Clinical and personal utility of population screening for neurodevelopmental psychiatric copy number variants and sex chromosome aneuploidies in 580 adults
Clinical Genetics and Therapeutics
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Primary Categories:
- Population Genetics
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Secondary Categories:
- Population Genetics
Introduction:
Neurodevelopmental psychiatric disorders (NPDs), including autism, intellectual disability, epilepsy, and schizophrenia, are etiologically heterogeneous conditions affecting up to a quarter of individuals in North America. Pathogenic genomic variants that cause NPDs, including recurrent copy number variants (CNVs) and sex chromosome aneuploidies (SCAs), have been found in >1% of population-based cohorts. Although clinical genetic testing is recommended for many pediatric NPDs, most adults with rare variants have never been genetically diagnosed. Instead, they live with etiologically-linked cognitive, psychiatric, and medical symptoms without ever receiving a unifying explanation for these findings. The MyCode Community Health Initiative has consented >350,000 patient-participants, including >230,000 with exome data and linked electronic health records (EHRs). The cohort predominantly includes older adults of European ancestry and is unselected with regard to medical diagnoses or presenting symptoms. Consented participants agree to be recontacted about clinically relevant results including, but not limited to, medically actionable secondary findings. We previously defined a list of 31 pathogenic, recurrent NPD-related CNVs, as well as 7 non-mosaic SCAs, to evaluate in the MyCode cohort, prioritizing those with high penetrance and a strong likelihood of impacting medical management. Here, we report our experience with population screening for these variants.
Methods:
CNV and SCA calling were carried out using exome sequencing and genotyping arrays on blood or saliva samples from 169,876 MyCode participants, among whom 1,706 (1.0%) were found to have a pathogenic CNV or SCA. Certified genetic counselors developed a disclosure process for NPD-related variants based on the broader MyCode genomic screening and counseling protocol which has already returned medically actionable findings, primarily related to cancer and cardiovascular disease, to over 5,000 individuals. All participants with clinically confirmed pathogenic variants were initially contacted by EHR message, surface mail, and/or telephone and offered a genetic counseling appointment to discuss their results. Primary care providers were also given information and resources about their patients’ genetic diagnoses.
Results:
The return-of-results process is ongoing, beginning with well-established, highly penetrant CNVs and non-mosaic SCAs. To date, disclosure has been completed for 580 (34.0%) participants (mean age: 54 years), representing 10 recurrent deletions (1q21.1; 3q29; 7q11.23; 15q13.3; 15q24; 16p11.2; 16p13.11; 17q11.2; 17q12; 22q11.2), one recurrent duplication (17q12), and seven SCAs (45,X; 47,XXY; 47,XXX; 47,XYY; 48,XXYY; 48,XXXY; 48,XXXX). In 22 individuals with CNVs (5.7%) and 45 with SCAs (23.3%), the genetic diagnosis was already known and recorded in their EHRs. None of the remaining 513 participants (88.4%) had a clinically documented genetic diagnosis. Of these, 53.8% met with a genetic counselor to discuss their findings. Genetic counseling resulted in referrals for medical follow-up in at least 13% of these adults, and 25 additional CNV diagnoses were made through family cascade testing. Among 183 participants who completed a follow-up survey, most reported positive (50.8%) or neutral (47.6%) reactions to learning their genetic diagnosis, while 1.6% expressed negative reactions. Eighty-nine (15.3%) participants did not respond to communications despite repeated attempts, and 79 (13.6%) were lost to follow-up due to inaccurate contact information.
Conclusion:
The decreasing cost of genomic sequencing has led to a rise in population-based risk screening for common health conditions, such as cancer and cardiovascular diseases, yet experience with NPD etiologies has been limited. Early identification of NPD-related variants can improve clinical outcomes, as in the prompt treatment of psychosis in 22q11.2 deletion syndrome and preventive monitoring for venous thromboembolism in SCAs. Many adults in this study expressed profound relief at finally having a medical explanation for a lifelong history of cognitive and psychiatric disabilities. We conclude that identification and disclosure of NPD-causative variants is clinically and psychologically important and should be considered more broadly as part of genomic screening.
