Atypical Aicardi-Goutieres syndrome: is the WRN locus a modifier?

[werner syndrome]

We describe a 28 -year -old Turkish man with consanguineous parents who presented with an aged appearance with prematurely gray hair and scleroderma -like skin , spastic paraplegia , and apparent disability . The proband and each of his parents were heterozygous for a mutation in WRN , which could not explain his symptoms . Exome sequencing of the proband 's blood DNA showed a homozygous c .626 -1 G > C mutation in intron 5 of the SAMHD 1 gene , which encodes a triphosphohydrolase involved in the regulation of intracellular dNTP pools and which is mutated in Aicardi-Goutieres syndrome . The RNA studies confirmed aberrant splicing of exon 6 , and family studies showed that both parents are heterozygous for this mutation . We conclude that mutations in SAMHD 1 - in addition to causing an early -onset form of encephalopathy in Aicardi-Goutieres syndrome - may present with modest signs of accelerated aging similar to Werner syndrome . The extent to which heterozygosity at the WRN locus may modify the effect of biallelic SAMHD 1 mutations is unknown . It is conceivable that synergistic effects of these two mutations might be responsible for the unusual phenotype .