CBX2 gene analysis in patients with 46 XY and 46 XX gonadal disorders of sex development

Capsule:
CBX2 gene disruption, described in one case of 46,XY ovarian disorder of sex development (DSD), is not a common cause of other gonadal DSD forms.

Authors:
Ameli Norling, M.D., Angelica Lindén Hirschberg, M.D., Ph.D., Erik Iwarsson, M.D., Ph.D., Anna Wedell, M.D., Ph.D., Michela Barbaro, Ph.D.

Volume 99, Issue 3, Pages 819-826.e3, 1 March 2013

Abstract:

Objective:
To investigate a cohort of patients with gonadal disorders of sex development (DSD) for causative CBX2 gene mutations and or gene copy number changes.

Design:
Genetic association study.

Setting:
University laboratory and tertiary university-based referral center.

Patients:
Forty-seven patients with different forms of 46,XY or 46,XX gonadal DSD.

Intervention:
CBX2 gene sequencing and development of a synthetic probe set for multiplex ligation probe amplification (MLPA) to detect CBX2 copy number changes. RTPCR to evaluate CBX2 expression in two different cell line types.

Main Outcome Measures:
Gene sequence alteration and or partial or complete gene copy number variations. Detection of CBX2 mRNA isoforms.

Results:
Ten sequence alterations were detected, 9 reported single nucleotide polymorphisms (SNPs) and a previously unreported variant. This was a silent c.1356G>A transition which may represent a normal variant. A rare SNP (c.1411C>G, p.471Pro>Ala), was found in heterozygous form in one patient. No deletions or duplications were detected by MLPA. Expression of both CBX2 mRNA isoforms was documented in gonadal fibroblasts and EBV-transformed lymphocytes.

Conclusions:
No pathogenic CBX2 mutation was detected. Both CBX2 isoforms are expressed in gonadal fibroblasts and EBV-transformed lymphocytes. This study does not support CBX2 gene disruption as a common cause of gonadal DSD.

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