The Phenotypic Spectrum of Contiguous Deletion of CYP21A2 and Tenascin XB: Quadricuspid Aortic Valve and Other Midline Defects

Laboratory of Clinical Investigation, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 12/2009; 149A(12):2803-8. DOI: 10.1002/ajmg.a.33092
Source: PubMed

ABSTRACT Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disorder and is the most common cause of ambiguous genitalia in the newborn. The genes encoding 21-hydroxylase, CYP21A2, and tenascin-X (TNX), TNXB, are located within the HLA complex, in a region of high gene density termed the RCCX module. The module has multiple pseudogenes as well as tandem repeat sequences that promote misalignment during meiosis leading to complex gene rearrangements, deletions and gene conversion events. CYP21A2 mutations cause CAH, and TNX deficiency has been identified as a cause of hypermobility type Ehlers-Danlos syndrome (EDS). Here we report on a three-generation family with a heterozygous deletion encompassing CYP21A2 and TNXB that initially came to medical attention due to the diagnosis of CAH in the proposita. Southern blotting and PCR-based analysis of the RCCX module revealed a CYP21A2 deletion extending into TNXB in one allele and a CYP21A2 point mutation in the other allele. Family history is notable for joint hypermobility. Additional radiological and clinical investigations showed a quadricuspid aortic valve, single kidney, bicornuate uterus and a bifid uvula in the proposita, and mitral valve prolapse in her mother. These findings further delineate the phenotype of the CAH-TNX contiguous gene deletion syndrome and point to an intersection of connective tissue dysplasias with a common gene-mediated endocrine disorder.

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Available from: Sujata M Shanbhag, Dec 19, 2013
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    • "An association of EDS and CAH has been described in only a few patients, which is compatible with a contiguous gene deletion syndrome . In those cases, the patients had a deletion in the region with a TNXB / XA fusion gene [Burch et al., 1997; Schalkwijk et al., 2001; Chen et al., 2009]. MSH5 is another gene whose deletion could explain other clinical features , specifically hypergonadotrophic hypogonadism. "
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    ABSTRACT: Cryptic deletions in balanced de novo translocations represent a frequent cause of abnormal phenotypes, including Mendelian diseases. In this study, we describe a patient with multiple congenital abnormalities, such as late-onset congenital adrenal hyperplasia (CAH), primary ovarian failure and Ehlers-Danlos syndrome (EDS), who carries a de novo t(6;14)(p21;q32) translocation. Genomic array analysis identified a cryptic 1.1-Mb heterozygous deletion, adjacent to the breakpoint on chromosome 6, extending from 6p21.33 to 6p21.32 and affecting 85 genes, including CYP21A2,TNXB and MSH5. Multiplex ligation-dependent probe amplification analysis of the 6p21.3 region was performed in the patient and her family and revealed a 30-kb deletion in the patient's normal chromosome 6, inherited from her mother, resulting in homozygous loss of genes CYP21A1P and C4B. CYP21A2 sequencing showed that its promoter region was not affected by the 30-kb deletion, suggesting that the deletion of other regulatory sequences in the normal chromosome 6 caused a loss of function of the CYP21A2 gene. EDS and primary ovarian failure phenotypes could be explained by the loss of genes TNXB and MSH5, a finding that may contribute to the characterization of disease-causing genes. The detection of this de novo microdeletion drastically reduced the estimated recurrence risk for CAH in the family. © 2014 S. Karger AG, Basel.
    Sexual Development 06/2014; 8(4). DOI:10.1159/000363779 · 2.29 Impact Factor
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    • "In particular, large gene deletions result in chimera genes at the centromeric tail of the RCCX module, which account for approximately 30 % of CYP21A2 mutations (Finkielstain et al. 2011; Stikkelbroeck et al. 2003). These chimera genes are mostly present in a form of CYP21A1P/CYP21A2 (Chen et al. 2012), but also TNXA/ TNXB in subset of patients in which the functional CYP21A2 gene is completely deleted and the deletion extends into the TNXB gene (Burch et al. 1997; Chen et al. 2009). As expected, we found that having a chimera gene at the RCCX locus was associated with a decrease in total C4 copy number, but this was not associated with autoimmune disease. "
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    ABSTRACT: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) is an autosomal recessive disorder of cortisol biosynthesis caused by CYP21A2 mutations. An increase in gene copy number variation (CNV) exists at the CYP21A2 locus. CNV of C4, a neighboring gene that encodes complement component 4, is associated with autoimmune disease susceptibility. In this study, we performed comprehensive genetic analysis of the RP-C4-CYP21-TNX (RCCX) region in 127 unrelated 21-OHD patients (100 classic, 27 nonclassic). C4 copy number was determined by Southern blot. C4 CNV and serum C4 levels were evaluated in relation to CYP21A2 mutations and relevant phenotypes. We found that the most common CYP21A2 mutation associated with the nonclassic form of CAH, V281L, was associated with high C4 copy number (p = 7.13 × 10(-16)). Large CYP21A2 deletion, a common mutation associated with the classic form of CAH, was associated with low C4 copy number (p = 1.61 × 10(-14)). Monomodular RCCX with a short C4 gene, a risk factor for autoimmune disease, was significantly less frequent in CAH patients compared to population estimates (2.8 vs. 10.6 %; p = 1.08 × 10(-4)). In conclusion, CAH patients have increased C4 CNV, with mutation-specific associations that may be protective for autoimmune disease. The study of CYP21A2 in relation to neighboring genes provides insight into the genetics of CNV hotspots, an important determinant of human health.
    Human Genetics 08/2012; 131(12). DOI:10.1007/s00439-012-1217-8 · 4.82 Impact Factor
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    ABSTRACT: At the Pulse Physics Laboratory', Netherlands, research is being performed to develop a counterpulse technique for the controlled interruption of very high currents in inductive storage pulsed power systems. Presently, a repetitive mechanical high current opening switch is applied to commutate current to an inductive load (for example a rail accelerator) from a storage inductor charged by a homopolar generator. To increase the current level, the mechanical switch is able to interrupt the application of a counterpulse technique and a separate closing switch looks promising. Otherwise, the arc that would occur between the contacts of the switch during opening and closing at high currents (mega-ampere level), would severely damage the contacts. To prevent the damage caused by arcing, the current must be reduced to zero or a low level before opening the switch. To be able to achieve this, a resonant series counterpulse circuit has been proposed. The circuit incorporates units consisting of a capacitor bank of electrolytic capacitors with parallel connected diodes and a thyristor connected in series. Upon command, these units will create a resonant counterpulse current through the opening switch. The current through the switch then reduces to zero and the switch is opened without damaging the contacts. The units have been designed to generate currents up to 50 kA. By placing several units in parallel, higher counterpulse currents can be generated. This paper presents experimental results of the parallel operation of eight units
    Pulsed Power Conference, 1997. Digest of Technical Papers. 1997 11th IEEE International; 01/1997
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