Genomic basis of aromatase excess syndrome: recombination- and replication-mediated rearrangements leading to CYP19A1 overexpression.

[aromatase deficiency]

Genomic rearrangements at 15 q 21 have been shown to cause overexpression of CYP 19 A 1 and resultant aromatase excess syndrome (AEXS ). However , mutation spectrum , clinical consequences , and underlying mechanisms of these rearrangements remain to be elucidated .The aim of the study was to clarify such unsolved matters .We characterized six new rearrangements and investigated clinical outcome and local genomic environments of these rearrangements and of three previously reported duplications /deletions .Novel rearrangements included simple duplication involving exons 1 -10 of CYP 19 A 1 and simple and complex rearrangements that presumably generated chimeric genes consisting of the coding region of CYP 19 A 1 and promoter-associated exons of neighboring genes . Clinical severities were primarily determined by the copy number of CYP 19 A 1 and the property of the fused promoters . Sequences at the fusion junctions suggested nonallelic homologous recombination , nonhomologous end-joining , and replication-based errors as the underlying mechanisms . The breakpoint-flanking regions were not enriched with GC content , palindromes , noncanonical DNA structures , or known rearrangement-associated motifs . The rearrangements resided in early -replicating segments .T hese results indicate that AEXS is caused by duplications involving CYP 19 A 1 and simple and complex rearrangements that presumably lead to the usage of cryptic promoters of several neighboring genes . Our data support the notion that phenotypes depend on the dosage of CYP 19 A 1 and the characteristics of the fused promoters . Furthermore , we show that the rearrangements in AEXS are generated by both recombination- and replication-mediated mechanisms , independent of the known rearrangement-inducing DNA features or late -replication timing . Thus , AEXS represents a unique model for human genomic disorders .

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Diseases presenting "previously reported duplications/deletions" symptom

aromatase deficiency

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