Abstracts

Rationale:
Variants in the KCNQ2 gene are associated with benign familial neonatal seizures and early onset epileptic encephalopathy. Timely genetic evaluation is essential to establish the molecular diagnosis, inform therapeutic treatment and risk of recurrence, and connect children and families to support services and clinical trials. Anecdotally, parents often report long delays in obtaining a genetic diagnosis. Here we report on multiple testing methods leading to identification of a KCNQ2 variant and length of time to a genetic diagnosis in order to evaluate testing modalities and length of diagnostic journey.
Method:
Pediatric patients with previously identified variants in KCNQ2 were enrolled in a Boston Children’s Hospital IRB-approved Natural History Study. Recruitment of participants was facilitated by the KCNQ2 Cure Alliance Foundation, self-referral, and physician referral. We collected medical, genetic and family history by review of medical records and parent completion of a detailed questionnaire. We focused specifically on the laboratory methods utilized in an attempt to identify a genetic etiology, and the time elapsed between onset of seizures and genetic diagnosis.
Results:
A total of 71 families enrolled in the BCH KCNQ2 Natural History Study, and of those 41 completed the questionnaire. KCNQ2 variants were present in all 41 patients, whose age ranged from 11 months to 29 years at the time of enrollment. Twenty-nine of the 41 participants (70.73%) had variants which were identified via multi-gene panel (MGPT), ten (24.39%) had variants which were identified via whole exome sequencing (WES), and 1 (2.44%) had a variant identified via chromosomal microarray analysis (CMA). In 1 participant (2.44%) the genetic testing type that identified the KCNQ2 variant was unreported. The majority of reported variants were de novo (34/41, 82.93%), and 2/41 (4.88%) variants were inherited. Parental testing was not complete in 5/41 (12.2%) of participating families. All 41 patients began having seizures by or before 5 months of age, with 82.93% presenting within the first week of life. We were able to determine the exact date of laboratory diagnosis for 25 of the 41 participants (19 MGPT, 6 WES).The average time from seizure onset to molecular diagnosis was 566 days, with a range of 14 to 4,878 days. Patients diagnosed via MGPT waited an average of 245 days, while those diagnosed via WES waited an average of 1,354 days. Of the six patients diagnosed via WES for which the time to diagnosis was known, five had more than three genetic evaluations performed prior to WES but only one had MGPT prior to WES. Twenty-six of the 41 participants (63%) had two or fewer genetic tests completed.
Conclusion:
Data suggests that a KCNQ2 diagnosis may be made with several different testing methodologies. There are multiple modalities that can be used to reach a diagnosis, and a large range in length of time elapsed between seizure onset and genetic diagnosis. The diagnostic journey for patients is significant as it contributes to reproductive counseling and family planning, opportunities for families to participate in gene-specific support groups and services, and opportunities to participate in natural history studies and clinical trials. Additionally, the rate of de novo variants reported in our cohort may be an overestimate, as parental mosaicism is challenging to detect. There is some evidence that low level somatic or gonadal parental mosaicism in epilepsy-related neurodevelopmental disorders is higher than what has been reported in the past. Mosaic carrier testing, which has recently become available, may be important for parents of children with apparently de novo variants, in order to more accurately assess recurrence risk for future pregnancies.
Funding:
:N/A