Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders
Open accessAbstract
While genes with an excess of de novo mutations (DNMs) have been identified in children with neurodevelopmental disorders (NDDs), few studies focus on DNM patterns where the sex of affected children is examined separately. We considered ∼8,825 sequenced parent-child trios (n ∼26,475 individuals) and identify 54 genes with a DNM enrichment in males (n = 18), females (n = 17), or overlapping in both the male and female subsets (n = 19). A replication cohort of 18,778 sequenced parent-child trios (n = 56,334 individuals) confirms 25 genes (n = 3 in males, n = 7 in females, n = 15 in both male and female subsets). As expected, we observe significant enrichment on the X chromosome for females but also find autosomal genes with potential sex bias (females, CDK13, ITPR1; males, CHD8, MBD5, SYNGAP1); 6.5% of females harbor a DNM in a female-enriched gene, whereas 2.7% of males have a DNM in a male-enriched gene. Sex-biased genes are enriched in transcriptional processes and chromatin binding, primarily reside in the nucleus of cells, and have brain expression. By downsampling, we find that DNM gene discovery is greatest when studying affected females. Finally, directly comparing de novo allele counts in NDD-affected males and females identifies one replicated genome-wide significant gene (DDX3X) with locus-specific enrichment in females. Our sex-based DNM enrichment analysis identifies candidate NDD genes differentially affecting males and females and indicates that the study of females with NDDs leads to greater gene discovery consistent with the female-protective effect.
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A nonsense WASF3 variant, p.Glu88Ter, was identified in a patient with neurodevelopmental disorders.
“A nonsense WASF3 variant, p.Glu88Ter, was identified in a patient with NDDs103,104,106 (Table 2h).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [106]
The Results and Discussion passages describe de novo variants in patients with neurodevelopmental disorders, but none identifies a WASF3 variant in a patient. Searches of our copy for “WASF3,” “p.Glu88Ter,” and “Glu88Ter” found no passage addressing the specific nonsense variant. (LLM, conf=0.70)
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A global reference for human genetic variation
The 1000 Genomes Project Consortium, authors, C., Auton, A., Abecasis, G. R., Steering committee, Altshuler, D. M., Durbin, R. M., Abecasis, G. R., Bentley, D. R., Chakravarti, A., et al. (2015) · Nature · doi:10.1038/nature15393 · Cited by 18,247 · see citing works
Self-citationVan der Auwera, G. A., Carneiro, M. O., Hartl, C., Poplin, R., del Angel, G., Levy‐Moonshine, A., Jordan, T., Shakir, K., Roazen, D., Thibault, J., et al. (2013) · Current Protocols in Bioinformatics · doi:10.1002/0471250953.bi1110s43 · Cited by 6,687 · see citing works
O'Leary, N. A., Wright, M. W., Brister, J. R., Ciufo, S., Haddad, D., McVeigh, R., Rajput, B., Robbertse, B., Smith-White, B., Ako-Adjei, D., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkv1189 · Cited by 6,357 · see citing works
Synaptic, transcriptional and chromatin genes disrupted in autism
Study, T. D., De Rubeis, S., Autism, H. M. C. F., UK10K Consortium, The Autism Sequencing Consortium, He, X., Goldberg, A. P., Poultney, C. S., Samocha, K., Ercument Cicek, A., et al. (2014) · Nature · doi:10.1038/nature13772 · Cited by 2,746 · see citing works
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., et al. (2012) · Nature · doi:10.1038/nature10989 · Cited by 2,165 · see citing works
Self-citationConserved cell types with divergent features in human versus mouse cortex
Hodge, R. D., Bakken, T. E., Miller, J. A., Smith, K. A., Barkan, E. R., Graybuck, L. T., Close, J. L., Long, B., Johansen, N., Penn, O., et al. (2019) · Nature · doi:10.1038/s41586-019-1506-7 · Cited by 1,775 · cited 2× · see citing works
“A total of 15,928 single nuclei were isolated from the middle temporal gyrus of adult post-mortem brains of three human donors and profiled with RNA-seq.(38,42) Unsupervised clustering identified 75 distinct transcriptomic clusters, including 45 GABAergic (inhibitory) neuronal, 24 glutamatergic (excitatory) neuronal,”
MethodSelf-citationSex differences in autism spectrum disorders
Werling, D. M., & Geschwind, D. H. (2013) · Current Opinion in Neurology · doi:10.1097/wco.0b013e32835ee548 · Cited by 1,245 · cited 1× · see citing works
“For example, male to female biases ranging from 4 to 15 have been reported among individuals with high-functioning autism.(5,6) The reasons for these differences are not fully understood but potential biological factors include involvement of the sex chromosomes,(7) hormonal regulation of genes,(8) sex-specific imprin…”
BackgroundNeurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity
Coe, B. P., Stessman, H. A. F., Sulovari, A., Geisheker, M. R., Bakken, T. E., Lake, A. M., Dougherty, J. D., Lein, E. S., Hormozdiari, F., Bernier, R. A., et al. (2019) · Nature Genetics · doi:10.1038/s41588-018-0288-4 · Cited by 330 · see citing works
Self-citationTalkowski, M. E., Mullegama, S. V., Rosenfeld, J. A., van Bon, B. W. M., Shen, Y., Repnikova, E. A., Gastier-Foster, J., Thrush, D. L., Kathiresan, S., Ruderfer, D. M., et al. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.09.011 · Cited by 249 · see citing works
Guo, H., Wang, T., Wu, H., Long, M., Coe, B. P., Li, H., Xun, G., Ou, J., Chen, B., Duan, G., et al. (2018) · Molecular Autism · doi:10.1186/s13229-018-0247-z · Cited by 154 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 5
- Robinson, E.B., Lichtenstein, P., Anckarsa ¨ter, H., Happe ´, F., and Ronald, A. (2013). Examining and interpreting the female protective effect against autistic behavior. Proc. Natl. Acad. Sci. USA 110, 5258-5262.
