Summary: A new study presents a practical framework for recall-by-genotype (RbG) research in large, diverse healthcare-system biobanks to advance precision psychiatry. Using Mount Sinai’s BioMe biobank, researchers recontacted individuals carrying rare copy number variants (CNVs) associated with elevated risk for neurodevelopmental disorders and performed direct clinical and cognitive assessments that revealed critical details not captured in routine electronic health records (EHRs).
Investigators at the Icahn School of Medicine at Mount Sinai used BioMe, one of the nation’s largest and most ancestrally diverse healthcare biobanks, to identify carriers of rare CNVs that increase risk for conditions such as autism spectrum disorder, intellectual disability, and schizophrenia. The team then recontacted a targeted group of participants to test whether a recall-by-genotype approach could be implemented at scale within a multi-ancestry healthcare population.
Key Facts
- Targeted genomic recontact: The study recontacted 892 BioMe participants: 335 rare CNV carriers, 217 individuals with schizophrenia who did not carry these CNVs, and 340 neurotypical controls without NDD CNVs.
- Recruitment outcomes and yield: Overall response to recruitment was 18%, and 8% of contacted individuals completed comprehensive, in-person psychiatric and cognitive assessments.
- Diverse participant mix: The final evaluated cohort reflected BioMe’s diversity: participants self-identified as 37% African ancestry, 34% Hispanic/Latino ancestry, and 26% European ancestry.
- Value of deep phenotyping: Direct clinical and cognitive evaluations uncovered developmental, psychiatric, and cognitive traits that were not captured in routine EHR data, supporting the added value of recontact and detailed assessment.
- Framework for precision psychiatry: The operational benchmarks and procedures described establish practical foundations for stratified clinical trials, targeted therapeutic development, and improved clinical translation of psychiatric risk variants.
Source: Mount Sinai Hospital
Clinical biobanks that link genotypes with EHRs are powerful tools for genetic discovery in real-world populations. Beyond discovery, these resources can be used to locate individuals who carry clinically relevant genetic variants and invite them back for focused research evaluations. The new study, published in npj Genomic Medicine, demonstrates how a recall-by-genotype design can work in a large, multi-ancestry healthcare biobank and provides empirical benchmarks for future precision psychiatry efforts.
The research team recontacted a cross-section of BioMe participants to measure feasibility and value. Of the 892 recontacted, 18% responded to outreach, and 8% completed in-depth psychiatric and cognitive testing. The participants who completed evaluations included 30 carriers of neurodevelopmental-disorder CNVs, 20 individuals with schizophrenia (without those CNVs), and 23 neurotypical controls. The mean age across evaluated participants was 48.8 years, 66% were female, and self-reported ancestry was 37% African, 34% Hispanic, and 26% European.
Detailed assessments revealed that 70% of CNV carriers had at least one neuropsychiatric or developmental condition. Mood and anxiety disorders were common, reported in roughly 40% of carriers. In cognitive testing, CNV carriers at loci associated with impaired cognition performed worse than controls on measures such as Digit Span Backward (β = −1.76, FDR = 0.04) and Digit Span Sequencing (β = −2.01, FDR = 0.04). CNV carriers also performed better than the schizophrenia group on verbal learning (β = 4.5, FDR = 0.05).
Crucially, many of the developmental and psychiatric features identified during direct evaluation were absent from participants’ EHR billing codes and problem lists, underscoring how deep phenotyping can uncover clinically relevant details needed for accurate diagnosis, patient stratification, and therapeutic targeting.
“Clinical biobanks with genetic data are an extraordinary resource for genetic discovery,” said Rebecca Birnbaum, MD, Assistant Professor of Psychiatry and Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai and senior author of the paper. “By recontacting participants who carry rare CNVs for detailed assessments, we demonstrated both the opportunities and practical challenges of implementing recall-by-genotype in a large, diverse healthcare-system biobank.”
Key Questions Answered
Q: What is a recall-by-genotype study design?
A: Recall-by-genotype (RbG) is a research strategy that uses existing genetic data from biobanks to identify individuals with specific genetic variants—such as rare CNVs—and invites those individuals back for focused clinical evaluations, cognitive testing, or enrollment in targeted trials.
Q: Why does diversity in the BioMe cohort matter?
A: Much genomics research has historically overrepresented people of European ancestry. The diverse composition of BioMe—37% African ancestry, 34% Hispanic, 26% European—helps ensure that findings and operational benchmarks are relevant across ancestries and can support equitable translation of genetic discoveries into clinical practice.
Q: How did direct phenotyping compare with information in electronic health records?
A: EHRs provide valuable medical histories but often lack the granular developmental, psychiatric, and cognitive details uncovered by in-person assessments. Direct phenotyping captured nuanced clinical features that are essential for precision diagnosis and stratification but are typically missing from routine EHR billing codes.
Editorial Notes
- Article edited by editorial staff.
- Journal paper reviewed in full by staff.
- Additional context provided by the editorial team.
About this genetics and mental health research news
Author: Elizabeth Dowling
Source: Mount Sinai Hospital
Contact: Elizabeth Dowling – Mount Sinai Hospital
Image: Image credited to Neuroscience News
Original Research: Open access. “Recall-by-genotype of neurodevelopmental disorder copy number variants in a multi-ancestry, healthcare-system biobank” by Nina Zaks, Behrang Mahjani, Abraham Reichenberg & Rebecca Birnbaum. npj Genomic Medicine. DOI: 10.1038/s41525-026-00597-6
Abstract
Recall-by-genotype of neurodevelopmental disorder copy number variants in a multi-ancestry, healthcare-system biobank
Linking EHRs with genotype data in clinical biobanks enables the study of genomic risk factors in diverse, real-world populations. Despite this potential, recall-by-genotype (RbG) of psychiatric risk variants in multi-ancestry healthcare biobanks remains uncommon. Using BioMe, a multi-ancestry biobank within the Mount Sinai Health System, researchers recalled carriers of rare CNVs that confer increased risk for neurodevelopmental disorders to establish empirical benchmarks for RbG implementation.
They recontacted 892 participants (335 NDD CNV carriers, 217 individuals with schizophrenia without NDD CNVs, and 340 neurotypical controls). Overall, 18% of contacted participants responded and 8% completed clinical and cognitive assessments: 30 NDD CNV carriers, 20 individuals with schizophrenia, and 23 controls. The evaluated group had a mean age of 48.8 years, was 66% female, and self-reported ancestry as 37% African, 34% Hispanic, and 26% European. Seventy percent of NDD CNV carriers had at least one neuropsychiatric or developmental diagnosis; mood and anxiety disorders were common. Cognitive testing showed lower performance among certain CNV carriers compared with controls on Digit Span measures and differences versus the schizophrenia group on verbal learning.
Recontacting individuals, including those with psychiatric illness, yielded clinically important phenotypes not captured in EHRs and provides practical benchmarks for implementing RbG studies and advancing precision psychiatry within diverse healthcare systems.