Prospective Identification of Long QT Syndrome in Fetal Life
Condition: Long QT Syndrome
MeSH terms: Long QT Syndrome; Syndrome
Study type: Observational

Summary: 
      The postnatal diagnosis of Long QT Syndrome (LQTS) is suggested by a prolonged QT interval on
      12 lead electrocardiogram (ECG), strengthened by a positive family history and/or
      characteristic arrhythmias and confirmed by genetic testing. However, for several reasons
      such LQTS testing cannot be performed successfully before birth. First, fetal ECG is not
      possible and direct measure of the fetal QT interval by magnetocardiography is limited to
      fewer than 10 sites world-wide. Second, while genetic testing can be performed in utero,
      there is risk to the pregnancy and the fetus. Third, although some fetuses present with
      arrhythmias easily recognized as LQTS (torsade des pointes (TdP) and/or 2° atrioventricular
      (AV) block, this is uncommon, occurring in <25% of fetal LQTS cases. Rather, the most common
      presentation of fetal LQTS is sinus bradycardia, a subtle rhythm disturbance that often is
      unappreciated to be abnormal. Consequently, the majority of LQTS cases are unsuspected and
      undiagnosed during fetal life, with dire consequences. For example, maternal medications
      commonly used during pregnancy can prolong the fetal QT interval and may provoke lethal fetal
      ventricular arrhythmias. But the most significant consequence is the missed opportunity for
      primary prevention of life threatening ventricular arrhythmias after birth because the infant
      is not suspected to have LQTS before birth. The over-arching goal of the study is to overcome
      the barriers to prenatal detection of LQTS. The investigators plan to do so by developing an
      algorithm using fetal heart rate (FHR) which will discriminate fetuses with or without LQTS.

      Immediate Goal: The investigators propose a multicenter pre-birth observational cohort study
      to develop a Fetal Heart Rate (FHR)/Gestational Age (GA) algorithm from a cohort of fetuses
      recruited from 13 national and international centers where one parent is known by prior
      genetic testing to have a mutation in one of the common LQTS genes: potassium voltage-gated
      channel subfamily Q member 1 (KCNQ1), potassium voltage-gated channel subfamily H member 2
      (KCNH2), or sodium voltage-gated channel alpha subunit 5 (SCN5A). The investigators have
      chosen this population because 1) These mutations are the most common genetic causes of LQTS,
      and 2) Offspring will have high risk of LQTS as inheritance of these LQTS gene mutations is
      autosomal dominant. Thus, progeny of parents with a known mutation are at high (50%) risk of
      having the same parental LQTS mutation. The algorithm will be developed using FHR measured
      serially throughout pregnancy. All offspring will undergo postnatal genetic testing for the
      parental mutation as the gold standard for diagnosing the presence or absence of LQTS.
    

Detailed description: 
      Ascertainment of LQTS, an inherited arrhythmia disorder in a group of conditions known as the
      channelopathies, is challenging before birth. Recently, in a retrospective study it was
      reported that a gestational age dependent bradycardia allows a much higher recognition of
      genotype positive LQTS than the standard obstetrical gestational age independent definition
      of bradycardia (Mitchell 2012).

      However, the fetal heart rate in pregnancies with maternal or paternal LQTS diagnosed prior
      to the pregnancy has not been evaluated prospectively from the first trimester to birth. Nor
      is it known if the fetal heart rate /gestational age profile might be mutation specific. In
      addition, the use of fetal heart rate to successfully distinguish between LQTS and normal
      fetuses of pregnancies in which a parent has a known mutation has not been tested.

      The investigators believe that fetuses with an LQTS mutation born to families in which the
      mother or father has an LQTS mutation will have slower heart compared to fetuses, shown after
      birth not to have the family mutation. If the investigators hypothesis is correct, these
      findings could be applied to the general population of pregnant women to prospectively
      identify fetuses with LQTS and without a known family history. Since a fetal proband has been
      led to the identification of unsuspecting family members, prospectively identifying affected
      fetuses would increase ascertainment of life-threatening mutations in all ages (Cuneo 2013).
    

Observational model: Cohort
Time perspective: Other
Sampling method: Non-Probability Sample
Study population: 
        Up to 500 total subjects will be enrolled globally. Up to 303 subjects will be enrolled
        locally. This number includes mothers, fetuses, and fathers who have long QT syndrome.