Discordant phenotype caused by TREX1 variant in siblings with Aicardi-Goutières syndrome.

backgroundAutosomal recessive Aicardi-Goutières syndrome (AGS) and autosomal dominant familial chilblain lupus (FCL) are rare type I interferonopathies that can both result from loss-of-function variants in the TREX1 gene, which encodes a DNA exonuclease. Although phenotypic variability is well recognized in TREX1-related disorders, intrafamilial phenotypic discordance is seldom seen. CASE PRESENTATION: We describe two siblings carrying a novel homozygous TREX1 variant (c.341G > T, p.Arg114Leu) who exhibit strikingly different clinical phenotypes. The younger sibling presented at 4 months of age with features of AGS, including tetraspasticity, muscular hypotonia and global developmental delay. Brain MRI showed brain atrophy and white matter abnormalities. In contrast, his older brother developed cutaneous chilblain lesions during the cold season at age 3 but was otherwise normally developed. Despite these divergent clinical presentations, both children demonstrated a highly elevated interferon signature.

conclusionsThis case report expands the genetic and clinical spectrum of TREX1-related disorders and illustrates the considerable phenotypic variability associated with biallelic TREX1 variants in AGS. It highlights the complexity of genotype-phenotype correlations in type I interferonopathies and underscores the need for further research into factors that modulate disease expression.