Next generation sequencing for disorders of sex development

Advances in sequencing technologies are having a major impact on our understanding of the genetic causes of many human congenital disorders. Next generation sequencing (NGS) approaches are particularly important for determining the inherited genetic changes leading to disorders of sex development (DSD). Knowledge of the genetic pathways involved in ovary or testis development is incomplete and, currently, a molecular diagnosis is made in a minority of DSD cases. Here, we review the different NGS strategies applied to the analysis of rare diseases and highlight the potential pitfalls and advantages that are associated with each approach. We also discuss the problems of variant calling as well as the challenges involved in the identification and interpretation of pathogenic mutations from NGS datasets. As clinics start to use NGS on a routine basis, a close collaboration between the molecular and clinical geneticists is essential. This is particularly relevant in the context of unsolicited genetic findings, where clear guidelines regarding counseling, truly informed consent and precise data interpretation will be invaluable.