A new study of disorders of sex development presents

an improved targeted next-generation sequencing

approach for their diagnosis

Achermann, JC

Buonocore, F

Genome Biology

PubMed

Federica Buonocore

John C. Achermann

Springer - Publisher Connector

Buonocore and Achermann Genome Biology  (2016) 17:257 
DOI 10.1186/s13059-016-1128-4RESEARCH HIGHLIGHT Open AccessHuman sex development: targeted
technologies to improve diagnosis
Federica Buonocore and John C. Achermann*Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1105-yAbstract
A new study of disorders of sex development presents
an improved targeted next-generation sequencing
approach for their diagnosis.
Keywords: Disorders of sex development, DSD,
Haloplex, Gonadal dysgenesis, Genetic testing, Sex
determinationMaking a genetic diagnosis of DSD can have importantHuman sex development
Disorders of (or differences in) sex development (DSD)
are a broad range of conditions that can affect repro-
ductive development and function in humans. Typically,
a child might first present with atypical genitalia at birth,
in such a way that it is not immediately possible to say
whether the newborn is a boy or girl. Other individuals
can present in childhood or teenage years, or even first
in adulthood. It is estimated that approximately 1 in
every 4000 people has DSD, although other variations of
these conditions (e.g. some forms of hypospadias) are
much more prevalent.
The past 25 years have seen significant progress in our
understanding of the genetic basis of sex development
and related conditions. In the early 1990s, SRY (‘sex-de-
termining region Y protein’) was identified as the main
Y-chromosomal driver for testis development, supported
by the generation of ‘Randy’, an XX mouse that devel-
oped testes and a male phenotype owing to the presence
of a Sry transgene [1]. SRY is also crucially important in
human testis determination, although only approxi-
mately 5% of individuals with testicular dysgenesis have
disruption of this transcription factor. More than 40
other genes have now been implicated in human DSD,
some of which can disrupt the male-typical development
pathway in individuals with a 46,XY karyotype, whereas* Correspondence: j.achermann@ucl.ac.uk
Genetics and Genomic Medicine, UCL Great Ormond Street Institute for
Child Health, 30 Guilford Street, London WC1N 1EH, UK
© The Author(s). 2016 Open Access This artic
International License (http://creativecommons
reproduction in any medium, provided you g
the Creative Commons license, and indicate if
(http://creativecommons.org/publicdomain/zeothers can cause excess androgen production in the de-
veloping 46,XX child (Fig. 1). Sometimes biochemical
data, associated features or family history can help target
a diagnosis, especially in conditions affecting steroido-
genesis, but, for most children with gonadal dysgenesis
or hypospadias, a genetic cause is not typically found [2].Moving into the next generation
implications for counselling young people and their fam-
ilies about the likely course of their condition, associated
features that might need monitoring, hormonal function
and fertility, and gonadal tumor risk [2]. A specific gen-
etic diagnosis can also predict the likelihood of other
family members being affected. Traditionally, potential
candidate genes have been sequenced one at a time,
often as part of research studies. With the exception of
changes in steroidogenic factor-1 (NR5A1), the returns
are usually meagre [3]. This is in part due to the diverse
number of different genes that can cause DSD in af-
fected individuals, each of which only contributes a
small percentage to the overall picture.
In recent years, next-generation sequencing (NGS) ap-
proaches have provided great potential for upscaling
genetic analysis and investigating many genes in parallel.
Studies using whole-exome sequencing (WES) have in-
vestigated small cohorts of children with DSD and have
identified changes in genes known to be altered in DSD
as well as novel genes [4]. However, WES approaches
have the disadvantage of still being relatively expensive
and also producing extensive additional (often unrelated)
genetic information of uncertain importance.
An alternative approach, reported in a recent study by
Eggers and colleagues, is to use targeted panels of
known (and candidate) genes for high-throughput deep
sequencing to try to reach a diagnosis for DSD [5]. This
involved using a targeted panel (HaloPlex) that included
64 known DSD-associated genes (and 967 candidate
genes), in an international multi-centre study of 326le is distributed under the terms of the Creative Commons Attribution 4.0
.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
ive appropriate credit to the original author(s) and the source, provide a link to
changes were made. The Creative Commons Public Domain Dedication waiver
ro/1.0/) applies to the data made available in this article, unless otherwise stated.
Fig. 1 a–c Overview of some of the single genes currently
associated with disorders/differences of sex development (DSD).
Targeted next-generation sequencing (NGS) panels can be valuable