Neurodevelopmental psychiatric disorders (NPDs), including autism, intellectual disability, epilepsy, and schizophrenia, are etiologically heterogeneous conditions affecting up to a quarter of individuals in North America. Pathogenic genomic variants that cause NPDs, including recurrent copy number variants (CNVs) and sex chromosome aneuploidies (SCAs), have been found in >1% of population-based cohorts. Although clinical genetic testing is recommended for many pediatric NPDs, most adults with rare variants have never been genetically diagnosed. Instead, they live with etiologically-linked cognitive, psychiatric, and medical symptoms without ever receiving a unifying explanation for these findings. The MyCode Community Health Initiative has consented >350,000 patient-participants, including >230,000 with exome data and linked electronic health records (EHRs). The cohort predominantly includes older adults of European ancestry and is unselected with regard to medical diagnoses or presenting symptoms. Consented participants agree to be recontacted about clinically relevant results including, but not limited to, medically actionable secondary findings. We previously defined a list of 31 pathogenic, recurrent NPD-related CNVs, as well as 7 non-mosaic SCAs, to evaluate in the MyCode cohort, prioritizing those with high penetrance and a strong likelihood of impacting medical management. Here, we report our experience with population screening for these variants.
Methods:
CNV and SCA calling were carried out using exome sequencing and genotyping arrays on blood or saliva samples from 169,876 MyCode participants, among whom 1,706 (1.0%) were found to have a pathogenic CNV or SCA. Certified genetic counselors developed a disclosure process for NPD-related variants based on the broader MyCode genomic screening and counseling protocol which has already returned medically actionable findings, primarily related to cancer and cardiovascular disease, to over 5,000 individuals. All participants with clinically confirmed pathogenic variants were initially contacted by EHR message, surface mail, and/or telephone and offered a genetic counseling appointment to discuss their results. Primary care providers were also given information and resources about their patients’ genetic diagnoses.
Results:
The return-of-results process is ongoing, beginning with well-established, highly penetrant CNVs and non-mosaic SCAs. To date, disclosure has been completed for 580 (34.0%) participants (mean age: 54 years), representing 10 recurrent deletions (1q21.1; 3q29; 7q11.23; 15q13.3; 15q24; 16p11.2; 16p13.11; 17q11.2; 17q12; 22q11.2), one recurrent duplication (17q12), and seven SCAs (45,X; 47,XXY; 47,XXX; 47,XYY; 48,XXYY; 48,XXXY; 48,XXXX). In 22 individuals with CNVs (5.7%) and 45 with SCAs (23.3%), the genetic diagnosis was already known and recorded in their EHRs. None of the remaining 513 participants (88.4%) had a clinically documented genetic diagnosis. Of these, 53.8% met with a genetic counselor to discuss their findings. Genetic counseling resulted in referrals for medical follow-up in at least 13% of these adults, and 25 additional CNV diagnoses were made through family cascade testing. Among 183 participants who completed a follow-up survey, most reported positive (50.8%) or neutral (47.6%) reactions to learning their genetic diagnosis, while 1.6% expressed negative reactions. Eighty-nine (15.3%) participants did not respond to communications despite repeated attempts, and 79 (13.6%) were lost to follow-up due to inaccurate contact information.
Conclusion:
The decreasing cost of genomic sequencing has led to a rise in population-based risk screening for common health conditions, such as cancer and cardiovascular diseases, yet experience with NPD etiologies has been limited. Early identification of NPD-related variants can improve clinical outcomes, as in the prompt treatment of psychosis in 22q11.2 deletion syndrome and preventive monitoring for venous thromboembolism in SCAs. Many adults in this study expressed profound relief at finally having a medical explanation for a lifelong history of cognitive and psychiatric disabilities. We conclude that identification and disclosure of NPD-causative variants is clinically and psychologically important and should be considered more broadly as part of genomic screening.