A two year prospective population-based molecular autopsy evaluation of post-mortem negative sudden death in 0-40 year olds

  • A/Prof Jonathan Skinner, Starship Childrens Hospital, Auckland, New Zealand
  • Ms Jackie Crawford, Starship Childrens Hospital, Auckland, New Zealand
  • Ms Carey-Anne Eddy, University of Auckland, New Zealand
  • Ms Katherine Neas, Central and Southern Regional Clinical Genetic Service, New Zealand
  • Dr Simon Stables, National Forensic Service, Lab Plus, Auckland, New Zealand
  • Dr Lloyd Denmark, Lab Plus, Auckland, New Zealand
  • Prof Donald Love, Lab Plus, Auckland, New Zealand
  • A/Prof Andrew Shelling, University of Auckland, New Zealand

    • Background
    Referral-based genetic studies of sudden unexplained death suggest about 30% of 1-40 year old deaths (SUDY) and 0-10% of infant deaths(SIDS) are due to long QT syndrome .
    Aims
    To ascertain the value of post mortem long QT genetic analysis in a prospective population-based study of SIDS and SUDY.
    Methods
    Coroners and pathologists in New Zealand (population 4.2 million) agreed a national policy of molecular autopsy in SIDS/SUDY. Over 2 years long QT (LQT) genes 1, 2, 3, 5, 6, and 7 were sequenced.
    Results
    Autopsy DNA was originally stored from 69 SIDS and 71 SUDY, In 59, other tests revealed a diagnosis (eg. bacterial infection 9, cardiomyopathy 7, myocarditis 5). Of the others, 47 LQT genetic tests are completed. 42 (89%) were uninformative.
    3 of 32 SIDS (9%) had the unclassified variant R1193Q in the SCN5A gene (of questionable pathogenicity).
    Two of seven (29%) 1-18 yr olds had LQT gene variants. A 17 yr old girl (nocturnal death) had variant R67H in minK (LQT5), previously seen in a LQTS family. A 10 yr old boy (death following light activity) had the novel variant T96R in KCNQ1 (LQT1), which displayed abnormal ion channel electrophysiology (loss-of-function and positively shifted voltage dependence of activation). None of 8 19-40 year olds had variants.
    Conclusions
    Early results show that molecular autopsy for LQTS in post mortem-negative sudden death is of value in 1-18 year olds. Larger numbers are still required in those <1 year and over 18 years of age.