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MG-125 CYP21A2 mutation spectrum in congenital adrenal hyperplasia identified from molecular genetic testing
  1. Yanwei Xi1,
  2. Jillian Parboosingh2,
  3. Heather Johnson1,
  4. Lisa Graham1,
  5. Ryan Lamont2
  1. 1Alberta Children’s Hospital, Calgary, AB, Canada
  2. 2University of Calgary, Calgary, AB, Canada

Abstract

Background Mutations in CYP21A2, the gene encoding 21-hydroxylase, are identified in >80% of individuals with congenital adrenal hyperplasia (CAH). CYP21A2 and its highly homologous pseudogene, CYP21A1P, reside in close proximity; as a result >90% of CYP21A2 mutation-containing alleles are caused by gene conversion from CYP21A1P or CYP21A2 deletions arising from non-allelic homologous recombination. Further, CYP21A2 duplications exist and provide a source of false negative and false positive results as carriers of a CYP21A2 deletion may be masked by a CYP21A2 duplication on the opposite allele (2+0 configuration) or carriers of a point mutation may also carry a second non-mutated CYP21A2 in cis.

Objectives The purpose of this study was to investigate the distribution of CYP21A2 mutations identified from molecular genetic tested CAH individuals and determine the frequency of 2+0 carriers in a control population.

Methods A total of 469 CAH individuals were screened for CYP21A2 mutation by MLPA and common mutation and/or sequencing analysis. A PCR-based assay was developed and to detect 2+0 CYP21A2 deletion carriers.

Results The p. V282L, c.293–13A/C >G, and CYP21A2 gene deletion were the most frequent mutations identified in CAH. Cases with two independent mutations in cis and mutation-containing CYP21A2 duplications were observed. No silent 2+0 CYP21A2 deletion carriers were identified in our control population.

Conclusions Segregation and copy number analysis are critical in CYP21A2 testing. A PCR-based assay can be used to detect CYP21A2 duplications, although the 2+0 silent carrier frequency is rare.

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