Molecular analysis of T-B-NK+severe combined immunodeficiency and Omenn syndrome cases in Saudi Arabia

Osama Alsmadi,Fadi Al-Kayal,Bandar Al-Saud,Rand Arnaout,Haya Al-Saud,Hamoud Al-Mousa,Saleh Al-Muhsen,Abdulaziz Al-Ghonaium,Hasan Al-Dhekri

doi:10.1186/1471-2350-10-116

Abstract

BackgroundChildren 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.MethodsPatients 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.ResultsWe 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.ConclusionMutation-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.

Highlights

Children with Severe Combined Immunodeficiency (SCID) lack autologous T lymphocytes and present with multiple infections early in infancy
Infants with autosomal recessive SCID caused by mutations in recombination activating genes 1&2 (RAG1 &RAG2) [13] that are necessary for the somatic rearrangement of antigen receptor genes on T- and B-lymphocytes [14,15], or in DCLRE1C (Artemis) [16], resemble all other forms of SCID in their infection susceptibility, their lymphocyte phenotype is charecterized by predominantly circulating NK cells and undetectable B or T lymphocytes (T-B-NK+ SCID) [13]
They presented with the typical clinical manifestations including chronic diarrhea, failure to thrive, severe opportunistic infections, lymphopenia, absent or reducded T- and B-lymphocytes, hypogammaglobulinemia, and poor lympohocytes response to mitogen stimulation (Additional File 1)

Summary

Introduction

Children with Severe Combined Immunodeficiency (SCID) lack autologous T lymphocytes and present with multiple infections early in infancy. Omenn syndrome (OS) shares the genetic aetiology of T-B-NK+ SCID, with mutations in RAG1, RAG2, or DCLRE1C. SCID is charecterized by high level of genetic and clinical heterogeniety, as more than 10 conditions have been identified and can be distinguished according to cellular phenotype, inheritance pattern, and the responsible genes [6,7,8,9,10,11,12]. Infants with autosomal recessive SCID caused by mutations in recombination activating genes 1&2 (RAG1 &RAG2) [13] that are necessary for the somatic rearrangement of antigen receptor genes on T- and B-lymphocytes [14,15], or in DCLRE1C (Artemis) [16], resemble all other forms of SCID in their infection susceptibility, their lymphocyte phenotype is charecterized by predominantly circulating NK cells and undetectable B or T lymphocytes (T-B-NK+ SCID) [13]. RAG1, RAG2, and DCLRE1C are the primary genes responsible for the T-BNK+ SCID phenotype [17] and in a recent report, mutations in LIG4 were documented in patients with this phenotype who have microcephaly and developmental delay [18]

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