VARIABLE EXPRESSION IN SAMHD1 - ASSOCIATED FAMILIAL AICARDI-GOUTIERES SYNDROME

Aicardi-Goutieres syndrome (AGS) is an encephalopathy of early childhood. This disorder is genetically heterogeneous, with mutations in seven genes having been identified to be disease-causing. Most patients with AGS present with poor developmental outcome and reduced survival in the neonatal period or early infancy. Significant variability can be found in the onset and phenotypic severity of the condition, sometimes even within the same family. Here we describe two sisters of mixed ancestry from the Western Cape province of South Africa presenting with skin manifestations of autoimmune disease resembling those of systemic lupus erythematosus (SLE) on histology but with negative serology. The two affected individuals carried a homozygous c. 1681_1682delAG; p. Ser561Phefs*61 mutation in exon 15 of SAMHD1 on chromosome 20. Both parents and the unaffected brother are heterozygous for this variant. The molecular investigation yielded a unifying diagnosis for an unusual combination of physical findings and differential phenotypic expression in the sisters. A confirmed diagnosis allowed for informed genetic counselling and targeted investigation and screening for complications such as glaucoma in the older sister.