for the parallel analysis of many genes simultaneously, especially for
forms of 46,XY DSD (b) where the diagnosis is unclear. A study by
Eggers and colleagues [5] raises the possibility that variants in genes
traditionally associated with central hypogonadism/Kallmann syndrome
might also contribute to a 46,XY DSD phenotype
Buonocore and Achermann Genome Biology  (2016) 17:257 Page 2 of 3individuals and 129 of their family members. This ap-
proach involved many more individuals than previous
reports, as well as a wider range of genes and greater
depth of sequencing [6, 7]. The panel also included
many genes involved in central hypogonadism (central
hypogonadotropic hypogonadism, CHH).
The study by Eggers et al. has generated several im-
portant findings [5]. First, a likely specific genetic diag-
nosis was reached in 43% of the individuals tested.
Although functional studies were not performed, the
American College of Medical Genetic and Genomics
guidelines were used to determine the likely pathogen-
icity of the variants [8]. Second, it was surprising that
the analysis of trios (proband and parents) did not sig-
nificantly improve the diagnostic yield. As many genetic
variants associated with DSD arise as de novo dominant
conditions, it would have been anticipated that trio ana-
lysis would have helped to identify de novo changes and
thereby strengthen evidence for likely pathogenicity.
Third, 13 individuals with 46,XY DSD had more than
one curated variant in a diagnostic DSD gene detected,
suggesting a potential oligogenic inheritance in some sit-
uations. Finally, there was an enrichment of likely patho-
genic variants found in several genes (e.g. CHD7,
WDR11, FGF8/FGFR1) that are traditionally associatedwith CHH/Kallmann syndrome. CHH is a hypothal-
amic–pituitary condition in which release of the gonad-
stimulating hormones follicle-stimulating hormone
(FSH) and luteinizing hormone (LH) is reduced. In the
current model of human sex development, congenital
gonadotropin insufficiency should only affect penile
growth (length) and testis descent in the later stages of
fetal development. The identification of changes in these
genes in individuals with hypospadias and other more
marked variations in genital anatomy suggest that some
genes function at multiple levels throughout the hypo-
thalamic–pituitary–gonadal axis and support previous
findings by Baxter and colleagues [4].
Several limitations of this study must also be
highlighted. With more-detailed clinical and biochemical
phenotyping, it is possible that a diagnosis could still
have been reached in a very small number of children
using single-gene analysis (e.g. WT1 in renal failure or
STAR in lipoid congenital adrenal hyperplasia) [2]. Fur-
thermore, analysis of several classic congenital adrenal
hyperplasia (CAH) genes (e.g. CYP21A2) can be difficult
using targeted capture and NGS because of the presence
of a pseudogene. As CAH is a common and important
diagnosis to make, a combination of biochemical ana-
lysis followed by single-gene testing is still the best ap-
proach, and accordingly children with CAH were not
entered into this study [2]. Finally, different personal
and cultural views on genetic testing need to be consid-
ered. Unlocking genetic knowledge is often of benefit,
but can also carry a burden of information, especially in
such a sensitive area as reproductive development. En-
gagement and education of families and young people,
together with balanced information and consent, are im-
portant. While bearing all these considerations in mind,
offering a more comprehensive panel-based approach to
genetic testing, as described by Eggers and colleagues,
certainly seems one way forward.Where do we go from here?
High-throughput panel-based genetic analysis has now
come of age in many settings, and similar studies have
recently been reported for other endocrine conditions.
For example, De Franco and colleagues used a targeted
NGS panel as part of their comprehensive evaluation of
an international cohort of more than 1000 children
with neonatal diabetes, where a final molecular diagno-
sis was reached in 82% [9]. Similarly, Guran and collab-
orators studied almost 100 patients with primary
adrenal insufficiency of unknown cause from a national
cohort study in Turkey and reached a genetic diagnosis
in 81% [9, 10].
Why then is the diagnostic yield in DSD not more
than 50%? Several reasons could account for this:
Buonocore and Achermann Genome Biology  (2016) 17:257 Page 3 of 31. Many of the children included had undergone prior
analysis of single genes, and so the diagnostic yield
of the array would likely have been higher if the
children had been recruited without any prior
testing.
2. Key novel genes involved in DSD might yet be
discovered. For example, important variants could
have been detected in some of the many candidate
genes included in the study by Eggers et al. but not
included in their report; novel variants might be
found in WES studies of DSD currently under way;
and genomic changes in enhancers or regulatory
regions might be detected by whole-genome
sequencing approaches, such as the 100,000 genomes
project. International collaborations might be needed
