Cardiac Ion Channelopathies in Stillbirths
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Cardiac Ion Channelopathies in Stillbirths

(pleasant music) – [Instructor] This is an overview of an article entitled
Post-Mortem Genetic Testing for Cardiac Ion
Channelopathies in Stillbirths published in the January 2018 issue of Circulation: Genomic
and Precision Medicine. Stillbirth is a substantial
health issue worldwide. With an estimated 3.2 million
cases occurring each year on the order of one in every 200 births in developed countries. Two thirds of the cases are attributed to placental complications
and an additional fraction of cases have gross genetic abnormalities as indicated by abnormal karyotypes. Perhaps up to 30% of
stillbirths have contributions from gene mutations with
the most likely candidates being mutations in genes previously linked to sudden cardiac death,
such as those involved in the long QT and short QT syndromes. The authors of the paper under discussion assessed a series of cases
of unexplained stillbirths in four hospitals in the
UK between 2007 and 2013. They were able to obtain high quality DNA suitable for sequencing
studies in 70 out 242 cases. For these 70 cases, they
performed targeted sequencing of 35 genes: 12 log QT or short QT genes and 23 genes nominated by
genome mod association studies and other genetic studies of
clinically relevant phenotypes such as QT interval, catecholaminergic, polymorphic ventricular tachycardia, developmental disorders
and sudden cardiac death. On the right is the schematic explaining how the authors prioritized variants identified by the sequencing studies. Out of a total of 327
non-synonymous variants in the 70 cases, after filtering by
rarity in the population and predictions of pathogenicity, there were 28 rare variants
of uncertain significance, seven rare variants of
uncertain significance that had not been previously cataloged and five rare variants for which there was either prior functional evidence or, in one case, for which functional data was obtained in this study. Here is that one variant:
Arginine 40 to Glutamine in the gene KCNJ2, which encodes an inwardly
rectifying potassium channel and has previously been
found to be a cause of a long QT syndrome
and a short QT syndrome. The variant is located in
the end terminal portion of the protein, as shown here. Just going by the location
alone, it is unclear without functional testing
whether this variant might be pathogenic. The authors tested whether
the KCNJ2 Arginine 40 to Glutamine variant impaired the function of the protein product. Without getting too deep
into the technical details, the experiment involved placing a normal or wild type or WT version of the KCNJ2 gene into cells, the Arginine 40 to Glutamine
or R40Q mutant version of the gene into cells, as well as the gene with
a different KCNJ2 variant, T535A and a negative control called pcDNA3.1 here. Compared to the normal
WT version of the gene, the R40Q mutant gene caused impaired electrophysiological
properties in the tested cells, as can be seen in the top
figure and the bottom figure shown on the slide. In contrast, the T535A mutant gene looks identical to the normal gene. These results indicate that
the Arginine 40 to Glutamine mutation might be pathogenic. Here are the five rare
variants in long QT syndrome related genes that have
prior functional evidence of pathogenicity,
including the KCNJ2 variant shown on the last two slides. There’s a higher likelihood
of these variants being the cause of fetal demise compared to variants of
uncertain significance identified in other cases in the study. In conclusion, this study
of 70 stillborn cases identified a number of rare
or novel variants in genes previously linked to
cardiac ion channelopathies in sudden cardiac death. Five of the variants
have functional evidence suggesting they might
have directly contributed to fetal demise via sudden cardiac death whereas causative roles
for the larger number of variants of uncertain
significance found in this study are less clear. Functional testing of those variants of uncertain significance
could potentially shed light on whether they contributed
to fetal demise. (upbeat music)

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