The Promise and Peril of Precision Medicine: Phenotyping Still Matters Most

Abstract

We illustrate the work necessary to reverse course after identification of a KCNQ1 variant interpreted erroneously as causing long QT syndrome (LQTS) and to identify the true cause of a case of sudden death in the young. Surrogate genetic testing of a decedent's living brother identified a rare KCNQ1-V133I variant, which prompted an implantable cardioverter defibrillator and subsequent diagnosis of LQTS in other family members. Subsequently, this presumed LQT1 family came to our institution for further clinical evaluation and research-based investigations, including KCNQ1-V133I variant-specific analysis of the decedent, heterologous expression studies of KCNQ1-V133I, and a whole-exome molecular autopsy along with genomic triangulation using his unaffected parents' DNA. After evaluating several V133I-positive family members, clinical doubt was cast on the veracity of the previously levied diagnosis of LQT1, resulting in a re-opening of the case and an intense pursuit of the lethal substrate. Furthermore, the decedent tested negative for V133I, and heterologous expression studies demonstrated a normal cellular phenotype for V133I-containing Kv7.1 channels. Instead, after whole-exome molecular autopsy, a de novo pathogenic variant (p.R454W) in DES-encoded desmin was identified. As detailed herein, the forensic evaluation of sudden death in the young requires meticulous focus on the decedent followed by a careful and deliberate assessment of the decedent's relatives. Surrogate genetic testing can have disastrous consequences and should be avoided. Genetic test results require careful scrutiny to avoid unintended and potentially devastating repercussions. Although the root cause of the decedent's tragic death would have remained a mystery, the unintended consequences for the living relatives described herein might have been avoided based on clinical grounds alone. All family members had electrocardiograms with normal QT intervals, making the diagnosis of familial LQTS unlikely. As such, if the clinicians caring for these patients had focused solely on clinical data from the survivors, there might have been no reason to embark on a path of inappropriate treatment based on genetic testing.

FIGURE 1.

Representative 12-lead electrocardiogram for the KCNQ1-V133Iepositive living brother of the boy with sudden death in the young. Note the normal QTc and normal T wave architecture, as well as an atrial-paced rhythm associated with the implanted pacemaker-defibrillator.

FIGURE 2.

Heterologous expression studies showed wild-type (WT) behavior for V133I-containing Kv7.1 channels. A, Representative families of IKs measured from cells co-expressing the beta subunit KCNE1 along with WT KCNQ1 (n=9), V133I-Kv7.1 (n=11), or WT plus V133I-Kv7.1 (WT/V133I, n=13). The dotted line corresponds to the zero current baseline. IKs values were recorded by applying steplike pulses from e80 mV (holding potential) to 70 mV in 10-mV increments for 5 seconds, immediately followed by a tail pulse for 5 seconds at e50 mV. Peak step (B) and tail (C) IKs values are plotted as a function of the step pulse potential for cells expressing WT, V133I-Kv7.1, or WT/V133I. Peak tail IKs values were measured at initiation of the tail pulse and were described using a Boltzmann equation (gray line,Figure 1C). The Boltzmann equation calculated the IMAX (D), V¹/₂(E), and slope factor, k (F). Data are reported as the mean ± SE. pA/pF = picoamperes per picofarad.

FIGURE 3.

Whole-exome molecular autopsy and genomic triangulation. Workflow for whole-exome sequencing (WES) and variant analysis for the identification of novel genetic variants causative of sudden unexplained death. ExAC = Exome Aggregation Consortium.

FIGURE 4.

Identification of a sporadic missense variant, p.R454W, in DES-encoded desmin. A, Sanger sequencing chromatograms for a healthy control (top) and the DES-R454Wepositive boy with sudden death in the young (bottom). B, Schematic representation of the linear topology for desmin with localization of the R454W mutation indicated. C, American College of Medical Genetics and Genomics’ variant assessment to determine pathogenicity for DES-R454W, with the fulfilled criterion shaded in light orange. INDEL = insertion/deletion; LOF = loss of function.