to understand the potential contribution of rare
variants in diverse genes of unknown function, or to
piece together any potential role for complex digenic
or oligogenic interactions. Data analysis in DSD can
be complicated further by the relative lack of large
pedigrees as these genetic conditions often result in
infertility and are not transmitted; by the observation
of sex-limited inheritance patterns (e.g. where
mothers can carry an autosomal dominant variant
but are not affected); and by variable phenotypic
penetrance. Even where there is a family history,
this might be private information that is not widely
shared among family members.
3. Several studies have shown that copy-number
variants can be involved in DSD, which are not so
easily detected using current NGS technologies or
bioinformatic pipelines.
4. Somatic changes in key factors during early
embryonic life can affect organ development in a
tissue- and time-specific manner. Such events would
not be detected unless the specific tissues were ana-
lysed (e.g. gonad), and this might be impossible once
an organ has undergone fibrosis or has regressed.
5. Epigenetic or environmental factors can influence
early gonad development or genital anatomy either
alone or in combination with rare genetic events.
Despite these many challenges with DSD, human gen-
etics has entered an exciting era, and the study by Eggers
and colleagues shows that the field is making progress.
Translation of research approaches into clinical service
is an important short-term goal, and providing benefits
for young people and their family must remain very
much the focus of investigators’ work. Smaller-scale tar-
geted NGS panels are already available in clinical service
in some centres, with the main drawback being the need
to batch several samples together for analysis, which can
slow down turnaround times. In the future, larger multi-
disorder panels, whole-exome and even whole-genomeapproaches might be used as first-line investigations,
with the initial bioinformatics analysis restricted only to
DSD-related genes. In most places, however, these ap-
proaches are still limited by cost and capacity, and so in
the meantime specific targeted panels have a lot to offer.
Abbreviations
CAH: Congenital adrenal hyperplasia; CHH: Central hypogonadotropic
hypogonadism; DSD: Disorders/differences of sex development; FSH: Follicle-
stimulating hormone; LH: Luteinizing hormone; NGS: Next-generation
sequencing; WES: Whole-exome sequencing
Acknowledgments
FB and JCA co-authored the manuscript.
Funding
JCA is a Wellcome Trust Senior Research Fellow in Clinical Science (grant
number 098513/Z/12/Z) with support from the National Institute for Health
Research Biomedical Research Centre at Great Ormond Street Hospital for
Children NHS Foundation Trust and University College London.
Authors’ contribution
Both authors read and approved the final manuscript.
Competing interests
FB and JCA have received educational support from Agilent to attend The
Festival of Genomics meeting in London, in 2016, but this has not
influenced the content of this article.
References
1. Koopman P, Sinclair A, Lovell-Badge R. Of sex and determination: marking
25 years of Randy, the sex-reversed mouse. Development. 2016;143:1633–7.
2. Achermann JC, Domenice S, Bachega TA, Nishi MY, Mendonca BB. Disorders
of sex development: effect of molecular diagnostics. Nat Rev Endocrinol.
2015;11:478–88.
3. Suntharalingham JP, Buonocore F, Duncan AJ, Achermann JC. DAX-1
(NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best
Pract Res Clin Endocrinol Metab. 2015;29:607–19.
4. Baxter RM, Arboleda VA, Lee H, Barseghyan H, Adam MP, Fechner PY, et al.
Exome sequencing for the diagnosis of 46, XY disorders of sex
development. J Clin Endocrinol Metab. 2015;100:E333–44.
5. Eggers S, Sadedin S, van den Bergen J, Robevska G, Ohnesorg T, Hewitt J,
et al. Disorders of sex development: insights from targeted gene
sequencing of a large patient cohort. Genome Biol. 2016;17:243.
6. Arboleda VA, Lee H, Sánchez FJ, Délot EC, Sandberg DE, Grody WW, et al.
Targeted massively parallel sequencing provides comprehensive genetic
diagnosis for patients with disorders of sex development. Clin Genet.
2013;83:35–43.
7. Dong Y, Yi Y, Yao H, Yang Z, Hu H, Liu J, et al. Targeted next-generation
sequencing identification of mutations in patients with disorders of sex
development. BMC Med Genet. 2016;17:23.
8. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and
guidelines for the interpretation of sequence variants: a joint consensus
recommendation of the American College of Medical Genetics and
Genomics and the Association for Molecular Pathology. Genet Med.
2015;17:405–24.
9. De Franco E, Flanagan SE, Houghton JA, Lango Allen H, Mackay DJ, Temple
IK, et al. The effect of early, comprehensive genomic testing on clinical care
in neonatal diabetes: an international cohort study. Lancet. 2015;386:957–63.
10. Guran T, Buonocore F, Saka N, Nuri Ozbek M, Aycan Z, Bereket A, et al. Rare
causes of primary adrenal insufficiency: Genetic and clinical characterization
of a large nationwide cohort. J Clin Endocrinol Metab. 2016;101:284–92.


