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).
Human genetics. 2018 Nov 21 [Epub ahead of print]
Qizong Lao, Marcia Des Jardin, Rahul Jayakrishnan, Monique Ernst, Deborah P Merke
National Institutes of Health Clinical Center, 10 Center Drive, Room 1-2740, Bethesda, MD, 20892-1932, USA., National Institute of Mental Health, National Institutes of Health, Bethesda, MD, 20892, USA., National Institutes of Health Clinical Center, 10 Center Drive, Room 1-2740, Bethesda, MD, 20892-1932, USA. .