DOCK8 mutation diagnosed using whole-exome sequencing of the dried blood spot-derived DNA: a case report of an Iraqi girl diagnosed in Japan

Abstract

Background: Dedicator of cytokinesis 8 (DOCK8) deficiency (MIM #243700) is a rare disease, leads to a combined primary immunodeficiency (PID), and accounts for the autosomal recessive-hyper immunoglobulin E syndrome (AR-HIES). DOCK8 deficiency status characterizes by recurrent infections, atopy, and risk of cancer. Lymphoproliferative disease complicating PID, is difficult to diagnose. Our aim is to present a rare case of PID, and to the best of our knowledge, she is the first case of DOCK8 deficiency from Iraq. The genetic diagnosis was carried out in Japan using dried blood spot-based DNA transfer and whole-exome sequencing. Case presentation: An 11-year-old Iraqi girl, of double first-cousin-parents, had a history of severe eczema, food allergy, and repeated infections. She presented with a jaw mass, bilateral cervical and axillary lymphadenopathy, and immunoglobulin (Ig) assays of 20, 3.3 and 1.7-fold above maximum normal level for age of IgE, IgA and IgG, respectively, along with a low IgM, eosinophilia and lymphopenia. Based on the jaw mass biopsy, non-Hodgkin lymphoma was suggested in Iraq, whereas histopathological re-evaluation in Japan revealed the diagnosis of a polyclonal reactive proliferation spectrum of lymphoproliferative disorders/plasmacytic hyperplasia, complicating PID. Whole-exome sequencing supported the diagnosis of PID by identifying a homozygous DOCK8 mutation with previously reported pathogenicity (NM_203447:c.3332delT, p.Phe1113Leufs*2), that may be attributed to consanguinity. Conclusions: International collaboration using an effective DNA transportation technique and next-generation sequencing was the key to pinpoint the diagnosis of DOCK8 deficiency. Our case asserted that careful pathogenetic evaluation, in an advanced setting, was crucial for ruling out the neoplastic process. Pediatricians in areas with a high prevalence of consanguinity marriage should have a high index of suspicion of DOCK8 deficiency in patients with recalcitrant eczema, and frequent respiratory and skin infectious episodes.

Genetics and Epigenetics of Atopic Dermatitis: An Updated Systematic Review

“…The results are shown in Figure 5. The appearance of DOCK8 in all these biological processes stands out, taking into account that it has been described as related to AD only in one study reporting a single case [77]. COSMIC analysis located 75.4% of genes in the skin (ACTL9, ADAM33, ADCY10, C11orf30, CARD11, CARD14, CLDN1, COL5A3, CRNN, CUX2, CYP27A1, DEFB1, DOCK8, FLG, GSDMB, IL12RB1, IL22, IL2RA, IL4, IL5RA, IL6R, IL9, KDR, LILRA6, LRRC32, MAST2, MCM10, MMP9, MTF1, NLRP2, ORM2, PANX3, PHLDB1, PRR5L, RPTN, RTEL1, SPINK5, STS, TCHHL1, TGFB1, TLR2, TLR4, and TNF).…”

“…As a result, 73 articles were evaluated. Out of 73 studies, 11 were related to epigenetics [13,[24][25][26][27][28][29][30][31][32][33], 39 were candidate gene studies , 5 were genome-wide association studies (GWAS) [5,13,[74][75][76], whole-exome sequencing (WES) was performed in 7 articles [77][78][79][80][81][82][83], and phenome-wide association sequencing was done in 1 article [84]. Four studies described results from next-generation sequencing (NGS) [85][86][87][88], and 2 showed analyses of copy number variations (CNV) [89,90].…”

Inmunodeficiencia combinada debida a deficiencia de DOCK8. Lo que sabemos hasta ahora

“…El análisis de variaciones en el número de copias por MLPA (amplificación múltiple de sondas dependiente de ligandos) es otro estudio de elección debido al número elevado de mutaciones por deleciones extensas en el gen DOCK8. 87,88,89…”

Heterogeneity in biomarkers, mitogenome and genetic disorders of Arab population with special emphasis on large-scale whole-exome sequencing

“…juvenile neuronal ceroid lipofuscinoses (CLN3 gene) [132], inherited thrombocytopenias (FYB gene) [133], microcephaly (TMX2 gene) [134], non-syndromic retinal dystrophy (POC1B gene) [135], progressive pseudorheumatoid dysplasia (WISP3 gene) [136], dedicator of cytokinesis 8 deficiency (DOCK8 gene) [137], and developmental delay (MED27 gene) [138]. Jordanian patient with hypotrichosis-lymphedema-telangiectasia syndrome was analysed using WES for causative genetic factors, the study uncovered SOX18 mutation associated with the syndrome [139].…”

“…Studies (WES) in Egyptian individuals revealed associated genes of primary hyperoxaluria type I ( AGXT gene), infantile hypercalcemia/hypophosphatemia/nephrolithiasis ( SLC34A1 gene) [ 115 ], severe combined immunodeficiency ( JAK3 gene) [ 116 ], propionic acidemia ( PCCA gene) [ 117 ], sulfite oxidase deficiency ( SUOX gene), molybdenum cofactor deficiency ( MOCS2 gene) [ 118 ], primary hereditary microcephaly ( ASPM gene) [ 119 ], familial Mediterranean fever ( MEFV gene) [ 120 ], thiamine-responsive megaloblastic anemia ( SLC19A2 gene) [ 121 ], cerebellar atrophy and developmental delay ( PLA2G6 , KIF1A and MOCS2A genes) [ 122 ], micro-/anophthalmia ( VSX2 , SOX2 , and FOXE3 genes) [ 123 ], RAG-deficiency ( RAG1 and RAG2 genes) [ 124 ], auriculocondylar syndrome ( PLCB4 , GNAI3 , and EDN1 genes) [ 125 ], ectodermal dysplasia ( EDA , EDAR , and EDARADD genes) [ 126 ], 3-phosphoglycerate dehydrogenase deficiency ( PHGDH gene) [ 127 ], Carpenter syndrome ( RAB23 gene) [ 128 ], disorders/differences of sex development (NR5A1, CYP19A1, AMH, AMHR2, WT1, HHAT, and FANCA and in the X-linked genes KDM6A and ARX genes) [ 129 ] and autosomal recessive polycystic kidney disease ( PKHD1 gene) [ 130 ]. WES studies in Iraqi people revealed associated genes of epileptic encephalopathy ( SLC13A5 gene) [ 131 ], juvenile neuronal ceroid lipofuscinoses ( CLN3 gene) [ 132 ], inherited thrombocytopenia ( FYB gene) [ 133 ], microcephaly ( TMX2 gene) [ 134 ], non-syndromic retinal dystrophy ( POC1B gene) [ 135 ], progressive pseudorheumatoid dysplasia ( WISP3 gene) [ 136 ], dedicator of cytokinesis 8 deficiency ( DOCK8 gene) [ 137 ], and developmental delay ( MED27 gene) [ 138 ]. A Jordanian patient with hypotrichosis-lymphedema-telangiectasia syndrome was analyzed using WES for causative genetic factors; the study revealed the SOX18 mutation associated with the syndrome [ 139 ].…”