Human sex development: targeted technologies to improve diagnosis

Crossref

English

UCL Discovery

Buonocore and Achermann Genome Biology  (2016) 17:257 DOI 10.1186/s13059-016-1128-4RESEARCH HIGHLIGHT Open AccessHuman sex development: targetedtechnologies to improve diagnosisFederica Buonocore and John C. Achermann*Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1105-yAbstractA new study of disorders of sex development presentsan improved targeted next-generation sequencingapproach for their diagnosis.Keywords: Disorders of sex development, DSD,Haloplex, Gonadal dysgenesis, Genetic testing, SexdeterminationMaking a genetic diagnosis of DSD can have importantHuman sex developmentDisorders of (or differences in) sex development (DSD)are a broad range of conditions that can affect repro-ductive development and function in humans. Typically,a child might first present with atypical genitalia at birth,in such a way that it is not immediately possible to saywhether the newborn is a boy or girl. Other individualscan present in childhood or teenage years, or even firstin adulthood. It is estimated that approximately 1 inevery 4000 people has DSD, although other variations ofthese conditions (e.g. some forms of hypospadias) aremuch more prevalent.The past 25 years have seen significant progress in ourunderstanding of the genetic basis of sex developmentand related conditions. In the early 1990s, SRY (‘sex-de-termining region Y protein’) was identified as the mainY-chromosomal driver for testis development, supportedby the generation of ‘Randy’, an XX mouse that devel-oped testes and a male phenotype owing to the presenceof a Sry transgene [1]. SRY is also crucially important inhuman testis determination, although only approxi-mately 5% of individuals with testicular dysgenesis havedisruption of this transcription factor. More than 40other genes have now been implicated in human DSD,some of which can disrupt the male-typical developmentpathway in individuals with a 46,XY karyotype, whereas* Correspondence: j.achermann@ucl.ac.ukGenetics and Genomic Medicine, UCL Great Ormond Street Institute forChild Health, 30 Guilford Street, London WC1N 1EH, UK© The Author(s). 2016 Open Access This articInternational License (http://creativecommonsreproduction in any medium, provided you gthe Creative Commons license, and indicate if(http://creativecommons.org/publicdomain/zeothers can cause excess androgen production in the de-veloping 46,XX child (Fig. 1). Sometimes biochemicaldata, associated features or family history can help targeta diagnosis, especially in conditions affecting steroido-genesis, but, for most children with gonadal dysgenesisor hypospadias, a genetic cause is not typically found [2].Moving into the next generationimplications for counselling young people and their fam-ilies about the likely course of their condition, associatedfeatures that might need monitoring, hormonal functionand fertility, and gonadal tumor risk [2]. A specific gen-etic diagnosis can also predict the likelihood of otherfamily members being affected. Traditionally, potentialcandidate genes have been sequenced one at a time,often as part of research studies. With the exception ofchanges in steroidogenic factor-1 (NR5A1), the returnsare usually meagre [3]. This is in part due to the diversenumber of different genes that can cause DSD in af-fected individuals, each of which only contributes asmall percentage to the overall picture.In recent years, next-generation sequencing (NGS) ap-proaches have provided great potential for upscalinggenetic analysis and investigating many genes in parallel.Studies using whole-exome sequencing (WES) have in-vestigated small cohorts of children with DSD and haveidentified changes in genes known to be altered in DSDas well as novel genes [4]. However, WES approacheshave the disadvantage of still being relatively expensiveand also producing extensive additional (often unrelated)genetic