Repeated 2nd trimester fetal demise often due to “long QT syndrome”

by faithgibson on October 24, 2014

Here is info from a recent study; possibly related, though not very helpful to someone suffering from these experiences.

Judith Rooks, CNM, MPH
Portland, Oregon

Lost Pregnancies Linked to Long QT Mutations

Main Points

In this convenience sample of unexplained fetal loss, 9% of embryos studied had mutations in genes associated with long QT syndrome.
Minor gene variants that play a role in long QT syndrome were not assessed; the impact of long QT genes on fetal loss may be higher than estimated.

At least some unexplained miscarriages and stillbirths appear to be
associated with mutations in genes for long QT syndrome susceptibility,
researchers found.

Abnormalities in the three most common such genes — KCNQ1, KCNH2, and SCN5A
— turned up in eight out of 91 fetal deaths examined in a molecular genetic
analysis by Michael J. Ackerman, MD, PhD, of the Mayo Clinic in Rochester,
Minn., and colleagues.

Three were potentially pathogenic and another five cases had rare genetic
variants found to affect long QT syndrome-associated ion channel function in
a way that could cause life-threatening arrhythmias, the group reported in
the April 10 issue of the Journal of the American Medical Association.

That overall rate of 9% long QT syndrome-related genetics far exceeded the
general population prevalence of less than 1%, coming closer to the 10% of
sudden infant death syndrome (SIDS) cases thought to be attributed to long
QT syndrome.

A role in unexplained fetal death is “an intriguing concept” given the link
in SIDS and the described continuum between stillbirths and SIDS, Alan E.
Guttmacher, MD, of the NIH National Human Genome Research Institute in
Bethesda, Md., and colleagues wrote in an accompanying editorial.

They agreed with the researchers, though, that further study of cardiac
arrhythmias as a cause of fetal loss is needed to confirm the preliminary

“Understanding the etiology of stillbirth is essential not just for crafting
effective prevention strategies but also for providing families and
clinicians with counseling information and the opportunity for a greater
sense of closure,” they wrote.

While about half of fetal deaths can be attributed to chromosomal or
congenital abnormalities, maternal or fetal infection, hemorrhage, placental
or cord abnormalities, and maternal diseases, another 25% to 40% go

Translating these results into prescreening for women or even correction of
the genetic dysfunction is far off, noted Wojciech Zareba, MD, PhD, a
cardiologist and long QT syndrome expert at the University of Rochester,
N.Y., but the study did turn up a finding that could have ramifications for
treatment of adult arrhythmias, he commented in an interview with MedPage

Some of the genetic variants found have been previously described as related
to long QT syndrome, but several new abnormalities in two channel genes were
identified in the study and shown to have functional significance in in
vitro testing.

“Some of those variations may play a major role in proarrhythmia in
drug-induced QT prolongation as well as may eventually cause sudden death in
people with conditions like myocardial infarction or with cardiomyopathy,”
Zareba said.

The retrospective postmortem genetic testing included a convenience sample
of 91 unexplained intrauterine fetal deaths (30 before 20 weeks’ gestation)
over a 6-year period examined by the Mayo Clinic in Rochester and another
center in Italy, looking at the three major susceptibility genes that
account for 75% of long QT syndrome.

The analysis looked for “putative pathogenic mutations based on their
absence in more than 1,000 ethnically similar controls, a heterozygote
frequency below the prevalence of long QT syndrome in the general population
(0.05%) as determined by analysis of more than 10,000 publicly available
exomes, and an abnormal functional electrophysiological profile.”

They found one girl and one boy both of whom died at 16 weeks’ gestation
with a loss-of-function mutation in KCNQ1 consistent with in-utero long QT
syndrome type 1.

A third case, a boy who died at 33 weeks, had a loss-of-function mutation in
KCNH2 consistent with in utero long QT syndrome type 2.

Another five had rare nonsynonymous genetic variants in SCN5A consistent
with potentially proarrhythmic phenotypes when tested for functional
consequences through in vitro electrophysiological studies.

The researchers cautioned that they may have underestimated the prevalence
of long QT syndrome-associated mutations in unexplained fetal deaths by not
assessing the 12 known minor susceptibility genes and by using a type of
analysis that may miss homozygous mutations and large gene rearrangements,
such as copy number variations.

Other limitations pointed out by the editorialists were lack of description
of how fetal age was determined or the extent and uniformity of workup for
fetal deaths.

Moreover, the convenience sample meant the study couldn’t estimate the
prevalence of the genetic abnormalities among all unexplained pregnancy
losses or how the findings might apply to families with multiple losses,
they added.

The study was supported by the Mayo Clinic Windland Smith Rice Comprehensive
Sudden Cardiac Death Program, the Sheikh Zayed Saif Mohammed Al Nahyan Fund
in Pediatric Cardiology Research, the Dr. Scholl Foundation, the Hannah M.
Wernke Memorial Foundation, the National Institutes of Health, and the
Italian Ministry of Health.

Ackerman reported receiving royalties personally and to his institution from
Transgenomic and received a grant from the NIH.

Intellectual property derived from the research program resulted in license
agreements between Mayo Clinic Health Solutions and PGxHealth, now acquired
by Transgenomic.

The editorialists and Zareba reported having no conflicts of interest to

Primary source: Crotti L “Long QT syndrome‚Äďassociated mutations in intrauterine fetal death”
JAMA 2013; 309: 1473-1482.

Additional source: Guttmacher AE, et al “Long QT syndrome susceptibility mutations and pregnancy loss: Another piece of a still unfinished puzzle?” JAMA 2013; 309:

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