DNA recombination defects in Kuwait: Clinical, immunologic and genetic profile

Waleed Al-Herz 1, Michel J Massaad 2, Janet Chou 2, Luigi D Notarangelo 3, Raif S Geha 2

Affiliations

01 February 2018

-

doi: 10.1016/j.clim.2017.10.006

Abstract

Defects in DNA Recombination due to mutations in RAG1/2 or DCLRE1C result in combined immunodeficiency (CID) with a range of disease severity. We present the clinical, immunologic and molecular characteristics of 21 patients with defects in RAG1, RAG2 or DCLRE1C, who accounted for 24% of combined immune deficiency cases in the Kuwait National Primary Immunodeficiency Disorders Registry. The distribution of the patients was as follow: 8 with RAG1 deficiency, 6 with RAG2 deficiency and 7 with DCLRE1C deficiency. Nine patients presented with SCID, 6 with OS, 2 with leaky SCID and 4 with CID and granuloma and/or autoimmunity (CID-G/AI). Eight patients [(7 SCID and 1 OS) (38%)] received hematopoietic stem cell transplant (HSCT). The median age of HSCT was 11.5months and the median time from diagnosis to HSCT was 6months. Fifty percent of the transplanted patients are alive while only 23% of the untransplanted ones are alive.

Keywords: Artemis; Combined immunodeficiency; DCLRE1C; DNA recombination; Rag; SCID.


 

