Atypical Aicardi‐Goutieres syndrome: Is the WRN locus a modifier?

Abstract

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.626-1G>C mutation in intron 5 of the SAMHD1 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 SAMHD1 - 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 SAMHD1 mutations is unknown. It is conceivable that synergistic effects of these two mutations might be responsible for the unusual phenotype.

Werner syndrome: Clinical features, pathogenesis and potential therapeutic interventions

“…Both of the SPRTN mutant individuals we studied developed hepatomas. We have also identified homozygous SAMHD1 (SAM domain- and HD domain-containing protein 1) mutation in a patient with progeroid feature and progressive ataxia (Lessel et al, 2014a). SAMHD1 encodes a dNTP pool regulator with 3′→5′ exonuclease activity, has been implicated in DNA damage response (Beloglazova et al, 2013), and when mutant has been linked to a subset of Aicardi-Goutieres syndrome (AGS).…”

“…AGS is a genetically heterogeneous neurological disorder known for pronounced phenotypic variability. Our SAMHD1 mutant AWS patient carried a heterozygous WRN mutation which might have synergistic effects with SAMHD1 mutation (Lessel et al, 2014a). Searches for novel genetic alterations in additional AWS cases are currently in progress.…”

Limb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations

“…46 In this family, both parents were doubly heterozygous for RAPSN and AK9 variants and were asymptomatic, indicating the digenic inheritance is of autosomal recessive inheritance, this is the first time that this specific genotype-phenotype correlation is reported. A number of heterozygous AK9 probablydamaging missense variants have been identified in normal populations.…”

How Research on Human Progeroid and Antigeroid Syndromes Can Contribute to the Longevity Dividend Initiative

“…Genomic rearrangements with or without involvement of neighboring loci have also been identified. With the advancement of next-generation DNA sequencing, WRN heterozygous disease mutations have been identified in association with at least one other known genetic disorder (see below, Aicardi–Goutieres syndrome) (Lessel et al 2014a). …”

“…In particular, phenotypes associated with SAMHD1 mutations range from “classical” presentations to those with mild intellectual disability or a nonspecific chronic inflammatory skin condition (Rice et al 2009; Dale et al 2010). A Turkish pedigree with a homozygous AGS mutation was identified among subjects enrolled in the International Registry of WS as having atypical WS (Lessel et al 2014a). The patient also carried a heterozygous WRN mutation, raising the possibility that heterozygosity at the WRN locus may modify AGS phenotypes.…”