Aicardi goutières syndrome is associated with pulmonary hypertension

Abstract

While pulmonary hypertension (PH) is a potentially life threatening complication of many inflammatory conditions, an association between Aicardi Goutières syndrome (AGS), a rare genetic cause of interferon (IFN) overproduction, and the development of PH has not been characterized to date. We analyzed the cardiac function of individuals with AGS enrolled in the Myelin Disorders Bioregistry Project using retrospective chart review (n = 61). Additional prospective echocardiograms were obtained when possible (n = 22). An IFN signature score, a marker of systemic inflammation, was calculated through the measurement of mRNA transcripts of type I IFN-inducible genes (interferon signaling genes or ISG). Pathologic analysis was performed as available from autopsy samples. Within our cohort, four individuals were identified to be affected by PH: three with pathogenic gain-of-function mutations in the IFIH1 gene and one with heterozygous TREX1 mutations. All studied individuals with AGS were noted to have elevated IFN signature scores (Mann-Whitney p < .001), with the highest levels in individuals with IFIH1 mutations (Mann-Whitney p < .0001). We present clinical and histologic evidence of PH in a series of four individuals with AGS, a rare interferonopathy. Importantly, IFIH1 and TREX1 may represent a novel cause of PH. Furthermore, these findings underscore the importance of screening all individuals with AGS for PH.

Genetic and phenotypic spectrum associated with IFIH1 gain‐of‐function

“…Furthermore, psoriatic-like skin disease is a well-recognized feature of the SMS phenotype. As recently described (Adang et al, 2018) Despite documented clinical nonpenetrance in some cases, all putative IFIH1 gain-of-function substitutions are rare, with only two of the 30 discrete mutations described here and in previous reports recorded in gnomAD. Furthermore, all ascertained type I interferonopathy associated mutations are missense variants, likely conferring increased sensitivity to a self-derived nucleic acid.…”

Cardiac valve involvement in ADAR-related type I interferonopathy

“…Together with a recent description of lethal pulmonary hypertension with IFIH1 and TREX1 mutations,16 our findings highlight the need to monitor cardiopulmonary status with regular echocardiograms to detect valvular disease early in the type I interferonopathy context, and further emphasise a likely shared pathogenesis. The favourable postoperative course in patient 3 suggests that surgical intervention with cardiac valve replacement may be indicated where medical management has failed in interferonopathy-related valvular cardiac disease.…”

Developmental Outcomes of Aicardi Goutières Syndrome

“…1,2 Genetic abnormalities in the intracellular nucleic acid sensing machinery (TREX1, RNASEH2A, RNA-SEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1) trigger an aberrant interferon response, which results in extensive end organ damage. 1,[3][4][5] Although all identified individuals affected by Aicardi Goutières syndrome exhibit some degree of neurologic impairment, this can range from mild spastic paraparesis with normal intelligence to tetraparesis and severe cognitive disability. The magnitude of this developmental heterogeneity challenges clinical trial development.…”