Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency

Abstract

SASH3 is a lymphoid-specific adaptor protein. In a recent study, SASH3 deficiency was described as a novel X-linked combined immunodeficiency with immune dysregulation, associated with impaired TCR signaling and thymocyte survival in humans. The small number of patients reported to date showed recurrent sinopulmonary, cutaneous and mucosal infections, and autoimmune cytopenia. Here we describe an adult patient previously diagnosed with common variable immunodeficiency (CVID) due to low IgG and IgM levels and recurrent upper tract infections. Two separate, severe viral infections drew our attention and pointed to an underlying T cell defect: severe varicella zoster virus (VZV) infection at the age of 4 years and bilateral pneumonia due type A influenza infection at the age of 38. Genetic testing using an NGS-based custom-targeted gene panel revealed a novel hemizygous loss-of-function variant in the SASH3 gene (c.505C>T/p.Gln169*). The patient’s immunological phenotype included marked B cell lymphopenia with reduced pre-switch and switch memory B cells, decreased CD4+ and CD8+ naïve T cells, elevated CD4+ and CD8+ TEMRA cells, and abnormal T cell activation and proliferation. The patient showed a suboptimal response to Streptococcus pneumoniae (polysaccharide) vaccine, and a normal response to Haemophilus influenzae type B (conjugate) vaccine and SARS-CoV-2 (RNA) vaccine. In summary, our patient has a combined immunodeficiency, although he presented with a phenotype resembling CVID. Two severe episodes of viral infection alerted us to a possible T-cell defect, and genetic testing led to SASH3 deficiency. Our patient displays a milder phenotype than has been reported previously in these patients, thus expanding the clinical spectrum of this recently identified inborn error of immunity.

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

“…Novel gene defects have been found for most categories of IEI, including novel causes of: Combined immunodeficiencies ( LCP2 (SLP76) [ 12 ], PAX1 [ 13 , 14 ], ITPKB [ 15 ]; SASH3 [ 16 , 17 ], MAN2B2 [ 18 ], COPG1 [ 19 ], IKZF2 [ 20 – 23 ], CHUK [ 24 ], IKZF3 [ 25 , 26 ], CRACR2A [ 27 ], CD28 [ 28 ]) (Table 1 ; Supplementary Table 1 ); Combined immunodeficiencies with syndromic features ( MCM10 [ 29 , 30 ], IL6ST [ 31 – 33 ], DIAPH1 [ 34 ]) (Table 2 ; Supplementary Table 1 ); B cell deficiencies, agammaglobulinemia, or hypogammaglobulinemia ( FNIP1 [ 35 , 36 ], SP1I [ 37 ] , PIK3CG [ 38 , 39 ], POU2AF1 [ 40 ], CTNNBL1 [ 41 ], TNSRSF13 [ 42 ]) (Table 3 ; Supplementary Table 1 ); Immune dysregulation ( RHOG [ 43 ], SOCS1 [ 44 – 46 ], PDCD1 [ 47 ], ELF4 [ 48 , 49 ], TET2 [ 50 ], CEBPE [ 51 ], IKZF1 GOF [ 52 ]) (Table 4 ; Supplementary Table 1 ) neutropenia CXCR2 [ 53 ...…”

“…There can be clinical overlap between some genes listed here and those listed in Table 7 Total number of mutant genes: 66. New inborn errors of immunity: 8 ( SLP76 [ 12 ], PAX1 [ 13 , 14 ], ITPKB [ 15 ]; SASH3 [ 16 , 17 ], MAN2B2 [ 18 ], COPG1 [ 19 ], IKZF2 [ 20 – 23 ], CHUK [ 24 ]) SCID severe combined immunodeficiency, CID combined immunodeficiency, EBV Epstein-Barr virus, MHC major histocompatibility complex, HPV human papillomavirus, Treg T regulatory cell, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function, FTT failure to thrive…”

“…Combined immunodeficiencies ( LCP2 (SLP76) [ 12 ], PAX1 [ 13 , 14 ], ITPKB [ 15 ]; SASH3 [ 16 , 17 ], MAN2B2 [ 18 ], COPG1 [ 19 ], IKZF2 [ 20 – 23 ], CHUK [ 24 ], IKZF3 [ 25 , 26 ], CRACR2A [ 27 ], CD28 [ 28 ]) (Table 1 ; Supplementary Table 1 );…”

“…Total number of mutant genes: 66. New inborn errors of immunity: 8 ( SLP76 [ 12 ], PAX1 [ 13 , 14 ], ITPKB [ 15 ]; SASH3 [ 16 , 17 ], MAN2B2 [ 18 ], COPG1 [ 19 ], IKZF2 [ 20 – 23 ], CHUK [ 24 ])…”

“…The latest IEI have also revealed critical roles for genes not previously strongly associated with immune regulation and/or host defense. For instance, we have now learned that: The SH3-domain containing protein SASH3 contributes to B and T cell developments [ 16 , 17 ]. ZNFX1 , a member of an RNA helicase superfamily, plays a dual role in human immunity, including in innate immune responses against viruses, bacteria, mycobacteria, and fungi, as well as in restraining type 1 IFN-mediated inflammation [ 63 – 65 ].…”