Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency

Lawless, Dylan; Geier, Christoph; Farmer, Jocelyn R.; Allen, Hana Lango; Thwaites, D.I.; Atschekzei, Faranaz; Brown, Matthew; Buchbinder, David; Burns, Siobhan O.; Butte, Manish J.; Csomós, Krisztián; Egner, William; Ehl, Stephan; Eibl, Martha M.; Fadugba, Olajumoke; Foldvari, Zsofia; Green, Deanna M.; Henrickson, Sarah E.; Holland, Steven M.; John, Tami; Klemann, Christian; Kuijpers, Taco W.; Moreira, Fernando; Piller, Alexander; Rayner-Matthews, Paula; Romberg, Neil; Sargur, Ravishankar; Schmidt, Reinhold; Schröder, Claudia; Schuetz, Catharina; Sharapova, Svetlana O.; Smith, Kenneth G. C.; Sogkas, Georgios; Speckmann, Carsten; Stirrups, Kathleen; Thrasher, Adrian J.; Wolf, Hermann M.; Notarangelo, Luigi D.; Anwar, Rashida; Boyes, Joan; Ujházi, Boglárka; Thaventhiran, James; Walter, Jolán E.; Savic, Sinisa

doi:10.1016/j.jaci.2018.02.007

Cited by 36 publications

(48 citation statements)

References 30 publications

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“…P (H) is known since the rate of RAG deficiency is estimated at an incidence of 1:181,000 [68], SCID at a rate of 1:330,000 [2], and we also recently show the rate of RAG deficiency in adults with PID [16]. Being a recessive disease, P (E) must account for biallelic variants and is the most difficult value to determine.…”

Section: Bayesian Probabilitymentioning

confidence: 93%

“…The recombination activity of RAG1 and RAG2 was previously measured on known or candidate pathogenic variants [16][17][18]. Briefly, the pathogenicity of variants in RAG1 and RAG2 was measured functionally in vitro by either expression of RAG1 and RAG2 in combination with a recombination substrate plasmid containing recombination signal sequence (RSS) sites which are targeted by RAG complex during normal V(D)J recombination, or Abelson virus-transformed Rag2-/-pro-B cells with an RSS-flanked inverted GFP cassette.…”

Section: Validation Of Mrf Against Functional Datamentioning

confidence: 99%

“…Functionally characterising protein activity is both costly and time consuming. RAG1 and RAG2 have now been investigated by multiple functional assays for at least 110 coding variants [16][17][18]. In each case, researchers selected variants in RAG1 and RAG2 that were potentially damaging or were identified from PID patients as the most probable genetic determinant of disease.…”

Section: Top Candidate Variants Require Validationmentioning

confidence: 99%

“…We have previously measured the recombination activity of RAG1 and RAG2 disease-causing variants in several patients [16]. We have compiled our own and other functional assay data from Lee et al [17] and Tirosh et al [18] to produce a panel of recombination activity measurements for coding variants in both RAG1 and RAG2.…”

Section: Mrf Predicts Rag Deficiency Amongst Pid Patients Harbouring mentioning

confidence: 99%

“…The first reported cases of Omenn syndrome identified infants with hypomophic RAG variants which retained partial recombination activity [15]. RAG deficiency can be measured by in vitro quantification of recombination activity [16][17][18]. Hypomorphic RAG1 and RAG2 mutations, responsible for residual V(D)J recombination activity (on average 5-30%), result in a distinct phenotype of combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A) [2,19,20].…”

Section: Introductionmentioning

confidence: 99%

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Predicting the occurrence of variants in RAG1 and RAG2

Lawless

Allen²,

Thaventhiran

et al. 2018

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13While widespread genome sequencing ushers in a new era of preventive medicine, the tools for predictive genomics are still lacking. The greatest hurdle in diagnosis of rare disease is validation for variants of unknown significance. RAG deficiency presents at an early age with a distinct phenotype of combined immunodeficiency with granuloma and/or autoimmunity. Allele frequency of a SNV in the general population is an indicator of the functional or structural importance of a particular amino acid residue. However, rare diseases are often attributable to variants in genes which are highly conserved. Mutation of a conserved residue does not confirm pathogenicity and functional validation must be confirmed to correctly identify a monogenic disorders such as RAG deficiency. We present protein variants in RAG1 and RAG2 which are most likely to be seen clinically as disease-causing. Our method of mutation rate residue fre- *

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Section: Bayesian Probabilitymentioning

confidence: 93%

Section: Validation Of Mrf Against Functional Datamentioning

confidence: 99%