Case Report

A Novel Non-frameshift ADA Deletion Detected by Whole Exome Sequencing in an Iranian Family with Severe Combined Immunodeficiency


Severe combined immunodeficiency (SCID) comprises a heterogeneous group of genetic disorders caused by early defects in the development and function of T cells. Other lymphocyte lineages (B and/or natural killer cells) are variably affected. With a worldwide frequency of approximately 1:50,000 live births, SCID may result from diverse mutations in over 16 genes. Whole-exome sequencing (WES) provides an opportunity for parallel screening of all those genes. This approach is also useful for genetic diagnosis in parents whose infant expired before genetic testing. Here, we describe a heterozygous novel non-frameshift deletion (c.587_598del p.196_199del) in the adenosine deaminase (ADA) gene identified by WES in healthy parents of an expired child with SCID. The mutation was subsequently confirmed to be homozygous in the deceased baby whose left-over blood sample volume was insufficient for direct WES analysis. In conclusion, we here describe a novel mutation in ADA, a well-known SCID gene.

1. Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, et al. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Reporton Inborn Errorsof Immunity. J Clin Immunol 2018; 38(1):96-128.
2. Van der Burg M, Gennery AR. Educational Paper. The Expanding Clinical and Immunological Spectrum of Severe Combined Immunodeficiency. Eur J Pediatr 2011; 170(5):561-71.
3. Fischer A. Severe Combined Immunodeficiencies (SCID). Clin Exp Immunol 2000; 122(2):143-9.
4. Tasher D, Dalal I. The Genetic Basis of Severe Combined Immunodeficiency and its Variants. Appl Clin Genet 2012; 5:67-80.
5. Fazlollahi M, Pourpak Z, Hamidieh A, Movahedi M, Houshmand M, Badalzadeh M, et al. Clinical, Laboratory and Molecular Findings of 63 Patients with Severe Combined Immunodeficiency. A Decade s Experience. J Investig Allergol Clin Immunol 2017; 27(5):299-304.
6. Kwan A, Abraham RS, Currier R, Brower A, Andruszewski K, Abbott JK, et al. Newborn Screening for Severe Combined Immunodeficiency in 11 Screening Programs in the United States. JAMA 2014; 312(7):729-38.
7. Cossu F. Genetics of SCID. Ital J Pediatr 2010; 36(1):76.
8. Ameratunga R, Woon S-T, Neas K, Love DR. The Clinical Utility of Molecular Diagnostic Testing for Primary Immune Deficiency Disorders: a Case-Based Review. Allergy Asthma Clin Immunol 2010; 6(1):12.
9. Govindaraj GM, Vellarikkal SK, Jayarajan R, Ravi R, Verma A, Chakkiyar K, et al. Case Report: Whole Exome Sequencing Identifies Variation c. 2308G> A p. E770K in RAG1Associated with B-T-NK+ Severe Combined Immunodeficiency. F1000Res 2016; 5:2532.
10. Chou J, Ohsumi TK, Geha RS. Use of Whole-Exome and Genome Sequencing in the Identification of Genetic Causes of Primary Immunodeficiencies. Curr Opin Allergy Clin Immunol 2012; 12(6):623-8.
11. Gallo V, Dotta L, Giardino G, Cirillo E, Lougaris V, D'Assante R, et al. Diagnostics of Primary Immunodeficiencies through Next-Generation Sequencing. Front Immunol 2016; 7:466.
12. Fischer A, Notarangelo LD, Neven B, Cavazzana M, Puck JM. Severe Combined Immunodeficiencies and Related Disorders. Nat Rev Dis Primers 2015; 1:15061.
