Compound Heterozygous Mutations of IL2-Inducible T cell Kinase in a Swedish Patient: the Importance of Early Genetic Diagnosis

Abstract

Primary immunodeficiency diseases (PIDs) are composed by a group of highly heterogeneous immune system diseases, of which approximately 350 forms of PID have been described so far. The causative gene of around 60% of patients with PIDs has yet unknown. In recent years, Next Generation Sequencing (NGS) has been increasingly adopted for gene identification and molecular diagnosis of rare diseases, including PIDs. An overview of the genetic makeup that underlies PID using NGS has been suggested as a promising approach to elucidate the etiology of PIDs, which could yield diagnostic and, possibly, provide new treatment advances for PID.To approach this goal, we performed either whole exome sequencing (WES, 454 samples) or targeted region sequencing (TRS, 217 samples) on 602 samples of 500 PID pedigrees. We have summarized the practical suggestions for the interpretation of NGS data and the techniques that can be used to search disease-causative PID genes in Paper I. This work aims to improve data annotation, interpretation, and application of NGS data in PIDs, which also facilitates a wide range of application of NGS data analysis in other Mendelian disorders.

Primary immunodeficiencies reveal the molecular requirements for effective host defense against EBV infection

“…There is strong overlap in the clinical phenotype and age of onset of ITK-and MAGT1-deficient patients. Thus, EBV viremia, EBV-induced lymphoproliferative disease, and/or 29 The average for these 25 patients (4.9 years) is consistent with the median reported by Booth et al 27 EBV 1 B lymphoma (Hodgkin, non-Hodgkin [including Burkitt and diffuse large B cell lymphoma]) have been reported for all but 1 ITK-deficient patient [35][36][37][38][39][40][41][42][43][44][45] and 19 out of 22 MAGT1-deficient patients, [48][49][50][51][52][53][54][55][56] with B-cell malignancies occurring in 70% to 80% of all patients (Table 1; Figure 1A-C).…”

“…48 Loss-of-function mutations in ITK and MAGT1 were first reported in 2009 35 and 2011, 49 respectively. To date, 22 patients with recessive ITK [35][36][37][38][39][40][41][42][43][44][45] or hemizygous MAGT1 mutations [48][49][50][51][52][53][54][55][56] (S.L., unpublished data) have been described in cohort studies, case reports, or outcomes from nextgeneration sequencing efforts in different centers 46,47 (Table 1).…”

“…Additional clinical features of these PIDs are CD4 1 T lymphopenia and hypogammaglobulinemia. Unlike XLP, patients with ITK or MAGT1 mutations are prone to infections with other viral (eg, VZV, CMV, HSV, KSHV, b-HPV, and Molluscum contagiosum) and bacterial (Pneumococcus and Haemophilus) pathogens [35][36][37][38][39][40][41][42][43][44][45][48][49][50][51][52][53][54][55][56]80 (Table 1). However, the major pathogenic threat to these patients is unquestionably EBV, even though HLH is less frequent than XLP1 (Figure 1A).…”

“…Of the 9 who underwent HSCT, 7 are currently alive (overall survival, ;55%; Figure 1D). [35][36][37][38][39][40][41][42][43][44][45]80 Survival for MAGT1-deficiency is better, as only 1 untransplanted patient died. 51 However, 4 out of 7 patients did not survive post-HSCT (overall survival, ;75%; Figure 1D; Table 1).…”

VIPPID: a gene-specific single nucleotide variant pathogenicity prediction tool for primary immunodeficiency diseases

“…For instance, newborn screening of severe combined immune deficiency (SCID) can lead to life-saving interventions before the occurrence of infections [ 5 ]. Accurate identification of disease-causing mutations can also facilitate earlier diagnosis and better management of the disease [ 6 , 7 ]. Moreover, accurate genetic testing allows better family planning and carrier detection in the patient’s family members [ 8 ].…”