard,Sergey Nejentsev,Thierry Jo Molina,Michael J. Lenardo,Sinisa Savic,Marina Cavazzana,Alain Fischer,Anne Durandy,Sven Kracker +42 more
TL;DR: APDS2 is a combined immunodeficiency with a variable clinical phenotype and Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD.
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Mutations in lrba are associated with a syndrome of immune deficiency and autoimmunity
G Lopez-Herrera,Giacomo Tampella,Manuela Baronio,Massimiliano Vitali,Vassilios Lougaris,Alessandro Plebani,Q Pan-Hammarstroem,L Hammarstroem,Likun Du,Kjell Hultenby,Claudia M. Trujillo-Vargas,Kanchan Phadwal,Anna Katharina Simon,Michel Moutschen,Amos Etzioni,Srugo Ami.,Doron Melamed,Chonghai Liu,P Philippet,Vinciane Dideberg,Asghar Aghamohammadi,N Rezai,V Enright,Hans J. Stauss,P Herholz,Ulrich Salzer,Hermann Eibel,Dietmar Pfeifer,H Velkeen,EM Gertz,AA Schaeffer,Bodo Grimbacher +31 more
TL;DR: In this paper, the authors performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia and concluded that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and susceptibility to apoptosis.
Iconographies supplémentaires de l'article : Phosphatase and tensin homolog ( PTEN ) mutation can cause activated phosphatidylinositol 3-kinase ? syndrome–like immunodeficiency
Yuki Tsujita,Kanako Mitsui-Sekinaka,Kohsuke Imai,Tzu-Wen Yeh,Noriko Mitsuiki,Takaki Asano,Hidenori Ohnishi,Zenichiro Kato,Yujin Sekinaka,Kiyotaka Zaha,Tamaki Kato,Tsubasa Okano,Takehiro Takashima,Kaoru Kobayashi,Mitsuaki Kimura,Tomoaki Kunitsu,Yoshihiro Maruo,Hirokazu Kanegane,Masatoshi Takagi,Kenichi Yoshida,Yusuke Okuno,Hideki Muramatsu,Yuichi Shiraishi,Kenichi Chiba,Hiroko Tanaka,Satoru Miyano,Seiji Kojima,Seishi Ogawa,Osamu Ohara,Satoshi Okada,Masao Kobayashi,Tomohiro Morio,Shigeaki Nonoyama +32 more
TL;DR: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes.
Combined immunodeficiency and epstein-barr virus-induced b cell malignancy in humans with inherited cd70 deficiency
TL;DR: In this paper, the authors describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)related diseases.
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Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK
Hongying Wang,Chi Ma,Yongge Zhao,Xiying Fan,Qing Zhou,Pamela Edmonds,Gulbu Uzel,Joao Bosco Oliveira,Jordan S. Orange,Ashish Jain +9 more
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Journal ArticleDOI
TRNT1 deficiency: clinical, biochemical and molecular genetic features
Yehani Wedatilake,Rojeen Niazi,Elisa Fassone,Christopher A. Powell,Sarah F. Pearce,Vincent Plagnol,José W. Saldanha,Robert Kleta,W. Kling Chong,Emma Footitt,Philippa B. Mills,Jan-Willem Taanman,Michal Minczuk,Peter E. Clayton,Shamima Rahman +14 more
TL;DR: Systematic review of all TRNT1 cases and mutations reported to date revealed a distinctive phenotypic spectrum and metabolic and other investigative findings, which will facilitate rapid clinical recognition of future cases.
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