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References

  1.  
    1. Buckley R.H. The long quest for neonatal screening for severe combined immunodeficiency. J. Allergy Clin. Immunol. 2012;129(3):597–604. - PMC - PubMed
  2.  
    1. Shearer W.T., Dunn E., Notarangelo L.D., Dvorak C.C., Puck J.M., Logan B.R., Griffith L.M., Kohn D.B., O'Reilly R.J., Fleisher T.A., Pai S.Y., Martinez C.A., Buckley R.H., Cowan M.J. Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J. Allergy Clin. Immunol. 2014 Apr;133(4):1092–1098. - PMC - PubMed
  3.  
    1. Kwan A., Abraham R.S., Currier R., Brower A., Andruszewski K., Abbott J.K., Baker M., Ballow M., Bartoshesky L.E., Bonilla F.A., Brokopp C., Brooks E., Caggana M., Celestin J., Church J.A., Comeau A.M., Connelly J.A., Cowan M.J., Cunningham-Rundles C., Dasu T., Dave N., De La Morena M.T., Duffner U., Fong C.T., Forbes L., Freedenberg D., Gelfand E.W., Hale J.E., Hanson I.C., Hay B.N., Hu D., Infante A., Johnson D., Kapoor N., Kay D.M., Kohn D.B., Lee R., Lehman H., Lin Z., Lorey F., Abdel-Mageed A., Manning A., McGhee S., Moore T.B., Naides S.J., Notarangelo L.D., Orange J.S., Pai S.Y., Porteus M., Rodriguez R., Romberg N., Routes J., Ruehle M., Rubenstein A., Saavedra-Matiz C.A., Scott G., Scott P.M., Secord E., Seroogy C., Shearer W.T., Siegel S., Silvers S.K., Stiehm E.R., Sugerman R.W., Sullivan J.L., Tanksley S., Tierce M.L., 4th, Verbsky J., Vogel B., Walker R., Walkovich K., Walter J.E., Wasserman R.L., Watson M.S., Weinberg G.A., Weiner L.B., Wood H., Yates A.B., Puck J.M., Bonagura V.R. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States. JAMA. 2014;312(7):729–738. - PMC - PubMed
  4.  
    1. Al-Herz W., Notarangelo L.D., Sadek A., Buckley R., USIDNET Consortium Combined immunodeficiency in the United States and Kuwait: comparison of patients' characteristics and molecular diagnosis. Clin. Immunol. 2015 Dec;161(2):170–173. - PMC - PubMed
  5.  
    1. Notarangelo L.D., Kim M.S., Walter J.E., Lee Y.N. Human RAG mutations: biochemistry and clinical implications. Nat. Rev. Immunol. 2016 Apr;16(4):234–246. - PMC - PubMed
  6.  
    1. Felgentreff K., Lee Y.N., Frugoni F., Du L., van der Burg M., Giliani S., Tezcan I., Reisli I., Mejstrikova E., de Villartay J.P., Sleckman B.P., Manis J., Notarangelo L.D. Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency. J. Allergy Clin. Immunol. 2015 Jul;136(1):140–150. - PMC - PubMed
  7.  
    1. Li H., Durbin R. Fast and accurate short read alignment with Burrows-Wheeler Transform. Bioinformatics. 2009;25:1754–1760. - PMC - PubMed
  8.  
    1. DePristo M., Banks E., Poplin R., Garimella K., Maguire J., Hartl C., Philippakis A., del Angel G., Rivas M.A., Hanna M., McKenna A., Fennell T., Kernytsky A., Sivachenko A., Cibulskis K., Gabriel S., Altshuler D., Daly M. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 2011;43:491–498. - PMC - PubMed
  9.  
    1. Shearer W.T., Rosenblatt H.M., Gelman R.S., Oyomopito R., Plaeger S., Stiehm E.R. Lymphocyte subsets in healthy children from birth through 18 years of age: the pediatric AIDS Clinical Trials Group P1009 study. J. Allergy Clin. Immunol. 2003;112(5):973–980. (Epub 2003/11/12) - PubMed
  10.  
    1. Ward A.M. eighth ed. PRU Publication; Sheffield: 2004. PRU Handbook of Clinical Immunochemistry.
  11.  
    1. Hedayat M., Massaad M.J., Lee Y.N., Conley M.E., Orange J.S., Ohsumi T.K., Al-Herz W., Notarangelo L.D., Geha R.S., Chou J. Lessons in gene hunting: a RAG1 mutation presenting with agammaglobulinemia and absence of B cells. J. Allergy Clin. Immunol. 2014 Oct;134(4):983–985. - PMC - PubMed
  12.  
    1. de Pagter A.P., Bredius R.G., Kuijpers T.W., Tramper J., van der Burg M., van Montfrans J., Driessen G.J., Dutch Working Party for Immunodeficiencies Overview of 15-year severe combined immunodeficiency in the Netherlands: towards newborn blood spot screening. Eur. J. Pediatr. 2015 Sep;174(9):1183–1188. - PMC - PubMed
  13.  
    1. Michos A., Tzanoudaki M., Villa A., Giliani S., Chrousos G., Kanariou M. Severe combined immunodeficiency in Greek children over a 20-year period: rarity of γc-chain deficiency (X-linked) type. J. Clin. Immunol. 2011 Oct;31(5):778–783. - PubMed
