Autosomal recessive complete STAT1 deficiency caused by compound heterozygous intronic mutations

Abstract

<jats:title>Abstract</jats:title> <jats:p>Autosomal recessive (AR) complete signal transducer and activator of transcription 1 (STAT1) deficiency is an extremely rare primary immunodeficiency that causes life-threatening mycobacterial and viral infections. Only seven patients from five unrelated families with this disorder have been so far reported. All causal STAT1 mutations reported are exonic and homozygous. We studied a patient with susceptibility to mycobacteria and virus infections, resulting in identification of AR complete STAT1 deficiency due to compound heterozygous mutations, both located in introns: c.128+2 T&amp;gt;G and c.542-8 A&amp;gt;G. Both mutations were the first intronic STAT1 mutations to cause AR complete STAT1 deficiency. Targeted RNA-seq documented the impairment of STAT1 mRNA expression and contributed to the identification of the intronic mutations. The patient’s cells showed a lack of STAT1 expression and phosphorylation, and severe impairment of the cellular response to IFN-γ and IFN-α. The case reflects the importance of accurate clinical diagnosis and precise evaluation, to include intronic mutations, in the comprehensive genomic study when the patient lacks molecular pathogenesis. In conclusion, AR complete STAT1 deficiency can be caused by compound heterozygous and intronic mutations. Targeted RNA-seq-based systemic gene expression assay may help to increase diagnostic yield in inconclusive cases after comprehensive genomic study.</jats:p>

Successful Hematopoietic Stem Cell Transplantation for Autosomal Recessive STAT1 Complete Deficiency

“…Given its poor prognosis, this illness requires early diagnosis and HSCT. However, in our case, the patient underwent transplantation at an age more advanced than that reported previously because the diagnosis could not be established until intronic mutations were identified [4].…”

“…The detailed clinical manifestation before HSCT is described in a previous report [4]. Briefly, our patient developed Bacille Calmette-Guerin lymphadenitis, with osteomyelitis due to mycobacteria and severe viral infections since early infancy.…”

“…However, the pathogen had never been identified by biopsy, culture investigation, or other tests, suggesting the presence of hyperinflammatory responses against unidentified infectious pathogen [8]. The patient was diagnosed AR STAT1 complete deficiency due to compound heterozygous mutations at the age of 5 years and was referred to our hospital for transplantation [4]. A whole-body CT scan and bone scintigraphy revealed mandibular osteomyelitis and associated cellulitis but no deep-seated abscess.…”

“…Germline mutations in STAT1 cause the following four types of primary immunodeficiency disorders (PIDs): (1) autosomal recessive (AR) STAT1 complete deficiency, (2) AR STAT1 partial deficiency, (3) autosomal dominant (AD) STAT1 partial deficiency, and (4) STAT1 gain of function [1]. AR STAT1 complete deficiency is a rare form of PID, with only nine cases in seven families reported to date [2][3][4][5][6]. It is characterized by a fatal course following severe viral and mycobacterial infections based on impaired IFN-α/β and IFN-γ responses, respectively.…”

“…It is characterized by a fatal course following severe viral and mycobacterial infections based on impaired IFN-α/β and IFN-γ responses, respectively. We previously reported a case of AR STAT1 complete deficiency due to compound heterozygous intronic mutations [4]. Herein, we describe a case of successful treatment and recovery via hematopoietic stem cell transplantation (HSCT).…”