information of uncertain importance.An alternative approach, reported in a recent study byEggers and colleagues, is to use targeted panels ofknown (and candidate) genes for high-throughput deepsequencing to try to reach a diagnosis for DSD [5]. Thisinvolved using a targeted panel (HaloPlex) that included64 known DSD-associated genes (and 967 candidategenes), in an international multi-centre study of 326le is distributed under the terms of the Creative Commons Attribution 4.0.org/licenses/by/4.0/), which permits unrestricted use, distribution, andive appropriate credit to the original author(s) and the source, provide a link tochanges were made. The Creative Commons Public Domain Dedication waiverro/1.0/) applies to the data made available in this article, unless otherwise stated.Fig. 1 a–c Overview of some of the single genes currentlyassociated with disorders/differences of sex development (DSD).Targeted next-generation sequencing (NGS) panels can be valuablefor the parallel analysis of many genes simultaneously, especially forforms of 46,XY DSD (b) where the diagnosis is unclear. A study byEggers and colleagues [5] raises the possibility that variants in genestraditionally associated with central hypogonadism/Kallmann syndromemight also contribute to a 46,XY DSD phenotypeBuonocore and Achermann Genome Biology  (2016) 17:257 Page 2 of 3individuals and 129 of their family members. This ap-proach involved many more individuals than previousreports, as well as a wider range of genes and greaterdepth of sequencing [6, 7]. The panel also includedmany genes involved in central hypogonadism (centralhypogonadotropic hypogonadism, CHH).The study by Eggers et al. has generated several im-portant findings [5]. First, a likely specific genetic diag-nosis was reached in 43% of the individuals tested.Although functional studies were not performed, theAmerican College of Medical Genetic and Genomicsguidelines were used to determine the likely pathogen-icity of the variants [8]. Second, it was surprising thatthe analysis of trios (proband and parents) did not sig-nificantly improve the diagnostic yield. As many geneticvariants associated with DSD arise as de novo dominantconditions, it would have been anticipated that trio ana-lysis would have helped to identify de novo changes andthereby strengthen evidence for likely pathogenicity.Third, 13 individuals with 46,XY DSD had more thanone curated variant in a diagnostic DSD gene detected,suggesting a potential oligogenic inheritance in some sit-uations. Finally, there was an enrichment of likely patho-genic variants found in several genes (e.g. CHD7,WDR11, FGF8/FGFR1) that are traditionally associatedwith CHH/Kallmann syndrome. CHH is a hypothal-amic–pituitary condition in which release of the gonad-stimulating hormones follicle-stimulating hormone(FSH) and luteinizing hormone (LH) is reduced. In thecurrent model of human sex development, congenitalgonadotropin insufficiency should only affect penilegrowth (length) and testis descent in the later stages offetal development. The identification of changes in thesegenes in individuals with hypospadias and other moremarked variations in genital anatomy suggest that somegenes function at multiple levels throughout the hypo-thalamic–pituitary–gonadal axis and support previousfindings by Baxter and colleagues [4].Several limitations of this study must also behighlighted. With more-detailed clinical and biochemicalphenotyping, it is possible that a diagnosis could stillhave been reached in a very small number of childrenusing single-gene analysis (e.g. WT1 in renal failure orSTAR in lipoid congenital adrenal hyperplasia) [2]. Fur-thermore, analysis of several classic congenital adrenalhyperplasia (CAH) genes (e.g. CYP21A2) can be difficultusing targeted capture and NGS because of the presenceof a pseudogene. As CAH is a common and importantdiagnosis to make, a combination of biochemical ana-lysis followed