Two Patients with AGS9: Divergent Clinical Courses of a Rare Metabolic Disease

Background/Purpose: Aicardi–Goutières syndrome type 9 (AGS9), first described in 2020, is a rare type I interferonopathy caused by biallelic RNU7-1 variants, leading to infantile developmental delay and progressive neurologic decline. We report two AGS9 patients with strikingly different phenotypes.

Methods: We retrospectively reviewed clinical imaging, laboratory, TRIO exome analysis, and interferon signatures of two pediatric AGS9 cases diagnosed at our center.

Results: Patient 1 exhibited prenatal growth restriction and splenomegaly. Postnatal MRI showed basal ganglia calcifications and frontal cysts. Within weeks, he developed hepatosplenomegaly, nephrocalcinosis, and dystonic cerebral palsy. Progressive multisystem involvement included glaucoma, congestive nephromegaly, hepatic venous stasis, pericardial effusions, cardiomyopathy, and brain atrophy. TRIO Exome in 2015 was nondiagnostic. At age 5, atypical HUS and multiorgan failure prompted an interferon signature and identification of compound heterozygous RNU7-1 mutations (c.31G>C; c.34_41del), a gene that had just been cloned. Patient 2 was noted at 13 months with global developmental delay. MRI revealed confluent white matter lesions. She developed spastic paraparesis and mild cognitive impairment. Early genetic evaluation at age 2 was unrevealing. After RNU7-1 cloning, reanalysis detected compound heterozygous variants (c.28C>T; c.54G>A). Type I interferon activation was marked. At age 10, she remains neurologically stable without systemic disease. JAK inhibitors were withheld, given uncertain efficacy and infection risk.

Conclusion: Interferon signatures should be part of the routine work-up in unclear neurologic disease with white matter involvement. Our cases demonstrate a genotype-phenotype correlation of AGS9 from fatal multisystem disease with a newly described atypical HUS in AGS9 to a milder, primarily neurologic form, and underpin the importance of periodic reevaluation of primary negative genetic analysis in order to identify variants in newly cloned genes.

Publication History

Article published online:
26 September 2025