Multi-dimensional insight into the coexistence of pathogenic genes for ADAR1 and TSC2: careful consideration is essential for interpretation of ADAR1 variants

Abstract

Background Aicardi-Goutières syndrome 6 (AGS6) is a serious auto immunization-associated acute neurologic decompensation. AGS6 manifests as acute onset of severe generalized dystonia of limbs and developmental regression secondary to febrile illness mostly. Dyschromatosis symmetrica hereditaria (DSH), as pigmentary genodermatosis, is characterized mixture of hyperpigmented and hypopigmented macules. Both AGS6 and DSH are associated with ADAR1 pathogenic variants. Methods To explore the etiology of a proband with developmental regression with mixture of hyperpigmentation and hypopigmentation macules, we used the trio-WES. Later, to clarify the association between variants and diseases, we used guidelines of ACMG for variants interpretation and quantitative Real-time PCR for verifying elevated expression levels of interferon-stimulated genes, separately. Results By WES, we detected 2 variants in ADAR1 and a variant in TSC2, respectively were NM_001111.5: c.1096_1097del, NM_001111.5: c.518A>G, and NM_000548.5: c.1864C>T. Variants interpretation suggested that these 3 variants were both pathogenic. Expression levels of interferon-stimulated genes also elevated as expected. Conclusion We verified the co-occurrence of pathogenic variants of ADAR1 and TSC2 in AGS6 patients with DSH. Our works contributed to the elucidation of ADAR1 pathogenic mechanism, given the specific pathogenic mechanism of ADAR1, it is necessary to consider with caution when variants were found in ADAR1.