IL-12Rβ1 Deficiency in Two of Fifty Children with Severe Tuberculosis from Iran, Morocco, and Turkey

BACKGROUND AND OBJECTIVES: In the last decade, autosomal recessive IL-12Rβ1 deficiency has been diagnosed in four children with severe tuberculosis from three unrelated families from Morocco, Spain, and Turkey, providing proof-of-principle that tuberculosis in otherwise healthy children may result from single-gene inborn errors of immunity. We aimed to estimate the fraction of children developing severe tuberculosis due to IL-12Rβ1 deficiency in areas endemic for tuberculosis and where parental consanguinity is common. METHODS AND PRINCIPAL FINDINGS: We searched for IL12RB1 mutations in a series of 50 children from Iran, Morocco, and Turkey. All children had established severe pulmonary and/or disseminated tuberculosis requiring hospitalization and were otherwise normally resistant to weakly virulent BCG vaccines and environmental mycobacteria. In one child from Iran and another from Morocco, homozygosity for loss-of-function IL12RB1 alleles was documented, resulting in complete IL-12Rβ1 deficiency. Despite the small sample studied, our findings suggest that IL-12Rβ1 deficiency is not a very rare cause of pediatric tuberculosis in these countries, where it should be considered in selected children with severe disease. SIGNIFICANCE: This finding may have important medical implications, as recombinant IFN-γ is an effective treatment for mycobacterial infections in IL-12Rβ1-deficient patients. It also provides additional support for the view that severe tuberculosis in childhood may result from a collection of single-gene inborn errors of immunity

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Table indicating the clinical presentations of TB recorded in the fifty patients.

<p>The two patients presenting with IL-12Rβ1 deficiency are in bold. N means number and age is indicated in years.</p

Mendelian mutations in <i>IL12RB1</i> leading to severe tuberculosis in two kindreds.

<p><b>A</b>. Pedigree of the two families (A and B) with IL-12Rβ1 deficiency. Each generation is designated by a roman numeral (I–II), and each individual by an Arabic numeral. The double lines connecting the parents indicate consanguinity. The probands are indicated by an arrow, with black indicating <i>Mycobacterium tuberculosis</i> disease status. Individuals whose genetic status could not be evaluated are indicated by the symbol “E?”. <b>B</b>. Electrophoregram showing the genomic sequences of exons 9 and 5 in patients 1 and 2, respectively, compared with a control sequence. <b>C</b>. Schematic diagram of the coding region of the IL-12Rβ1 chain containing 17 coding exons and encoding a 662-amino acid protein with a leader sequence (exon1, L), extracellular domain (exons 2 to 13, EC), transmembrane domain (exon 14, TM) and an intracellular cytoplasmic domain (exons 15 to 17, IC). Published and unpublished mutations are indicated as follows: missense mutations are shown in purple, nonsense mutations are shown in red and complex mutations are shown in brown. Splicing mutations are shown in blue, large deletions are shown in green, insertions are shown in orange, and duplication is shown in magenta. * The 700+362_1619-944del mutation is the only mutation resulting in at the expression of a protein at the cell surface. Mutations of P1 (K305X) and P2 (R173W) are underlined. <b>D</b>. Chest X ray of patient 1 showing the localization of the disease.</p