- Amir, R.E., Van den Veyver, I.B., Wan, M., Tran, C.Q., Francke, U., and Zoghbi, H.Y. (1999). Rett syndrome is caused by The American Journal of Human Genetics 105, 1274-1285, December 5, 2019 1283 mutations in X-linked MECP2, encoding methyl-CpG- binding protein 2. Nat. Genet. 23, 185-188.
- Li, H. (2013). Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. arXiv, 1303.3997. · arXiv
- Smyth, G.K. (1998). Numerical Integration (London: Wiley).
- Vollger, M.R., Logsdon, G.A., Audano, P.A., Sulovari, A., Por- ubsky, D., Peluso, P., Wenger, A.M., Concepcion, G.T., Kronen- berg, Z.N., Munson, K.M., et al. (2019). Improved assembly and variant detection of a haploid human genome using sin- gle-molecule, high-fidelity long reads. Ann. Hum. Genet. https://doi.org/10.1111/ahg.12364. · DOI
Cited by
Sorted by citations
Antaki, D., Guevara, J., Maihofer, A. X., Klein, M., Gujral, M., Grove, J., Carey, C. E., Hong, O., Arranz, M. J., Hervas, A., et al. (2022) · Nature Genetics · doi:10.1038/s41588-022-01064-5 · Cited by 206 · see citing works
Walsh, M. J. M., Wallace, G. L., Gallegos, S. M., & Braden, B. B. (2021) · NeuroImage: Clinical · doi:10.1016/j.nicl.2021.102719 · Cited by 97 · see citing works
Kissel, L. T., & Werling, D. M. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.11.023 · Cited by 46 · see citing works
Inherited risk for autism through maternal and paternal lineage
Bai, D., Marrus, N., Yip, B. H. K., Reichenberg, A., Constantino, J. N., & Sandin, S. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.03.013 · Cited by 45 · see citing works
Single cell epigenomic atlas of the developing human brain and organoids
Ziffra, R. S., Kim, C. N., Wilfert, A., Turner, T. N., Haeussler, M., Casella, A. M., Przytycki, P. F., Kreimer, A., Pollard, K. S., Ament, S. A., et al. (2019) · doi:10.1101/2019.12.30.891549 · Cited by 33 · see citing works
Self-citationThe WAVE complex in developmental and adulthood brain disorders
Kim, H.-G., Berdasco, C., Nairn, A. C., & Kim, Y. (2025) · Experimental & Molecular Medicine · doi:10.1038/s12276-024-01386-w · Cited by 8 · see citing works
- Authors
- Turner, T. N., Wilfert, A. B., Bakken, T. E., Bernier, R. A., Pepper, M. R., Zhang, Z., Torene, R. I., Retterer, K., & Eichler, E. E.
- Affiliations
- University of Washington (US)
- Allen Institute for Brain Science (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Eichler, Evan E.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2019-12
- Volume
- 105
- Issue
- 6
- Pages
- 1274-1285
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC6904808
- OpenAlex
- W2991349598
- Cited by
- 159
- References
- 10
- Citations by year
- 2026: 15 · 2025: 30 · 2024: 41 · 2023: 27 · 2022: 25 · 2021: 12 · 2020: 7 · 2019: 1
- FWCI
- 6.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Autism Science Foundation
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- de novo mutations, neurodevelopmental disorders, sex differences, sex-biased genes, X chromosome, parent-child trios, DDX3X, CDK13, IP3R1, CHD8, MBD5, SYNGAP1, brain gene expression, gene discovery
- MeSH terms
- Child, Female, Genetic Markers, Humans, Male, Mutation, Phenotype, Sex Factors, Cohort Studies, Gene Regulatory Networks, Genome-Wide Association Study, Exome, Neurodevelopmental Disorders
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