A groundbreaking evaluation of shared sections of the genome, which suggests distant ‘relatedness,’ has uncovered previously undiagnosed instances of Long QT syndrome, a rare condition that may cause irregular heartbeats, fainting spells, and even sudden cardiac death.
The results, published in the journal Nature Communications, demonstrate the practicality of a new method developed by researchers at Vanderbilt University Medical Center to discover undiagnosed carriers of rare genetic variants linked to diseases.
“Rare genetic disorders are typically examined in referral groups—individuals referred to specialized clinics for assessment—but this strategy often inflates the actual impact on the population. A better understanding would come from evaluating larger non-referral groups, like biobanks,” explained Jennifer (Piper) Below, PhD, a professor of Medicine in the Division of Genetic Medicine and the senior author of the study.
Since most biobanks draw their participants from similar geographical areas, there tends to be considerable undisclosed relatedness among them, leading to shared genomic regions stemming from a common ancestry—these are known as “identical-by-descent” segments, Below clarified.
“Identical-by-descent segments allow us to group related individuals and identify rare genetic variants that may have originated from a shared ancestor,” she added.
The researchers created a genetic inference technique named DRIVE (Distant Relatedness for Identification and Variant Evaluation). The studies were spearheaded by co-first authors Megan Lancaster, MD, PhD, a clinical fellow in the Division of Cardiovascular Medicine, and Hung-Hsin Chen, PhD, a former postdoctoral fellow in the Division of Genetic Medicine. Dan Roden, MD, the Sam L. Clark, MD, PhD Chair and Senior Vice President for Personalized Medicine, is a co-senior author.
For the DRIVE testing, the researchers concentrated on a rare variant in the KCNE1 gene responsible for Type 5 Long QT syndrome (LQT5). The KCNE1 gene encodes a protein that alters potassium currents.
An international team collectively representing 26 centers found 89 probands (individuals affected by the condition and first subjects of a genetic investigation) who potentially had LQT5, along with 140 additional carrier relatives and 19 cases of another syndrome linked to KCNE1 variants.
Out of 35 probands exhibiting the most prevalent KCNE1 variant (p.Asp76Asn), nine (26%) were evaluated at the Genetic Arrhythmia Clinic at VUMC, with no prior knowledge of familial relations. Additionally, three relatives of these probands were also found to carry the same variant.
“The apparent concentration of this rare variant at VUMC compared to other centers in the consortium suggested these local probands might be distantly connected, and we could leverage that connection to uncover more carriers in BioVU,” Below stated. BioVU is VUMC’s DNA biobank linked to anonymized electronic health records.
The team initially estimated the genome-wide relatedness of the 12 clinically identified p.Asp76Asn carriers and constructed pedigree charts. They found eighth to ninth degree relatedness among the lineages (for context, fourth cousins—great-grandchildren of first cousins—are ninth-degree relatives), which supported the idea of a local common ancestor carrying the p.Asp76Asn variant.
Subsequently, the researchers identified common genomic regions that included the KCNE1 gene and employed DRIVE on 69,819 BioVU subjects. They discovered 22 individuals from BioVU with the shared region, validated the p.Asp76Asn variant through DNA sequencing, and examined electrocardiograms and medical histories for signs of LQT5.
Both referred and non-referred carriers of this variant exhibited prolonged QT intervals compared to control subjects.
“In this research, we utilized DRIVE to quickly identify 22 carriers of a previously recognized pathogenic gene variant,” Below remarked. “DRIVE could also be applied to uncover undiscovered gene variants, by grouping individuals with shared identical-by-descent segments and evaluating the clusters for disease prevalence.”
“We are thrilled about the prospects of DRIVE in identifying undiagnosed genetic disorder cases.”
Co-first author Chen is currently a tenure-track assistant research fellow at the Institute of Biomedical Science at Academia Sinica in Taiwan and holds a joint faculty position at VUMC. Other authors of the Nature Communications study include Benjamin Shoemaker, MD, Matthew Fleming, MD, PhD, Teresa Strickland, James Baker, Grahame Evans, Hannah Polikowsky, David Samuels, PhD, and Chad Huff, PhD. This research was partially funded by the National Institutes of Health (grants R01GM133169, R01HL159557, P50GM115305, U01HG011181, T32HG008962, T32GM007569, T32GM145734) and by the American Heart Association.
