Diagnosis of Atypical Iron Disorders: Clinical application of Next Generation Sequencing — ASN Events
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Diagnosis of Atypical Iron Disorders: Clinical application of Next Generation Sequencing (#372)

Cameron J McDonald 1 , Daniel F Wallace 1 , Darrell HG Crawford 2 3 , V Nathan Subramaniam 1 2
  1. The Membrane Transport Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia
  2. Liver Research Centre, School of Medicine, University of Queensland, Brisbane, Queensland, Australia
  3. Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Brisbane, Queensland, Australia

Most disorders of primary iron overload and iron-refractory anaemia have a genetic origin. Hereditary haemochromatosis (HH) due to mutations in the HFE gene affects around 1 in 200 people of northern European descent. Mutations in a number of other genes are collectively termed non-HFE HH. Our group has identified and characterised a number of novel mutations associated with genetic iron disorders in the Asia-Pacific region.

We have applied Next Generation Sequencing technology to the identification and diagnosis of genetic iron disorders in a systematic fashion, enabling the rapid and comprehensive analysis of many genes implicated in iron disorders.

The Ion Torrent Personal Genome Machine is the first sequencing platform to utilise post-light technology. Sequencing is performed directly on silicon chips, reducing the run and analysis processing time from weeks to a single day.

This technology has been combined with a custom designed amplification approach to provide high coverage sequencing of 11 core iron regulatory genes including full coding, UTRs, intron-exon boundaries, and promoter regions. These genes cover known causative genes of both iron overload and anaemia including HFE, HJV, Hepcidin, TFR2, Ferroportin, FTL, FTH1, TFR1, TF and TMPRSS6. A further 20 genes with potential regulatory effects will also be sequenced.

Ultimately, we intend to establish an International Referral Centre for Iron Disorders where these analyses are performed routinely utilising this technology. This Centre will provide a valuable resource for both clinicians and researchers within the Asia-Pacific region, and eventually worldwide. The comprehensive gene panel eliminates the individual candidate genes approach, significantly increasing the probability of identifying causative mutations in genetic iron disorders. The sequencing and clinical data will also be compiled into a database, building an un-paralleled resource for the identification of modifiers of iron status, disease penetrance and the natural history of these disorders.