title: Molecular analysis of T-B-NK+ severe combined immunodeficiency and Omenn syndrome cases in Saudi Arabia.
abstract: BACKGROUND
  Children with Severe Combined Immunodeficiency (SCID) lack autologous T lymphocytes and present with multiple infections early in infancy. Omenn syndrome is characterized by the sole emergence of oligoclonal auto-reactive T lymphocytes, resulting in erythroderma and enteropathy. Omenn syndrome (OS) shares the genetic aetiology of T-B-NK+ SCID, with mutations in RAG1, RAG2, or DCLRE1C.
  
  
  METHODS
  Patients diagnosed with T-B-NK+ SCID or phenotypes suggestive of Omenn syndrome were investigated by molecular genetic studies using gene tightly linked microsatellite markers followed by direct sequencing of the coding regions and splice sites of the respective candidate genes.
  
  
  RESULTS
  We report the molecular genetic basis of T-B-NK+ SCID in 22 patients and of OS in seven patients all of Arab descent from Saudi Arabia. Among the SCID patients, six (from four families) displayed four homozygous missense mutations in RAG1 including V433M, R624H, R394W, and R559S. Another four patients (from three familes) showed 3 novel homozygous RAG2 mutations including K127X, S18X, and Q4X; all of which predict unique premature truncations of RAG2 protein. Among Omenn patients, four (from two families) have S401P and R396H mutations in RAG1, and a fifth patient has a novel I444M mutation in RAG2. Seven other patients (six SCID and one OS) showed a gross deletion in exons 1-3 in DCLRE1C. Altogether, mutations in RAG1/2 and DCLRE1C account for around 50% and 25%, respectively, in our study cohort, a proportion much higher than in previous reported series. Seven (24%) patients lack a known genetic aetiology, strongly suggesting that they carry mutations in novel genes associated with SCID and Omenn disorders that are yet to be discovered in the Saudi population.
  
  
  CONCLUSIONS
  Mutation-free patients who lack a known genetic aetiology are likely to carry mutations in the regulatory elements in the SCID-causing genes or in novel genes that are yet to be discovered. Our efforts are underway to investigate this possibility by applying the whole genome scans on these cases via the use of Affymetrix high density DNA SNP chips in addition to homozygosity mapping.
authors.affiliation: 1Genetics Department, Research Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. oalsmadi@gmail.com
authors.forename: Osama
authors.initials: O
authors.lastname: Alsmadi
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Al-Ghonaium
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
authors.forename: Rand
authors.initials: R
authors.lastname: Arnaout
authors.forename: Hasan
authors.initials: H
authors.lastname: Al-Dhekri
authors.forename: Bandar
authors.initials: B
authors.lastname: Al-Saud
authors.forename: Fadi
authors.initials: F
authors.lastname: Al-Kayal
authors.forename: Haya
authors.initials: H
authors.lastname: Al-Saud
authors.forename: Hamoud
authors.initials: H
authors.lastname: Al-Mousa
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology*; D018895:Microsatellite Repeats; D009154:Mutation; D012529:Saudi Arabia; D017422:Sequence Analysis, DNA; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology*; D045567:VDJ Recombinases / Q000235:genetics / Q000276:immunology
chemical_list: D045567:VDJ Recombinases