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Towards improved genetic diagnosis of human differences of sex development

Nature Reviews Genetics volume 22, pages 588–602 (2021)Cite this article

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Abstract

Despite being collectively among the most frequent congenital developmental conditions worldwide, differences of sex development (DSD) lack recognition and research funding. As a result, what constitutes optimal management remains uncertain. Identification of the individual conditions under the DSD umbrella is challenging and molecular genetic diagnosis is frequently not achieved, which has psychosocial and health-related repercussions for patients and their families. New genomic approaches have the potential to resolve this impasse through better detection of protein-coding variants and ascertainment of under-recognized aetiology, such as mosaic, structural, non-coding or epigenetic variants. Ultimately, it is hoped that better outcomes data, improved understanding of the molecular causes and greater public awareness will bring an end to the stigma often associated with DSD.

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Fig. 1: Disruption of processes in many different organs can result in isolated and syndromic forms of DSD.

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Acknowledgements

The authors thank P. Speiser for helpful discussions while preparing the case report for Box 2 and M. Almalvez for assistance with references and figures. E.C.D. and E.V. are supported in part by grant R01HD093450 (Disorders/Differences of Sex Development Translational Research Network, DSD-TRN) from the Eunice Kennedy Shriver National Institute of Child Health and Development.

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  1. Center for Genetic Medicine Research, Children’s Research Institute, Children’s National Hospital, Washington, DC, USA

    Emmanuèle C. Délot & Eric Vilain

  2. Department of Genomics and Precision Medicine, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA

    Emmanuèle C. Délot & Eric Vilain

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  1. Emmanuèle C. Délot
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The authors contributed equally to all aspects of the article.

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Correspondence to Eric Vilain.

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E.V. has scientifically advised Bionano Genomics. E.C.D. declares no competing interests.

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CAS Executive Summary: https://www.tas-cas.org/fileadmin/user_upload/CAS_Executive_Summary__5794_.pdf

ClinGen consortium: http://clinicalgenome.org/

Cystic Fibrosis Foundation: https://www.cff.org/What-is-CF/About-Cystic-Fibrosis/

Cystic Fibrosis Worldwide: https://www.cfww.org/

DSD-Life: https://www.dsd-life.eu/home/index.html

DSD/Primary adrenal deficiency WES-based test: https://www.radboudumc.nl/getmedia/ea3f05c7-2d81-4127-9d15-66aee97aff3e/DSDPRIMARYADRENALINSUFFICIENCY_DG300.aspx

DSD-TRN: https://dsdtrn.org

Franklin: https://franklin.genoox.com/clinical-db/home

Genoox sequence analysis platform: https://www.genoox.com/genoox-integrated-omsv-platform/

HIV.gov: https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics

I-DSD: https://home.i-dsd.org

IRDiRC: https://irdirc.org/about-us/vision-goals/

Leiden Open Variation Database: www.lovd.nl

PanelApp: https://panelapp.genomicsengland.co.uk/panels/9/

Parkinson’s Foundation: https://www.parkinson.org/Understanding-Parkinsons/Statistics

SVI General Recommendations for Using ACMG/AMP Criteria: https://clinicalgenome.org/working-groups/sequence-variant-interpretation/

Supplementary information

Glossary

Positive predictive value

(PPV). In a clinical test, the ratio of the number of individuals confirmed to have the condition being tested for to those who tested positive with the test, irrespective of disease status. The PPV predicts the likelihood of someone who tests positive for having the condition.

Isodicentric Y

An abnormal Y chromosome resulting in two centromeres and two identical arms (Yp or Yq). Breakpoints vary, but individuals with two short (Yp) arms may have two copies of the testis-determining gene SRY (located in Yp11.2), whereas those with two long arms typically do not carry SRY.

Cell-free fetal DNA

Fragments of DNA of fetal origin circulating in the maternal blood during pregnancy, which can be tested to screen for aneuploidies such as trisomy 21 or to ascertain the sex chromosome complement of the fetus.

Copy number variants

(CNVs). Variants, typically larger than 50 bp, that result in increased or decreased ploidy, such as a deletion on an autosome resulting in a single copy of the region instead of two. CNVs are a type of structural variant.

Chimerism

A condition whereby two different genomes are found in a single individual, usually as a result of fusion of two zygotes during a twin pregnancy. Differences of sex development can arise when the two genomes have a different sex chromosome complement (XX and XY).

Mosaicism

A condition whereby two different genomes are found in a single individual, typically resulting from a post-fertilization mutation that is found only in the daughter cells of a subset of embryonic cells and thereby results in different phenotypic expression in different tissues. A frequent type of mosaicism associated with differences of sex development is Turner syndrome variants with 45,X/46,XY mosaic karyotypes.

Structural variants

Variants including copy number variants, insertions, translocations or inversions. They can be balanced (when the rearrangement does not result in loss or gain of genomic material) or unbalanced.

Epimutations

Heritable variants that modify gene expression through gain or loss of DNA methylation or other modification of chromatin without affecting the underlying DNA sequence.

Episignatures

Unique patterns of epigenetic variation (typically DNA methylation) occurring at multiple nucleotide locations throughout the genome. Episignatures have shown potential diagnostic value in syndromic conditions where no underlying genetic aetiology is found.

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Délot, E.C., Vilain, E. Towards improved genetic diagnosis of human differences of sex development. Nat Rev Genet 22, 588–602 (2021). https://doi.org/10.1038/s41576-021-00365-5

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