The RCCX region has multiple pseudogenes and tandem repeat sequences that promote misalignment during meiosis leading to complex gene rearrangements, deletions and gene conversion events. CYP21A2 mutations cause Congenital Adrenal Hyperplasia (CAH) and TNX deficiency has been proposed as a cause of hypermobile Ehlers Danlos syndrome (EDS). The structure of the RCCX module in a cohort of patients with CAH seen at the National Institute of Child Health and Development under Protocol 06CH001, and in patients with EDS seen at the National Institute on Aging under protocol 2003-086 has been investigated using Southern blotting, PCR-based detection of deletions, and direct sequencing of exons of interest. CYP21A2 deletions were detected in 34.7% of the proband chromosomes in the CAH cohort, and 15% of those had a deletion extending into TNXB. Unique haplotypes, including three CAH probands with triplication of CYP21A2, a sibling pair with a deletion of TNXB and triplication of CYP21A2, were identified through Southern Blot analysis. A novel heterozygous 30 kB TNXB deletion that did not extend into CYP21A2 was found in a family with hypermobile form of EDS. A manuscript detailing the clinical features of patients affected by CAH and TNX deletion included situs inversus, quadrivalent aortic valve, bifid split uvula and bicorneate uterus has been accepted for publication in American Journal of Medical Genetics Part A and is in final stages of minor revision. Clinical findings led us to conclude that those with a salt-wasting form of CAH have severe developmental malformations and abnormal joint findings. Further studies, including RT-PCR and immunochemistry approach to study the TNXB expression and extracellular matrix organization, are under way to better define the clinical, molecular and biochemical aspects of this novel CAH-TNX (CAH-X) Contiguous Gene Deletion Syndrome. It represents an intersection of hereditary connective tissue disorders with an endocrine disorder.
|Chen, Wuyan; Xu, Zhi; Sullivan, Annie et al. (2012) Junction site analysis of chimeric CYP21A1P/CYP21A2 genes in 21-hydroxylase deficiency. Clin Chem 58:421-30|
|Chen, Wuyan; Xu, Zhi; Nishitani, Miki et al. (2012) Complement component 4 copy number variation and CYP21A2 genotype associations in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Genet 131:1889-94|
|Finkielstain, Gabriela P; Chen, Wuyan; Mehta, Sneha P et al. (2011) Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 96:E161-72|
|Nandagopal, Radha; Sinaii, Ninet; Avila, Nilo A et al. (2011) Phenotypic profiling of parents with cryptic nonclassic congenital adrenal hyperplasia: findings in 145 unrelated families. Eur J Endocrinol 164:977-84|
|Chen, Wuyan; Kim, Mimi S; Shanbhag, Sujata et al. (2009) The phenotypic spectrum of contiguous deletion of CYP21A2 and tenascin XB: quadricuspid aortic valve and other midline defects. Am J Med Genet A 149A:2803-8|