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Complement component 4 variations may influence psychopathology risk in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Open accessAbstract
CYP21A2 defects result in congenital adrenal hyperplasia (CAH), an autosomal recessive disorder characterized by impaired adrenal steroidogenesis. CYP21A2 lies within the major histocompatibility complex in an area of the genome highly susceptible to genetic variation. Alterations in the neighboring complement component 4 isotypes C4A and C4B have been associated with psychiatric and autoimmune disease. The purpose of this study was to evaluate C4A and C4B in patients with CAH in relation to CYP21A2 genotype and psychiatric and autoimmune comorbidity. We determined the copy numbers of C4A and C4B in 145 patients with CAH (median age: 15.5 years, IQR: 16.8) and 108 carrier relatives (median age: 41.5 years, IQR: 12.0) and evaluated serum C4 concentrations. Comorbidity was determined by medical record review. Only 30% of subjects had the expected two copies each of the two C4 genes. C4B copy number determined total C4 copy number and serum C4 concentration, negatively correlated with carriership of a 30-kb deletion (P < 10- 5), and positively correlated with carriership of p.V281L (P < 10- 5). High C4A copy number (≥ 3) was associated with increased risk of having an externalizing psychiatric condition (relative risk: 2.67, 95% CI: 1.03-6.89, P = 0.04). No association was found between C4 copy number and autoimmune disease. Mutation-specific C4 structural variations commonly occur in patients with CAH and may have important clinical consequences, including increased risk of psychiatric morbidity. Trial registration NCT00250159 (November 7, 2005).
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“All subjects had comprehensive genetic records, including a complete CAH and CAH-X genotype by a CLIA-accredited laboratory (PreventionGenetics, LLC, Marshfield, WI), as well as copy numbers of TNXB exons 35, 40, C4A, C4B genes determined as previously described [10,32,33].”
From Pseudogene TNXA Variants May Interfere with the Genetic Testing of CAH-X (2023) · cites this paper as [33]
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“Although the sexual orientation of women with CAH is less likely to be exclusively heterosexual than is true for unaffected women, the majority are heterosexual (227,600).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [227]
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“which in turn is highly correlated with group 0 and A genotypes (227).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [227]
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“but gender dysphoria does tend to be most severe in women with SW CAH, which in turn is highly correlated with group 0 and A genotypes (227).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [227]
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Schizophrenia risk from complex variation of complement component 4
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Speiser, P. W., Azziz, R., Baskin, L. S., Ghizzoni, L., Hensle, T. W., Merke, D. P., Meyer-Bahlburg, H. F. L., Miller, W. L., Montori, V. M., Oberfield, S. E., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2631 · Cited by 1,468
Self-citationSpeiser, P. W., Arlt, W., Auchus, R. J., Baskin, L. S., Conway, G. S., Merke, D. P., Meyer-Bahlburg, H. F. L., Miller, W. L., Murad, M. H., Oberfield, S. E., et al. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-01865 · Cited by 1,234
Self-citationTenascin-X deficiency is associated with Ehlers-Danlos syndrome
Burch, G. H., Gong, Y., Liu, W., Dettman, R. W., Curry, C. J., Smith, L., Miller, W. L., & Bristow, J. (1997) · Nature Genetics · doi:10.1038/ng0997-104 · Cited by 366
A comparison of the properties of two classes, C4A and C4B, of the human complement component C4
Law, S. K., Dodds, A. W., & Porter, R. R. (1984) · The EMBO Journal · doi:10.1002/j.1460-2075.1984.tb02052.x · Cited by 303
Speiser, P., Arlt, W., Rj, A., Baskin, L., Conway, G. S., Merke, D. P., Meyer‐Bahlburg, H. F. L., Miller, W. L., Murad, M. H., Oberfield, S., et al. (2019) · Yearbook of pediatric endocrinology · doi:10.1530/ey.16.8.5 · Cited by 301
Finkielstain, G. P., Chen, W., Mehta, S. P., Fujimura, F. K., Hanna, R. M., Van Ryzin, C., McDonnell, N. B., & Merke, D. P. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0319 · Cited by 192
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Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management
Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556
Self-citationLong-Term Outcomes of Congenital Adrenal Hyperplasia
Nordenström, A., Lajić, S., & Falhammar, H. (2022) · Endocrinology and Metabolism · doi:10.3803/enm.2022.1528 · Cited by 43
Genes and Pseudogenes: Complexity of the RCCX Locus and Disease
Carrozza, C., Foca, L., De Paolis, E., & Concolino, P. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.709758 · Cited by 37
Lao, Q., Brookner, B., & Merke, D. P. (2019) · The Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2019.06.001 · Cited by 29
Self-citationFalhammar, H., Frisén, L., Hirschberg, A. L., Nordenskjöld, A., Almqvist, C., & Nordenström, A. (2019) · Journal of the Endocrine Society · doi:10.1210/js.2019-00122 · Cited by 23
Metadata
- Authors
- Lao, Q., Jardin, M. D., Jayakrishnan, R., Ernst, M., & Merke, D. P.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Merke, Deborah P.
- Venue
- Human Genetics
- Published
- 2018-11-21
- Volume
- 137
- Issue
- 11-12
- Pages
- 955-960
- ISSN
- 0018-7348 (ISSN-L)
- 0340-6717
- 1432-1203
- PMC
- PMC6702947
- OpenAlex
- W2901313314
- Cited by
- 12
- References
- 27
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 3 · 2022: 1 · 2021: 2 · 2019: 2
- FWCI
- 0.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Human Genetics (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99CL999999)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- complement C4, C4A, C4b, congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21A2, copy number variation, psychiatric comorbidity, externalizing problems, autoimmune disease, major histocompatibility complex
- MeSH terms
- Adolescent, Adrenal Hyperplasia, Congenital, Adult, Complement C4, Female, Genotype, Haplotypes, Humans, Male, Mutation, Psychopathology, Steroid 21-Hydroxylase, Young Adult, DNA Copy Number Variations
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