Novel homozygous nonsense mutations in the luteinizing hormone receptor (LHCGR) gene associated with 46,XY primary amenorrhea

Abstract

Objective: To determine the genetic cause of 46,XY primary amenorrhea in three 46,XY girls.

Design: Whole exome sequencing.

Setting: University cytogenetics center.

Patient(s): Three patients with unexplained 46,XY primary amenorrhea were included in the study.

Intervention(s): Potentially pathogenic variants were confirmed by Sanger sequencing, and familial segregation was determined where parents' DNA was available.

Main outcome measure(s): Exome sequencing was performed in the three patients, and the data were analyzed for potentially pathogenic mutations. The functional consequences of mutations were predicted.

Result(s): Three novel homozygous nonsense mutations in the luteinizing hormone receptor (LHCGR) gene were identified:c.1573 C→T, p.Gln525Ter, c.1435 C→T p.Arg479Ter, and c.508 C→T, p.Gln170Ter.

Conclusion(s): Inactivating mutations of the LHCGR gene may be a more common cause of 46,XY primary amenorrhea than previously considered.

Keywords: Exome sequencing; LHCGR mutation; disorders of sex development (DSD); primary amenorrhea.