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Clinical, immunological and molecular findings of 8 patients with typical and atypical severe combined immunodeficiency: identification of 7 novel mutations by whole exome sequencing

Genes & Immunity volume 24, pages 207–214 (2023)Cite this article

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Abstract

Severe combined immunodeficiency (SCID) is one of the severe inborn errors of the immune system associated with life-threatening infections. Variations in SCID phenotypes, especially atypical SCID, may cause a significant delay in diagnosis. Therefore, SCID patients need to receive an early diagnosis. Here, we describe the clinical manifestations and genetic results of four SCID and atypical SCID patients. All patients (4 males and 4 females) in early infancy presented with SCID phenotypes within 6 months of birth. The mutations include RAG2 (p.I273T,p.G44X), IL7R (p.F361WfsTer17), ADA (c.780+1G>A), JAK3 (p.Q228Ter), LIG4 (p.G428R), and LAT (p.Y207fsTer33), as well as a previously reported missense mutation in RAG1 (p.A444V). The second report of LAT deficiency in SCID patients is presented in this study. Moreover, all variants were confirmed in patients and their parents as a heterozygous state by Sanger sequencing. The results of our study expand the clinical and molecular spectrum associated with SCID and leaky SCID phenotypes and provide valuable information for the clinical management of the patients.

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Fig. 1: Schematic figures of the proteins, Sanger sequencing validation, and pedigrees of the patients who presented in this study.
Fig. 2: Predicted impression of Gly428Arg substitution on LIG4 protein.

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The data are available on request.

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Funding

This work was supported by Elite Researcher Grant Committee under award number 958326 from the National Institutes for Medical Research Development (NIMAD), Tehran, Iran; Immunology, Asthma & Allergy Research Institute, Tehran University of Medical Science, Tehran, Iran; B.G. is funded by the Deutsche Forschungsgemeinschaft (GR1617/14-1/iPAD; SFB1160/2_B5; RESIST–EXC 2155–Project ID 390874280; and CIBSS–EXC-2189–Project ID 390939984) and the BMBF (GAIN 01GM1910A) and S.B. is funded by Service d’Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, 1 place de l’Hôpital, 67091 Strasbourg, France.

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Authors and Affiliations

  1. Immunology, Asthma & Allergy Research Institute, Tehran University of Medical Sciences, Tehran, Iran

    Zahra Alizadeh, Mohammad Reza Fazlollahi, Mohsen Badalzadeh, Hanieh Heydarlou, Maryam Soleimani Bavani, Leila Moradi & Zahra Pourpak

  2. Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Zahra Alizadeh, Mohammad Reza Fazlollahi, Mohsen Badalzadeh, Hanieh Heydarlou, Maryam Soleimani Bavani, Leila Moradi & Zahra Pourpak

  3. Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Marzieh Mazinani

  4. Laboratoire d’ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, Strasbourg, France

    Raphael Carapito, Anne Molitor & Seiamak Bahram

  5. Service d’Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, 1 place de l’Hôpital, 67091, Strasbourg, France

    Raphael Carapito, Anne Molitor & Seiamak Bahram

  6. Department of Rheumatology and Clinical Immunology, Hannover Medical School, Hannover, Germany

    Andrés Caballero Garcia de Oteyza, Michele Proietti & Bodo Grimbacher

  7. RESIST – Cluster of Excellence 2155, Hannover Medical School, Hannover, Germany

    Andrés Caballero Garcia de Oteyza, Michele Proietti & Bodo Grimbacher

  8. DZIF – German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany

    Michele Proietti & Bodo Grimbacher

  9. Department of Allergy and Clinical Immunology, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Mansoureh Shariat & Masoud Movahedi

  10. Department of Allergy and Clinical Immunology, Rasool-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran

    Morteza Fallahpour

Authors
  1. Zahra Alizadeh
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  17. Zahra Pourpak
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Contributions

Conceptualization: ZP, ZA, MRF, SB; Methodology: ZA, MM, HH, MB, RC, AM, ACGO, MP; Validation: ZA, MM, HH, MB, RC, AM, MSB; Formal analysis: ZA, MM, HH, MB; Investigation: ZA, RC, AM, ACGO, MP; Clinical data and analysis: ZP, MRF, MS, MF, MM and LM; Supervision: ZP, ZA, MRF, SB, BG, Writing Original Drafts: ZA, ZP MRF; Revision: MRF, ZP, ZA SB; All authors read and approved the manuscript before submission.

Corresponding authors

Correspondence to Seiamak Bahram or Zahra Pourpak.

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The authors declare no competing interests.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Immunology, Asthma & Allergy Research Institute. Written informed consent was obtained from the patients’ parents.

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Alizadeh, Z., Fazlollahi, M.R., Mazinani, M. et al. Clinical, immunological and molecular findings of 8 patients with typical and atypical severe combined immunodeficiency: identification of 7 novel mutations by whole exome sequencing. Genes Immun 24, 207–214 (2023). https://doi.org/10.1038/s41435-023-00215-w

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