Striking intrafamilial phenotypic variability in Aicardi–Goutières syndrome associated with the recurrent Asian founder mutation in RNASEH2C

Abstract

Aicardi-Goutières syndrome (AGS) is an encephalopathy of early childhood which is most commonly inherited as an autosomal recessive trait. The disorder demonstrates significant genetic heterogeneity with causative mutations in five genes identified to date. Although most patients with AGS experience a severe neonatal or infantile presentation, poor neurodevelopmental outcome and reduced survival, clinical variability in the onset and severity of the condition is being increasingly recognized. A later presentation with a more variable effect on development, morbidity and mortality has been particularly observed in association with mutations in SAMHD1 and RNASEH2B. In contrast, the recurrent c.205C > T (p.R69W) RNASEH2C Asian founder mutation has previously only been identified in children with a severe AGS phenotype. Here, to our knowledge, we present the first report of marked phenotypic variability in siblings both harboring this founder mutation in the homozygous state. In this family, one female child had a severe AGS phenotype with an onset in infancy and profound developmental delay, whilst an older sister was of completely normal intellect with a normal head circumference and was only diagnosed because of the presence of chilblains and a mild hemiplegia. An appreciation of intrafamilial phenotypic expression is important in the counseling of families considering prenatal diagnosis, and may also be relevant to the assessment of efficacy in future clinical trials. In addition, marked phenotypic variation raises the possibility that more mildly affected patients are not currently identified.

Type I interferonopathies: Mendelian type I interferon up-regulation

“…There is important clinical overlap in regards of the vasculitic skin lesions seen in SAVI and AGS, but clear phenotypic differences between these genotypes also exist; particularly, pulmonary disease has not been reported in AGS, and none of the SAVI patients so-far described demonstrated a neurological phenotype. These differences may relate to variable tissue expression, differential exposure to pathogens, or unrecognized stochastic factors -since it is clear that disease expression can vary within a single genotype, and indeed within a single family [34]. Of note, in a mouse model of AGS due to mutations in the DNA exonuclease Trex1, the development of disease features is STING [35 ], and likely cGAS [36], dependent.…”

Aicardi–Goutières syndrome and the type I interferonopathies

“…Some of these differences might reflect tissue-specific expression of the relevant gene or protein. However, variability in age of onset (agerelated penetrance) and disease expression can be observed across a single genotype 10 and even within a single family 79,92 . As an example, heterozygous mutations in IFIH1 can be associated with classical AGS showing a prenatal onset, sub acute neurodegeneration occurring after 1 year of age, slowly progressing non-syndromic spastic paraparesis into adulthood, or complete clinical non-penetrance 9 .…”

Type I interferonopathies—an expanding disease spectrum of immunodysregulation

“…AGS patients typically exhibit constitutive upregulation of ISGs in peripheral blood cells which is also referred to as type I IFN signature [23]. The intrafamilial variability can be high with one sibling presenting with classic AGS and the other with only mild spasticity and normal intellectual abilities [24,25]. AGS is a genetically heterogenous disorder caused by mutations in at least seven different genes ( Fig.…”