  14.  
    1. Pasic S., Vujic D., Veljković D., Slavkovic B., Mostarica-Stojkovic M., Minic P., Minic A., Ristic G., Giliani S., Villa A., Sobacchi C., Lilić D., Abinun M. Severe combined immunodeficiency in Serbia and Montenegro between years 1986 and 2010: a single-center experience. J. Clin. Immunol. 2014 Apr;34(3):304–308. - PubMed
  15.  
    1. Kim M.S., Lapkouski M., Yang W., Gellert M. Crystal structure of the V(D)J recombinase RAG1-RAG2. Nature. 2015 Feb 26;518(7540):507–511. - PMC - PubMed
  16.  
    1. Dalal I., Tasher D., Somech R., Etzioni A., Garti B.Z., Lev D., Cohen S., Somekh E., Leshinsky-Silver E. Novel mutations in RAG1/2 and ADA genes in Israeli patients presenting with T-B-SCID or Omenn syndrome. Clin. Immunol. 2011 Sep;140(3):284–290. - PubMed
  17.  
    1. Lee Y.N., Frugoni F., Dobbs K., Walter J.E., Giliani S., Gennery A.R., Al-Herz W., Haddad E., Le Deist F., Bleesing J.H., Henderson L.A., Pai S.Y., Nelson R.P., El-Ghoneimy D.H., El-Feky R.A., Reda S.M., Hossny E., Soler-Palacin P., Fuleihan R.L., Patel N.C., Massaad M.J., Geha R.S., Puck J.M., Palma P., Cancrini C., Chen K., Vihinen M., Alt F.W., Notarangelo L.D. A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J. Allergy Clin. Immunol. 2014 Apr;133(4):1099–1108. - PMC - PubMed
  18.  
    1. Sobacchi C., Marrella V., Rucci F., Vezzoni P., Villa A. RAG-dependent primary immunodeficiencies. Hum. Mutat. 2006 Dec;27(12):1174–1184. - PubMed
  19.  
    1. Alsmadi O., Al-Ghonaium A., Al-Muhsen S., Arnaout R., Al-Dhekri H., Al-Saud B., Al-Kayal F., Al-Saud H., Al-Mousa H. Molecular analysis of T-B-NK + severe combined immunodeficiency and Omenn syndrome cases in Saudi Arabia. BMC Med. Genet. 2009 Nov 13;10:116. - PMC - PubMed
  20.  
    1. Spanopoulou E., Zaitseva F., Wang F.H., Santagata S., Baltimore D., Panayotou G. The homeodomain region of Rag-1 reveals the parallel mechanisms of bacterial and V(D)J recombination. Cell. 1996 Oct 18;87(2):263–276. - PubMed
  21.  
    1. Noordzij J.G., de Bruin-Versteeg S., Verkaik N.S., Vossen J.M., de Groot R., Bernatowska E., Langerak A.W., van Gent D.C., van Dongen J.J. The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins. Blood. 2002 Sep 15;100(6):2145–2152. - PubMed
  22.  
    1. Corneo B., Moshous D., Güngör T., Wulffraat N., Philippet P., Le Deist F.L., Fischer A., de Villartay J.P. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B-severe combined immune deficiency or Omenn syndrome. Blood. 2001 May 1;97(9):2772–2776. - PubMed
  23.  
    1. Walter J.E., Rosen L.B., Csomos K., Rosenberg J.M., Mathew D., Keszei M., Ujhazi B., Chen K., Lee Y.N., Tirosh I., Dobbs K., Al-Herz W., Cowan M.J., Puck J., Bleesing J.J., Grimley M.S., Malech H., De Ravin S.S., Gennery A.R., Abraham R.S., Joshi A.Y., Boyce T.G., Butte M.J., Nadeau K.C., Balboni I., Sullivan K.E., Akhter J., Adeli M., El-Feky R.A., El-Ghoneimy D.H., Dbaibo G., Wakim R., Azzari C., Palma P., Cancrini C., Capuder K., Condino-Neto A., Costa-Carvalho B.T., Oliveira J.B., Roifman C., Buchbinder D., Kumanovics A., Franco J.L., Niehues T., Schuetz C., Kuijpers T., Yee C., Chou J., Masaad M.J., Geha R., Uzel G., Gelman R., Holland S.M., Recher M., Utz P.J., Browne S.K., Notarangelo L.D. Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency. J. Clin. Invest. 2015 Nov 2;125(11):4135–4148. - PMC - PubMed
  24.  
    1. Tabori U., Mark Z., Amariglio N., Etzioni A., Golan H., Biloray B., Toren A., Rechavi G., Dalal I. Detection of RAG mutations and prenatal diagnosis in families presenting with either T-B- severe combined immunodeficiency or Omenn's syndrome. Clin. Genet. 2004 Apr;65(4):322–326. - PubMed
  25.  
    1. Corneo B., Moshous D., Callebaut I., de Chasseval R., Fischer A., de Villartay J.P. Three-dimensional clustering of human RAG2 gene mutations in severe combined immune deficiency. J. Biol. Chem. 2000 Apr 28;275(17):12672–12675. - PubMed
  26.  
