RT Journal Article
SR Electronic
T1 Female-to-male sex reversal associated with unique Xp21.2 deletion disrupting genomic regulatory architecture of the dosage-sensitive sex reversal region
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP jmedgenet-2016-104128
DO 10.1136/jmedgenet-2016-104128
A1 Pankaj Dangle
A1 María Sol Touzon
A1 Miguel Reyes-Múgica
A1 Selma F Witchel
A1 Aleksandar Rajkovic
A1 Francis X Schneck
A1 Svetlana A Yatsenko
YR 2017
UL http://jmg.bmj.com/content/early/2017/05/07/jmedgenet-2016-104128.abstract
AB Background The XX male disorder of sex development (DSD) is a rare condition that is most commonly associated with the presence of the SRY gene on one of the X chromosomes due to unequal crossing-over between sex chromosomes during spermatogenesis. However, in about 20% of the XX male individuals, SRY is missing, although these persons have at least some testis differentiation. The genetic basis of genital ambiguity and the mechanisms triggering testis development in such patients remain unknown.Methods The proband with 46,XX SRY-negative testicular DSD was screened for point mutations by whole exome sequencing and CNVs using a high-resolution DSD gene-targeted and whole genome array comparative genomic hybridisation. The identified Xp21.2 genomic alteration was further characterised by direct sequencing of the breakpoint junctions and bioinformatics analysis.Results A unique, 80 kb microdeletion removing the regulatory sequences and the NR0B1 gene was detected by microarray analysis. This deletion disturbs the human-specific genomic architecture of the Xp21.2 dosage-sensitive sex (DSS) reversal region in the XX patient with male-appearing ambiguous genitalia and ovotestis.Conclusions Duplication of the DSS region containing the MAGEB and NR0B1 genes has been implicated in testis repression and sex reversal. Identification of this microdeletion highlights the importance of genomic integrity in the regulation and interaction of sex determining genes during gonadal development.