Project FIND-OUT: Outpatient Genome Sequencing in Expanded Pool of Symptomatic Infants at Risk for Genetic Neurodevelopmental Disorders Provides Earlier Diagnoses
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction:
While there are myriad challenges to diagnosing rare, genetic neurodevelopmental disorders (RGNDs), of particular concern is an average delay of 30 months between the first identification of symptoms and receipt of a diagnosis. Factors contributing to that delay include lack of guidelines for genetic testing of infants in outpatient settings, long wait times for specialist appointments, limited access to genetic specialists, and restrictive insurance policies. Project FIND-OUT aims to determine the utility of whole genome sequencing (WGS) for symptomatic infants at-risk for RGNDs in the outpatient setting. Here, we present the results of a pilot study of 50 participants.
Methods:
Project FIND-OUT provided free WGS to the families of 50 infants aged 3-12 months, most of whom were self-referred via internet search or social media. Several families were referred by healthcare providers (HCPs). All infants were required to be located in the US and have no prior WGS. To be eligible, infants needed to meet at least two of the seven FIND-OUT criteria: Feeding issues, Issues with movement, NICU admission, Developmental delay, Other (e.g., congenital malformations, atypical growth, specialist referral), Unprovoked seizures, or Tone issues. The study was conducted under Northstar IRB-approved protocol NB300133; buccal samples were analyzed at a CLIA/CAP-certified laboratory, and pre- and post-test genetic counseling was provided via telehealth.
The primary measure evaluated was diagnostic yield. A literature review was conducted, and while there were no studies on diagnostic yield in infants meeting the FIND-OUT criteria, available studies of children who received genetic testing based on one or more of the FIND-OUT criteria demonstrated diagnostic yields between 17%-47%. Therefore, we hypothesized that Project FIND-OUT would produce a 20% diagnostic yield.
Results:
From December 2023-September 2024, 50 patients were enrolled, meeting an average of 4.2 FIND-OUT criteria. 43 patients were self-referred, while 7 patients were referred to the study by HCPs. Families reported they enrolled in Project FIND-OUT due to physician (including specialists and geneticists) unwillingness to order testing, insurance barriers, long wait times to see genetics, and a desire to optimize their child's care and understand how their child’s symptoms may evolve.
The average age at enrollment was 8.8 months, ranging from 3-12 months. The average turnaround time from enrollment to results was 30.98 days, ranging from 16-73 days. To date, 48 WGS results have been returned. 12 patients (25%) received a pathogenic or likely pathogenic genetic diagnosis explaining their symptoms, 3 received a pathogenic secondary finding (7% of the 43 who opted in), 9 (19%) had a variant of uncertain significance, and 24 (50%) received a negative result. Additionally, 9 patients (19%) were found to have carrier status for a recessive disorder. Patients referred by HCPs had a higher diagnostic yield than self-referred patients. Other than G6PD deficiency, no two patients received the same diagnosis. 11 patients were diagnosed with neurodevelopmental disorders and one was diagnosed with a rare metabolic bone disorder.
Conclusion:
The diagnostic rate of 25% is similar to those in studies of WGS for other cohorts, despite our permissive eligibility criteria. This supports the use of the FIND-OUT protocol in a larger study. These preliminary findings lend additional support for the utility of WGS for infants at-risk for RGNDs. Time from enrollment to diagnosis was significantly shorter than the average of 30 months, allowing for much earlier interventions. Receiving WGS through FIND-OUT removed barriers to testing. Overall, these preliminary data support the value of WGS in infants at-risk for RGNDs to shorten the time to a diagnosis and increase the opportunity for intervention.
While there are myriad challenges to diagnosing rare, genetic neurodevelopmental disorders (RGNDs), of particular concern is an average delay of 30 months between the first identification of symptoms and receipt of a diagnosis. Factors contributing to that delay include lack of guidelines for genetic testing of infants in outpatient settings, long wait times for specialist appointments, limited access to genetic specialists, and restrictive insurance policies. Project FIND-OUT aims to determine the utility of whole genome sequencing (WGS) for symptomatic infants at-risk for RGNDs in the outpatient setting. Here, we present the results of a pilot study of 50 participants.
Methods:
Project FIND-OUT provided free WGS to the families of 50 infants aged 3-12 months, most of whom were self-referred via internet search or social media. Several families were referred by healthcare providers (HCPs). All infants were required to be located in the US and have no prior WGS. To be eligible, infants needed to meet at least two of the seven FIND-OUT criteria: Feeding issues, Issues with movement, NICU admission, Developmental delay, Other (e.g., congenital malformations, atypical growth, specialist referral), Unprovoked seizures, or Tone issues. The study was conducted under Northstar IRB-approved protocol NB300133; buccal samples were analyzed at a CLIA/CAP-certified laboratory, and pre- and post-test genetic counseling was provided via telehealth.
The primary measure evaluated was diagnostic yield. A literature review was conducted, and while there were no studies on diagnostic yield in infants meeting the FIND-OUT criteria, available studies of children who received genetic testing based on one or more of the FIND-OUT criteria demonstrated diagnostic yields between 17%-47%. Therefore, we hypothesized that Project FIND-OUT would produce a 20% diagnostic yield.
Results:
From December 2023-September 2024, 50 patients were enrolled, meeting an average of 4.2 FIND-OUT criteria. 43 patients were self-referred, while 7 patients were referred to the study by HCPs. Families reported they enrolled in Project FIND-OUT due to physician (including specialists and geneticists) unwillingness to order testing, insurance barriers, long wait times to see genetics, and a desire to optimize their child's care and understand how their child’s symptoms may evolve.
The average age at enrollment was 8.8 months, ranging from 3-12 months. The average turnaround time from enrollment to results was 30.98 days, ranging from 16-73 days. To date, 48 WGS results have been returned. 12 patients (25%) received a pathogenic or likely pathogenic genetic diagnosis explaining their symptoms, 3 received a pathogenic secondary finding (7% of the 43 who opted in), 9 (19%) had a variant of uncertain significance, and 24 (50%) received a negative result. Additionally, 9 patients (19%) were found to have carrier status for a recessive disorder. Patients referred by HCPs had a higher diagnostic yield than self-referred patients. Other than G6PD deficiency, no two patients received the same diagnosis. 11 patients were diagnosed with neurodevelopmental disorders and one was diagnosed with a rare metabolic bone disorder.
Conclusion:
The diagnostic rate of 25% is similar to those in studies of WGS for other cohorts, despite our permissive eligibility criteria. This supports the use of the FIND-OUT protocol in a larger study. These preliminary findings lend additional support for the utility of WGS for infants at-risk for RGNDs. Time from enrollment to diagnosis was significantly shorter than the average of 30 months, allowing for much earlier interventions. Receiving WGS through FIND-OUT removed barriers to testing. Overall, these preliminary data support the value of WGS in infants at-risk for RGNDs to shorten the time to a diagnosis and increase the opportunity for intervention.