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Severe combined immunodeficiency (SCID): From the detection of a new mutation to preimplantation genetic diagnosis

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Abstract

Purpose

To describe the identification of a new mutation responsible for causing human severe combined immunodeficiency syndrome (SCID). In a large consanguineous Israeli Arab family, this served as a diagnostic tool and enabled us to carry out preimplantation genetic diagnosis (PGD). We also demonstrated that PGD for homozygosity alleles is feasible.

Methods

We carried out genome-wide screening followed by fine mapping and linkage analysis in order to identify the candidate genes. We then sequenced DCLRE1C in order to find the familial mutation. The family was anxious to avoid the birth of an affected child, and therefore, because of their religious beliefs, PGD was the only option open to them. The embryos were biopsied at day 3, and a single blastomere from each embryo was analyzed by multiplex polymerase chain reaction for the SCID mutation and 5 additional polymorphic markers flanking DCLRE1C.

Results

Linkage analysis revealed linkage to chromosome 10p13, which harbors the DNA Cross-Link Repair Protein 1 C (DCLRE1C) ARTEMIS gene. Sequencing identified an 8 bp insertion in exon 14 (1306ins8) of DCLRE1C in all the affected patients; this causes an alteration in amino acid 330 of the protein from cysteine to a stop codon (p.C330X). One cycle of PGD was performed and two embryos were transferred, one homozygous wild-type and one a heterozygous carrier, and healthy twins were born.

Conclusions

Identifying the familial mutation enabled us to design a reliable and accurate PGD protocol, even in this case of a consanguineous family.

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References

  1. Altarescu G, Eldar Geva T, Brooks B, Margalioth E, Levy-Lahad E, Renbaum P. PGD on a recombinant allele: crossover between the TSC2 gene and “linked” markers impairs accurate diagnosis. Prenat Diagn. 2008;28:929–33.

    Article  PubMed  CAS  Google Scholar 

  2. Berthet F, Le Deist F, Duliege AM, Griscelli C, Fischer A. Clinical consequences and treatment of primary immunodeficiency syndromes characterized by functional T and B lymphocyte anomalies (combined immune deficiency). Pediatrics. 1994;93:265–70.

    PubMed  CAS  Google Scholar 

  3. Buckley RH, Schiff RI, Schiff SE, Markert ML, Williams LW, Harville TO, Roberts JL, Puck JM. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr. 1997;130:378–87.

    Article  PubMed  CAS  Google Scholar 

  4. Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol. 2004;22:625–55.

    Article  PubMed  CAS  Google Scholar 

  5. Elder ME. T-cell immunodeficiencies. Pediatr Clin North Am. 2000;47:1253–74.

    Article  PubMed  CAS  Google Scholar 

  6. Karolchik D, Baertsch R, Diekhans M, Furey TS, Hinrichs A, Lu YT, Roskin KM, Schwartz M, Sugnet CW, Thomas DJ, Weber RJ, Haussler D, Kent WJ. The UCSC genome browser database. Nucleic Acids Res. 2003;31:51–4.

    Article  PubMed  CAS  Google Scholar 

  7. Leonard WJ. Cytokines and immunodeficiency diseases. Nat Rev Immunol. 2001;1:200–8.

    Article  PubMed  CAS  Google Scholar 

  8. Lewis R. Human Genetics: Concepts and Applications. 6th ed. New York: McGraw Hill; 2005. p. 150–4.

    Google Scholar 

  9. Ma Y, Pannicke U, Schwarz K, Lieber MR. Hairpin opening and overhang processing by Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell. 2002;108:781–94.

    Article  PubMed  CAS  Google Scholar 

  10. Ma Y, Schwarz K, Lieber MR. The Artemis: DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps. DNA Repair (Amst). 2005;4:845–51.

    Article  CAS  Google Scholar 

  11. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res. 1988;16:1215.

    Article  PubMed  CAS  Google Scholar 

  12. Pesu M, Candotti F, Husa M, Hofmann SR, Notarangelo LD, O’Shea JJ. Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs. Immunol Rev. 2005;203:127–42.

    Article  PubMed  CAS  Google Scholar 

  13. Rechitsky S, Strom C, Verlinsky O, Amet T, Ivakhnenko V, Kukharenko V, Kuliev A, Verlinsky Y. Allele dropout in polar bodies and blastomeres. J Assist Reprod Genet. 1998;15:253–7.

    Article  PubMed  CAS  Google Scholar 

  14. Thornhill AR, McGrath JA, Eady RA, Braude PR, Handyside AH. A comparison of different lysis buffers to assess allele dropout from single cells for preimplantation genetic diagnosis. Prenat Diagn. 2001;21:490–7.

    Article  PubMed  CAS  Google Scholar 

  15. Verlinsky Y, Kuliev A. Micromanipulation and biopsy of polar bodies and blastomeres. In: Verlinsky Y, Kuliev A, editors. Atlas of preimplantation genetic diagnosis. 2nd ed. Oxon: Taylor and Francis, Abingdon; 2005. p. 15–22.

    Google Scholar 

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Acknowledgments

The authors thank Dr. Gabrielle J. Halpern for her help with editing the manuscript. This study was supported by the Adler Chair in Pediatric Cardiology—Tel Aviv University.

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Authors and Affiliations

  1. The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, 49100, Israel

    Reut Tomashov-Matar & Mordechai Shohat

  2. Infertility and IVF Unit, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, 49100, Israel

    Galia Biran, Neomi Kotler, Anat Stein, Benjamin Fisch & Onit Sapir

  3. Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, 69978, Israel

    Irina Lagovsky & Mordechai Shohat

  4. Felsenstein Medical Research Center, Rabin Medical Center, Petah-Tikva, 49202, Israel

    Irina Lagovsky & Mordechai Shohat

Authors
  1. Reut Tomashov-Matar
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  2. Galia Biran
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  3. Irina Lagovsky
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  4. Neomi Kotler
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  5. Anat Stein
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  6. Benjamin Fisch
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  7. Onit Sapir
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  8. Mordechai Shohat
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Corresponding author

Correspondence to Reut Tomashov-Matar.

Additional information

Capsule

Identifying the familial mutation in DCLRE1C was an important step for designing a reliable protocol even in the case of a consanguineous family.

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Tomashov-Matar, R., Biran, G., Lagovsky, I. et al. Severe combined immunodeficiency (SCID): From the detection of a new mutation to preimplantation genetic diagnosis. J Assist Reprod Genet 29, 687–692 (2012). https://doi.org/10.1007/s10815-012-9765-3

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  • DOI: https://doi.org/10.1007/s10815-012-9765-3

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