ESPE Yearbook of Paediatric Endocrinology

Mol Cell Endocrinol. 2018 Jun 15;468:60–69.

doi: 10.1016/j.mce.2018.04.003. PubMed PMID: 29655603

Since the description of the first DSD gene, SRY, in the early 1990s (OMIM 480000), genetics has become a major player in research and clinical workup of DSD. The advances of today’s technologies in genetics and the limitations are summarized in this review, which covers karyotyping, Sanger sequencing, exome sequencing and chromosomal microarrays. In addition, future possibilities with whole genome sequencing and whole genome mapping are predicted to solve more DSD cases.

Although the genetics of DSD has seen a tremendous evolution in the last two decades, with a recent technical shift from a gene-by-gene approach to massively parallel sequencing, the diagnostic yield is currently only about 30–40%. This is due to several factors including technical, interpretative and clinical factors as well as challenges in functional validation of genetic findings. Standardization of phenotyping and genetic workup not only with respect to technical methods, but also with respect to algorithms used for data interpretation is crucial for improving the diagnostic success (1).

Recently, new a pathogenetic insight revealed that the non-coding genome, modifier genes and oligogenic inheritance need to be considered, as also reviewed in (2). Such pathogenetic mechanisms are often difficult to prove with current experimental models. But even these difficulties may be overcome in the near future by using models based on human derived stem cells (3).

Referencess: 1. Audi L, Ahmed SF, Krone N, Cools M, McElreavey K, Holterhus PM, Greenfield A, Bashamboo A, Hiort O, Wudy SA, McGowan R; The EU COST Action. GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’. Eur J Endocrinol. 2018 Oct 1;179(4):R197–R206.

2. Baetens D, Verdin H, De Baere E, Cools M. Update on the genetics of differences of sex development (DSD). Best Pract Res Clin Endocrinol Metab. 2019 Apr 13. pii: S1521-690X(19)30014-4.

3. Ruiz-Babot G, Balyura M, Hadjidemetriou I, Ajodha SJ, Taylor DR, Ghataore L, Taylor NF, Schubert U, Ziegler CG, Storr HL, Druce MR, Gevers EF, Drake WM, Srirangalingam U, Conway GS, King PJ, Metherell LA, Bornstein SR, Guasti L. Modeling Congenital Adrenal Hyperplasia and Testing Interventions for Adrenal Insufficiency Using Donor-Specific Reprogrammed Cells. Cell Rep. 2018 Jan 30;22(5):1236–1249.