Biallelic ZNFX1 variants are associated with a spectrum of immuno‐hematological abnormalities

Abstract

Biallelic changes in the ZNFX1 gene have been recently reported to cause severe familial immunodeficiency. Through a search of our bio/databank with information from genetic testing of >55 000 individuals, we identified nine additional patients from seven families with six novel homozygous ZNFX1 variants. Consistent with the previously described phenotype, our patients suffered from monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and lymphadenopathy. The two most severely affected probands also had renal involvement and clinical presentations compatible with hemophagocytic lymphohistiocytosis. The disease was less lethal among our patients than previously reported. We identified two missense

Immune Dysregulation in Monogenic Inborn Errors of Immunity in Oman: Over A Decade of Experience From a Single Tertiary Center

“…However, the median age (in months) of a delay in obtaining a genotype was 69 for class VI, 26.5 for class V, 21.5 for class III, 14 for class IV, 13.5 for class II, and 6 for class I. Homozygosity was paramount, as 90% of all genotypes were autosomal recessive in inheritance (n = 108). In addition to the known mutations associated with the described groups of IEI, we reported three mutations in genes described to cause IEI that are not yet classified into IUIS [LIFR ( 16 ), DIAPH1 ( 17 ), ZNFX1 ( 18 )]. Additionally, there were two homozygous variants [LAT2 ( 19 ) and EBF3 ( 20 )] in genes implicated in immune function in mice that require further immunological functional studies to support a disease phenotype–genotype correlation in humans ( Table 4 ).…”

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

“…innate immune defects resulting in susceptibility to mycobacterial/bacterial ( TBX21 [ 55 , 56 ], IFNG [ 57 ], TLR8 [ 58 , 59 ]), viral ( NOS2 [ 60 ], SNORA31 [ 61 ], ATG4A, MAP1LC3B2 [ 62 ], ZNFX1 [ 63 – 65 ], TLR7 [ 66 – 68 ]), and/or fungal infections ( MAPK8 [ 69 ]) (Table 6 ; Supplementary Table 1 );…”

“… Total number of mutant genes in Table 6 : 74. New inborn errors of immunity: 10 ( TBX21 [ 55 ], IFNG [ 57 ], NOS2 [ 60 ], ZNFX1 [ 63 – 65 ], SNORA31 [ 61 ], ATG4A, MAP1LC3B2 [ 62 ], MAPK8 [ 69 ], TLR7 [ 66 – 68 ], TLR8 [ 58 , 59 ]) NF-κB nuclear factor kappa B, TIR Toll and interleukin 1 receptor, IFN interferon, TLR Toll-like receptor, MDC myeloid dendritic cell, CNS central nervous system, CMC chronic mucocutaneous candidiasis, HPV human papillomavirus, VZV varicella zoster virus, EBV Epstein-Barr virus …”

“…Total number of mutant genes in Table 6 : 74. New inborn errors of immunity: 10 ( TBX21 [ 55 ], IFNG [ 57 ], NOS2 [ 60 ], ZNFX1 [ 63 – 65 ], SNORA31 [ 61 ], ATG4A, MAP1LC3B2 [ 62 ], MAPK8 [ 69 ], TLR7 [ 66 – 68 ], TLR8 [ 58 , 59 ])…”

Mendelian susceptibility to mycobacterial diseases: state of the art

“…They also revealed the extended stability of ISG mRNAs in patient-derived cells, suggesting that ZNFX1 plays an important role in a balanced interferon response for viral defense via posttranscriptional regulation of ISGs. In addition, another group recently reported 9 patients from 7 families with homozygous ZNFX1 mutations with multiorgan inflammatory disease and recurrent infections by various pathogens, including Mycobacteria and viruses [60]. Taken together, total 13 different ZNFX1 variants in 26 patients from 17 families have been reported so far.…”