13. Shirkani A, Shahrooei M, Azizi G, Rokni-Zadeh H, Abolhassani H, Farrokhi S, et al. Novel Mutation of ZAP-70-related Combined Immunodeficiency: First Case from the National Iranian Registry and Review of the Literature. Immunol Invest 2017; 46(1):70-9.
14. Kelly BT, Tam JS, Verbsky JW, Routes JM. Screening for Severe Combined Immunodeficiency in Neonates. Clin Epidemiol 2013; 5(1):363-9.
15. Fallah S, Mesdaghi M, Mansouri M, Babaei D, Karimi A, Fahimzad SA, et al. Severe Combined Immunodeficiency: A Case Series and Review from a Tertiary Pediatric Hospital. Iran J Allergy Asthma Immunol 2018; 17(2):201-7.
16. Aghamohammadi A, Mohammadinejad P, Abolhassani H, Mirminachi B, Movahedi M, Gharagozlou M, et al. Primary Immunodeficiency Disorders in Iran: Update and New Insights from the Third Report of the National Registry. J Clin Immunol 2014; 34(4):478-90.
17. Picard C, Moshous D, Fischer A. The Genetic and Molecular Basis of Severe Combined Immunodeficiency. Curr Pediatr Rep 2015; 3(1):22-33.
18. Alunni S, Orrù M, Ottavi L. A Study on the Inhibition of Adenosine Deaminase. J Enzyme Inhib Med Chem 2008; 23(2):182-9.
19. Rivers L, Gaspar HB. Severe Combined Immunodeficiency: Recent Developments and Guidance on Clinical Management.Arch Dis Child 2015;100(7):667–72.
20. Stephan J, Vlekova V, Le Deist F, Blanche S, Donadieu J, De Saint-Basile G, et al. Severe Combined Immunodeficiency: a RetrospectiveSingle-Center Study of Clinical Presentation and Outcome in 117 Patients. J Pediatr 1993; 123(4):564-72.
21. Chan A, Scalchunes C, Boyle M, Puck JM. Early vs. Delayed Diagnosis of Severe Combined Immunodeficiency: a Family Perspective Survey.Clin Immunol 2011; 138(1):3-8.
22. Shirvani F, Chavoshzadeh Z, Arjmand R, Karimi A. Four-Month-Old Boy with Fever, Hepatosplenomegaly and Diffuse Pulmonary Infiltrations. Arch Clin Infect Dis 2012; 7(2):72-4.
23. Sawyer S, Hartley T, Dyment D, Beaulieu C, Schwartzentruber J, Smith A, et al. Utility of Whole‐Exome Sequencing for Those Near the End of the Diagnostic Odyssey: Time to Address Gaps in Care. Clin Genet 2016; 89(3):275-84.
24. Latif AH, Tabassomi F, Abolhassani H, Hammarström L. Molecular Diagnosis of Primary Immunodeficiency Diseases in a Developing Country: Iran as an Example. Expert Rev Clin Immunol 2014; 10(3):385-96.
25. Çalışkan M, Chong JX, Uricchio L, Anderson R, Chen P, Sougnez C, et al. Exome Sequencing Reveals a Novel Mutation for Autosomal Recessive Non-Syndromic Mental Retardation in the TECRGene on Chromosome 19p13. Hum Mol Genet 2011; 20(7):1285-9.
26. Maroofian R, Schuele I, Najafi M, Bakey Z, Rad A, Antony D, et al. Parental Whole-Exome Sequencing Enables Sialidosis Type II Diagnosis due to an NEU1Missense Mutation as an Underlying Cause of Nephrotic Syndrome in the Child. Kidney Int Rep 2018; 3(6):1454-63.
IssueVol 19, No 1 (2020) QRcode
SectionCase Report(s)
Adenosine deaminase Severe combined immunodeficiency Whole exome sequencing

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Talebi T, Biglari A, Shahroeei M, Changi-Ashtiani M, Dinmohammadi H, Navabi SS, Parvaneh N, Bossuyt X, Shahani T, Rokni-Zadeh H. A Novel Non-frameshift ADA Deletion Detected by Whole Exome Sequencing in an Iranian Family with Severe Combined Immunodeficiency. Iran J Allergy Asthma Immunol. 19(1):94-101.