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  • Review Article
  • Published:

Disorders of sex development: effect of molecular diagnostics

Nature Reviews Endocrinology volume 11, pages 478–488 (2015)Cite this article

Subjects

Key Points

  • Disorders of sex development (DSDs) can arise from a range of different chromosomal, copy number and single gene effects

  • Karyotype analysis or assessment of the sex chromosome complement can be used to diagnose forms of sex chromosome DSDs, and can help focus investigations and diagnoses in 46,XY and 46,XX DSDs

  • Traditional candidate gene Sanger sequencing is most appropriate where phenotypic, biochemical or familial data strongly suggest a specific single gene cause

  • Array-comparative genomic hybridization is useful for investigating children with complex phenotypes and can sometimes reveal copy number changes associated with DSDs

  • High-throughput next-generation sequencing using targeted arrays or exomes (or genomes) is rapidly being developed and clinical tests using these methods are likely to be increasingly available in the next few years

  • Genetic or chromosomal diagnosis can influence clinical management of patients with DSDs and focus support and counselling for families

Abstract

Disorders of sex development (DSDs) are a diverse group of conditions that can be challenging to diagnose accurately using standard phenotypic and biochemical approaches. Obtaining a specific diagnosis can be important for identifying potentially life-threatening associated disorders, as well as providing information to guide parents in deciding on the most appropriate management for their child. Within the past 5 years, advances in molecular methodologies have helped to identify several novel causes of DSDs; molecular tests to aid diagnosis and genetic counselling have now been adopted into clinical practice. Occasionally, genetic profiling of embryos prior to implantation as an adjunct to assisted reproduction, prenatal diagnosis of at-risk pregnancies and confirmatory testing of positive results found during newborn biochemical screening are performed. Of the available genetic tests, the candidate gene approach is the most popular. New high-throughput DNA analysis could enable a genetic diagnosis to be made when the aetiology is unknown or many differential diagnoses are possible. Nonetheless, concerns exist about the use of genetic tests. For instance, a diagnosis is not always possible even using new molecular approaches (which can be worrying for the parents) and incidental information obtained during the test might cause anxiety. Careful selection of the genetic test indicated for each condition remains important for good clinical practice. The purpose of this Review is to describe advances in molecular biological techniques for diagnosing DSDs.

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Figure 1: Molecular approach for genetic diagnosis of individuals with 46,XY DSDs.

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Acknowledgements

B.B.M. and T.A.S.S.B. are partially supported by grants from the Conselho Nacional de Desenvolvimento Científico e Tecnológico – CNPq (3057-43/2011-2 and 308318/2012-9, respectively). They are also partially supported by grants from Fundação de Amparo a Pesquisa do Estado de Sao Paulo FAPESP 2013/02162-8 and of the Nucleo de Estudos e Terapia Celular e Molecular (NETCEM), J.C.A. is a Wellcome Trust Senior Research Fellow in Clinical Science (098513). The authors acknowledge A.A.L. Jorge and A.M. Lerario for their helpful suggestions.

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Authors and Affiliations

  1. Developmental Endocrinology Research Group, Genetics and Genomic Medicine, UCL Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK

    John C. Achermann

  2. Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Av Dr Eneas de Carvalho Aguiar, 155, PAMB, 2 andar, Bloco 6, São Paulo, 05403-900, Brazil

    Sorahia Domenice, Tania A. S. S. Bachega, Mirian Y. Nishi & Berenice B. Mendonca

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  1. John C. Achermann
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Contributions

J.A.C., S.D. and B.B.M. researched data for the article, contributed to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission. T.A.S.S.B. and M.Y.N. researched data for the article, contributed to discussions of the content and wrote the article.

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Correspondence to Berenice B. Mendonca.

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Achermann, J., Domenice, S., Bachega, T. et al. Disorders of sex development: effect of molecular diagnostics. Nat Rev Endocrinol 11, 478–488 (2015). https://doi.org/10.1038/nrendo.2015.69

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