Innovative genomic approach identifies rare carriers of Long QT syndrome

A novel analysis of shared segments within the genome – an indication of distant “kinship” -? has identified undiagnosed cases of Long QT syndrome, a rare disorder that can lead to abnormal heart rhythms, fainting and sudden cardiac death.

The findings are reported in the journal Nature communicationsillustrate the feasibility of the new approach developed by researchers at Vanderbilt University Medical Center to detect undiagnosed carriers of rare disease-causing genetic variants.

Rare genetic diseases are usually studied in referral populations -; people referred to specialist clinics for assessment – but this approach often overestimates the true population impact, which could be better assessed in large non-referral populations such as biobanks.’

Jennifer (Piper) Below, PhD, professor of Medicine in the Division of Genetic Medicine and senior corresponding author of the new study

Because most biobanks recruit participants from the same region, there is often significant undocumented relatedness between participants, resulting in genomic segments shared by common ancestry -. segments “identical by origin”, explained below.

“Identical segments of ancestry give us the opportunity to bring together related people to find rare variants that were present in a common ancestor,” he said.

To do this, the researchers developed a genetic inference method called DRIVE (Distant Relatedness for Identification and Variant Evaluation). The studies were conducted by co-first authors Megan Lancaster, MD, PhD, a clinical fellow in the Division of Cardiovascular Medicine, and Hung-Hsin Chen, PhD, who was a postdoctoral fellow in the Division of Genetic Medicine. Dan Roden, MD, Sam L. Clark, MD, PhD Chair and Senior Vice President for Personalized Medicine, is co-senior author.

To test DRIVE, researchers focused on a rare variant of the KCNE1 gene that causes long QT syndrome type 5 (LQT5). The KCNE1 gene encodes a protein that modifies potassium currents.

An international consortium of 26 centers had identified 89 individuals (affected individuals who are the first subjects of a genetic study) with probable LQT5, 140 additional carrier relatives, and 19 cases of another syndrome attributable to KCNE1 variants.

Of 35 patients with the most common KCNE1 variant (p.Asp76Asn), nine (26%) were evaluated by the Genetic Arrhythmia Clinic at VUMC. None of the potentials were known to be related. Three relatives of the children were also found to carry the variant.

“This enrichment of a rare variant at VUMC relative to other consortium centers suggests that these local probands may be distantly related, and that we could use this association to identify additional carriers at BioVU,” Below said. BioVU is VUMC’s DNA biobank linked to de-identified electronic health records.

The team first calculated the genome-wide relatedness of 12 clinically identified p.Asp76Asn carriers and constructed pedigrees. They found eighth- to ninth-degree relatedness between these lineages (for reference, fourth cousins ​​-? great-grandchildren of first cousins ​​-? are ninth-degree relatives), supporting the hypothesis of a local common ancestor with the p.Asp76Asn variant.

The researchers then identified common genomic regions spanning the KCNE1 gene and applied DRIVE to 69,819 BioVU individuals. They identified 22 BioVU subjects with the common region, confirmed the p.Asp76Asn variant by DNA sequencing, and evaluated electrocardiograms and medical records for features of LQT5.

Both referral and non-referral carriers of the variant have a prolonged QT interval compared with controls.

“In this study, we used DRIVE to rapidly identify 22 carriers of a previously described pathogenic gene variant,” Below said. “DRIVE could also be used to identify unknown causative gene variants by grouping individuals with shared segments identical by ancestry and assessing disease enrichment within groups.

“We are excited about DRIVE’s potential to identify undiagnosed cases of genetic disease.”

Co-first author Chen is now a research assistant at the Institute of Biomedical Science at Academia Sinica in Taiwan and holds a joint professorship appointment at VUMC. Other authors of Nature communications The study includes Benjamin Shoemaker, MD, Matthew Fleming, MD, PhD, Teresa Strickland, James Baker, Grahame Evans, Hannah Polikowsky, David Samuels, PhD, and Chad Huff, PhD. The research was supported in part by the National Institutes of Health (grants R01GM133169, R01HL159557, P50GM115305, U01HG011181, T32HG008962, T32GM007569, T32GM007569, T32GM14 Art Association).