Long QT and Jervell & Lange-Nielsen

Long QT syndrome (LQT) Disease of heart electrophysiology

Long QT syndrome (LQT) Caused by mutations in ion channels (eg KCNQ1, KCNE1, KCNH2, KCNE2) Can be asymptomatic or result in irregular heartbeats, dizziness, fainting fits or sudden death.

Jervell & Lange-Nielsen syndrome (JLNS) Early onset, severely prolonged QT (50% of patients die before the age of 15 without intervention) Congenital sensorineural deafness Two mutations in KCNQ1 and/or KCNE1 (often truncating)

Clinical utility of testing Diagnostic tests: genotype-phenotype correlations can help to advise on appropriate therapy and prevention –eg Beta blockers can control symptoms in over most individuals with KCNQ1 but are not protective if patients have an SCN5A mutation –eg Patients with KCNQ1 mutations should avoid competitive sport while those with KCNH2 mutations should avoid loud noises or emotional triggers

Clinical utility of testing Family tests: –Affected individuals can help to clarify pathogenicity of an uncertain variant can reduce the likelihood of a second pathogenic variant within the family –Unaffected individuals Negative result gives relief and means the patient can be released from clinical screening Positive result can aid compliance with clinical screening and preventative measures

KCNQ1 R518X Family

R518X/N

KCNQ1 R518X Family R518X/N N/N

KCNQ1 R518X Family R518X/N N/N R518X/N N/N

KCNQ1 R518X Family R518X/N N/N R518X/N N/N JLNS

KCNQ1 R518X Family R518X/N N/N R518X/N N/N JLNS R518X/N

KCNQ1 R518X Family R518X/N N/N R518X/N N/N JLNS R518X/N Full screen = R518X/N

KCNQ1 R518X Family R518X/N N/N R518X/N N/N JLNS R518X/N Full screen = R518X/N ?

Strategy Asked clinician (Geneticist) for more clinical details regarding JLNS patient –Severity eg QTc –Age of onset Also suggested Connexin gene testing

Results Asked clinician (Geneticist) for more clinical details regarding JLNS patient –Cardiologist did not respond to enquiries Also suggested Connexin gene testing

Results Asked clinician (Geneticist) for more clinical details regarding JLNS patient –Cardiologist did not respond to enquiries Also suggested Connexin gene testing –Came back positive for two mutations expected to cause deafness –Enabled us to resume genetic testing within this family

Lessons Importance of testing all affected individuals within a pedigree before beginning predictive testing (even for known pathogenic mutations) Importance of checking the whole pedigree (not just the proband) prior to initiating genetic testing in the lab Importance of communication between cardiologists, geneticists and scientists Clinicians are trained to pattern spot but scientists may have more detailed knowledge of particular specialities Utility of other clinical/genetic tests