Development and Validation of a Cross-Dimensional Screening Protocol for Remote Phenotyping Applied to Individuals...

Advances in genomics have resulted in a rapid expansion of the number of known rare genetic disorders (RGDs). However, the low frequency of RGDs presents a challenge for accurately describing the phenotypic spectrum of a given disorder. Remote phenotyping strategies are uniquely poised to address this knowledge gap. Here, we have piloted remote evaluation of cognitive ability and psychosis spectrum symptoms in 3q29 deletion syndrome (3q29del), a hallmark RGD.

Individuals with 3q29del (n = 21, 57% male, mean age = 14.3 ± 8.6 years) were remotely evaluated using the Penn Computerized Neurocognitive Battery (Penn-CNB), Peabody Picture Vocabulary Test (PPVT) and the Structured Interview for Prodromal Syndromes (SIPS). Scores were compared with prior in-person IQ testing results and SIPS scores from our previously published study.

Remote cognitive assessment using the Penn-CNB and the PPVT accurately captured full-scale IQ (r = 0.710, p = 0.001) and verbal IQ (r = 0.637, p = 0.003), respectively, as compared with in-person assessment with gold-standard instruments. Psychosis spectrum symptoms measured using the SIPS were significantly correlated between in-person and remote evaluations (total score r = 0.753, p = 0.003; positive domain score r = 0.806, p = 0.0009).

Based on the successful pilot, we designed a protocol for remote phenotyping of individuals with 3q29del. The phenotyping battery is comprised of caregiver-report and direct assessments to capture the spectrum of neurodevelopmental, neuropsychiatric and medical features associated with the 3q29 deletion. While we focused on specific areas of concern for 3q29del, the high degree of phenotypic overlap between 3q29del and other RGDs renders this protocol amenable for implementation across a variety of RGDs, facilitating a deeper understanding of the phenotypic spectrum and cross-disorder comparison. Ultimately, we hope that the increased utilization of remote phenotyping strategies will help to expand our understanding of RGDs at large, which will lead to improved clinical management strategies and better long-term outcomes for affected individuals and their families.