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Cited by 25Genomics and Rare DiseasesGenetics and Neurodevelopmental DisordersAutism Spectrum Disorder Research

Prevalence and Penetrance of Rare Pathogenic Variants in Neurodevelopmental Psychiatric Genes in a Health Care System Population

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Shimelis, Hermela, Oetjens, Matthew T., Walsh, Lauren K., Wain, Karen E., Znidarsic, Masa, Myers, Scott M., Finucane, Brenda M., Ledbetter, David H. +1 more·2023·American Journal of Psychiatry
DOI 10.1176/appi.ajp.22010062PMC PMC10017070
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Abstract

OBJECTIVE: Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population. METHODS: The authors analyzed linked genomic and electronic health record (EHR) data in a subset of 90,595 participants from Geisinger's MyCode Community Health Initiative, known as the DiscovEHR cohort. Loss-of-function pathogenic variants in 94 high-confidence NPD genes were identified through exome sequencing, and NPD penetrance was calculated using preselected EHR diagnosis codes. NPD risk was estimated using a case-control comparison of DiscovEHR participants with and without NPD diagnoses. Results from single-gene variant analyses were also compared with those from 31 previously reported pathogenic NPD CNVs. RESULTS: Pathogenic variants were identified in 0.34% of the DiscovEHR cohort and demonstrated a 34.3% penetrance for NPDs. Similar to CNVs, sequence variants collectively conferred a substantial risk for several NPD diagnoses, including autism, schizophrenia, and bipolar disorder. Significant NPD risk remained after participants with intellectual disability were excluded from the analysis, confirming the association with major psychiatric disorders in individuals without severe cognitive deficits. CONCLUSIONS: Collectively, rare single-gene variants and CNVs were found in >1% of individuals in a large health care system population and play an important contributory role in mental health disorders. Diagnostic genetic testing for pathogenic variants among symptomatic individuals with NPDs could improve clinical outcomes through early intervention and anticipatory therapeutic support.

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  • An intragenic heterozygous deletion covering exons 4-11 of WASF1 was found in an individual with a neurodevelopmental psychiatric disorder.

    “An intragenic heterozygous deletion covering exons 4–11 of WASF1 was found in an individual with a neurodevelopmental psychiatric disorder101 (Table 2c).”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [101]

    The Results section, “Prevalence of NPD-Related Single-Gene Variants” (page unavailable), reports pathogenic variants and a deletion in ASXL3, but does not identify a WASF1 deletion. Searches for WASF1, an intragenic heterozygous deletion, and exons 4–11 found no passage in our copy documenting the claimed individual or variant. (LLM, conf=0.73)

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Cited by

Sorted by citations

Authors
Shimelis, H., Oetjens, M. T., Walsh, L. K., Wain, K. E., Znidarsic, M., Myers, S. M., Finucane, B. M., Ledbetter, D. H., & Martin, C. L.
Affiliations
Autism & Developmental Medicine Institute (US)
ORCID
Venue
American Journal of Psychiatry
Publisher
American Psychiatric Association Publishing
Published
2023-01-01
Volume
180
Issue
1
Pages
65-72
ISSN
  • 0002-953X (ISSN-L)
  • 1535-7228
DOI
10.1176/appi.ajp.22010062
PMC
PMC10017070
OpenAlex
W4311845947
Cited by
25
References
5
Citations by year
2026: 3 · 2025: 12 · 2024: 4 · 2023: 6
FWCI
3.30
Type
journal article
Language
en
Open access
Locations
  • American Journal of Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Regeneron Pharmaceuticals
  • Natera
  • National Institute of Mental Health (R01MH074090, U01MH119705)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
Keywords
rare pathogenic variants, copy number variation, penetrance, prevalence, autism spectrum disorder, schizophrenia, bipolar disorder, intellectual disability, genetic risk, loss-of-function mutations
MeSH terms
Delivery of Health Care, Genetic Testing, Humans, Schizophrenia, Prevalence, Penetrance, DNA Copy Number Variations

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