A Variety of Alu-Mediated Copy Number Variations Can Underlie IL-12Rβ1 Deficiency

Abstract

The IL12RB1 locus is Alu-enriched and therefore prone to rearrangements at various positions. CNVs should be considered in the genetic diagnosis of IL-12Rβ1 deficiency.

Mendelian susceptibility to mycobacterial disease: 2014–2018 update

“…Since the discovery of its first genetic etiology in 1996, MSMD has been reported and a causal genetic lesion described in 501 individuals from 356 kindreds originating from 57 countries on five continents (Figure a). Over this period, the genetic dissection of MSMD in these patients has revealed this condition to be caused by inborn errors of interferon (IFN)‐γ immunity . These findings confirm that IFN‐γ, first described in 1965 as an antiviral IFN, is actually the macrophage‐activating factor, as shown in 1983 .…”

“…Since the last comprehensive review on MSMD in 2014, three new genetic disorders have been reported, caused by mutations of TYK2 and SPPL2A, (two novel genetic etiologies) and IFNGR2 (a novel allelic form). Moreover, new mutations associated with the other 18 disorders have also been reported . We also discuss here two recently reported syndromic forms of MSMD: AR RORγ/RORγT and Janus kinase (JAK)1 deficiencies .…”

“…A sizeable proportion of patients with MSMD also display invasive infections because of other intra‐macrophagic microorganisms, such as Salmonella , or mucocutaneous infections caused by Candida species . Other infectious diseases have also been reported, albeit more rarely . Acquired and inherited immunodeficiencies conferring a predisposition to mycobacterial diseases in the context of other infections must first be excluded, before a diagnosis of MSMD can be reached .…”

“…Clinical manifestations are, therefore, highly variable. Macrophage activation syndrome or vasculitis may occur in rare cases, probably as a consequence of uncontrolled infection. Since the discovery of its first genetic etiology in 1996, MSMD has been reported and a causal genetic lesion described in 501 individuals from 356 kindreds originating from 57 countries on five continents (Figure a).…”

“…Allelic heterogeneity at the 11 loci underlies 21 different genetic forms of MSMD, defined on the basis of (1) the functional deficiency being partial or complete, (2) the protein being produced or not, and (3) the mechanism underlying the dysfunction of expressed proteins (Table ). The causal genetic lesions include single nucleotide variations, small deletions, duplications, insertions, or indels, and copy number variations (CNV; large deletions or duplications) . Since the last comprehensive review on MSMD in 2014, three new genetic disorders have been reported, caused by mutations of TYK2 and SPPL2A, (two novel genetic etiologies) and IFNGR2 (a novel allelic form).…”