    1. Noordzij J.G., Verkaik N.S., van der Burg M., van Veelen L.R., de Bruin-Versteeg S., Wiegant W., Vossen J.M., Weemaes C.M., de Groot R., Zdzienicka M.Z., van Gent D.C., van Dongen J.J. Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow. Blood. 2003 Feb 15;101(4):1446–1452. - PubMed
  27.  
    1. Li L., Moshous D., Zhou Y., Wang J., Xie G., Salido E., Hu D., de Villartay J.P., Cowan M.J. A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans. J. Immunol. 2002 Jun 15;168(12):6323–6329. - PubMed
  28.  
    1. Lagresle-Peyrou C., Benjelloun F., Hue C., Andre-Schmutz I., Bonhomme D., Forveille M., Beldjord K., Hacein-Bey-Abina S., De Villartay J.P., Charneau P., Durandy A., Fischer A., Cavazzana-Calvo M. Restoration of human B-cell differentiation into NOD-SCID mice engrafted with gene-corrected CD34 + cells isolated from Artemis or RAG1-deficient patients. Mol. Ther. 2008 Feb;16(2):396–403. - PubMed
  29.  
    1. Lee P.P., Woodbine L., Gilmour K.C., Bibi S., Cale C.M., Amrolia P.J., Veys P.A., Davies E.G., Jeggo P.A., Jones A. The many faces of Artemis-deficient combined immunodeficiency - two patients with DCLRE1C mutations and a systematic literature review of genotype-phenotype correlation. Clin Immunol. 2013 Dec;149(3):464–474. - PubMed
  30.  
    1. Pannicke U., Hönig M., Schulze I., Rohr J., Heinz G.A., Braun S., Janz I., Rump E.M., Seidel M.G., Matthes-Martin S., Soerensen J., Greil J., Stachel D.K., Belohradsky B.H., Albert M.H., Schulz A., Ehl S., Friedrich W., Schwarz K. The most frequent DCLRE1C (ARTEMIS) mutations are based on homologous recombination events. Hum. Mutat. 2010 Feb;31(2):197–207. - PubMed
  31.  
    1. Wang J., Aroumougame A., Lobrich M., Li Y., Chen D., Chen J., Gong Z. PTIP associates with Artemis to dictate DNA repair pathway choice. Genes Dev. 2014 Dec 15;28(24):2693–2698. - PMC - PubMed
  32.  
    1. Pai S.Y., Logan B.R., Griffith L.M., Buckley R.H., Parrott R.E., Dvorak C.C., Kapoor N., Hanson I.C., Filipovich A.H., Jyonouchi S., Sullivan K.E., Small T.N., Burroughs L., Skoda-Smith S., Haight A.E., Grizzle A., Pulsipher M.A., Chan K.W., Fuleihan R.L., Haddad E., Loechelt B., Aquino V.M., Gillio A., Davis J., Knutsen A., Smith A.R., Moore T.B., Schroeder M.L., Goldman F.D., Connelly J.A., Porteus M.H., Xiang Q., Shearer W.T., Fleisher T.A., Kohn D.B., Puck J.M., Notarangelo L.D., Cowan M.J., O'Reilly R.J. Transplantation outcomes for severe combined immunodeficiency, 2000–2009. N. Engl. J. Med. 2014 Jul 31;371(5):434–446. - PMC - PubMed
  33.  
    1. Dvorak C.C., Cowan M.J., Logan B.R., Notarangelo L.D., Griffith L.M., Puck J.M., Kohn D.B., Shearer W.T., O'Reilly R.J., Fleisher T.A., Pai S.Y., Hanson I.C., Pulsipher M.A., Fuleihan R., Filipovich A., Goldman F., Kapoor N., Small T., Smith A., Chan K.W., Cuvelier G., Heimall J., Knutsen A., Loechelt B., Moore T., Buckley R.H. The natural history of children with severe combined immunodeficiency: baseline features of the first fifty patients of the primary immune deficiency treatment consortium prospective study 6901. J. Clin. Immunol. 2013 Oct;33(7):1156–1164. - PMC - PubMed
  34.  
    1. Gennery A.R., Slatter M.A., Grandin L., Taupin P., Cant A.J., Veys P., Amrolia P.J., Gaspar H.B., Davies E.G., Friedrich W., Hoenig M., Notarangelo L.D., Mazzolari E., Porta F., Bredius R.G., Lankester A.C., Wulffraat N.M., Seger R., Güngör T., Fasth A., Sedlacek P., Neven B., Blanche S., Fischer A., Cavazzana-Calvo M., Landais P. Inborn Errors Working Party of the European Group for Blood and Marrow Transplantation; European Society for Immunodeficiency. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J. Allergy Clin. Immunol. 2010;126:602–610. - PubMed
  35.  
    1. Schuetz C., Neven B., Dvorak C.C., Leroy S., Ege M.J., Pannicke U., Schwarz K., Schulz A.S., Hoenig M., Sparber-Sauer M., Gatz S.A., Denzer C., Blanche S., Moshous D., Picard C., Horn B.N., de Villartay J.P., Cavazzana M., Debatin K.M., Friedrich W., Fischer A., Cowan M.J. SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID. Blood. 2014 Jan 9;123(2):281–289. - PMC - PubMed

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