by single-gene testing is still the best ap-proach, and accordingly children with CAH were notentered into this study [2]. Finally, different personaland cultural views on genetic testing need to be consid-ered. Unlocking genetic knowledge is often of benefit,but can also carry a burden of information, especially insuch a sensitive area as reproductive development. En-gagement and education of families and young people,together with balanced information and consent, are im-portant. While bearing all these considerations in mind,offering a more comprehensive panel-based approach togenetic testing, as described by Eggers and colleagues,certainly seems one way forward.Where do we go from here?High-throughput panel-based genetic analysis has nowcome of age in many settings, and similar studies haverecently been reported for other endocrine conditions.For example, De Franco and colleagues used a targetedNGS panel as part of their comprehensive evaluation ofan international cohort of more than 1000 childrenwith neonatal diabetes, where a final molecular diagno-sis was reached in 82% [9]. Similarly, Guran and collab-orators studied almost 100 patients with primaryadrenal insufficiency of unknown cause from a nationalcohort study in Turkey and reached a genetic diagnosisin 81% [9, 10].Why then is the diagnostic yield in DSD not morethan 50%? Several reasons could account for this:Buonocore and Achermann Genome Biology  (2016) 17:257 Page 3 of 31. Many of the children included had undergone prioranalysis of single genes, and so the diagnostic yieldof the array would likely have been higher if thechildren had been recruited without any priortesting.2. Key novel genes involved in DSD might yet bediscovered. For example, important variants couldhave been detected in some of the many candidategenes included in the study by Eggers et al. but notincluded in their report; novel variants might befound in WES studies of DSD currently under way;and genomic changes in enhancers or regulatoryregions might be detected by whole-genomesequencing approaches, such as the 100,000 genomesproject. International collaborations might be neededto understand the potential contribution of rarevariants in diverse genes of unknown function, or topiece together any potential role for complex digenicor oligogenic interactions. Data analysis in DSD canbe complicated further by the relative lack of largepedigrees as these genetic conditions often result ininfertility and are not transmitted; by the observationof sex-limited inheritance patterns (e.g. wheremothers can carry an autosomal dominant variantbut are not affected); and by variable phenotypicpenetrance. Even where there is a family history,this might be private information that is not widelyshared among family members.3. Several studies have shown that copy-numbervariants can be involved in DSD, which are not soeasily detected using current NGS technologies orbioinformatic pipelines.4. Somatic changes in key factors during earlyembryonic life can affect organ development in atissue- and time-specific manner. Such events wouldnot be detected unless the specific tissues were ana-lysed (e.g. gonad), and this might be impossible oncean organ has undergone fibrosis or has regressed.5. Epigenetic or environmental factors can influenceearly gonad development or genital anatomy eitheralone or in combination with rare genetic events.Despite these many challenges with DSD, human gen-etics has entered an exciting era, and the study by Eggersand colleagues shows that the field is making progress.Translation of research approaches into clinical serviceis an important short-term goal, and providing benefitsfor young people and their family must remain verymuch the focus of investigators’ work. Smaller-scale tar-geted NGS panels are already available in clinical servicein some centres, with the main drawback being the needto batch several samples together for analysis, which canslow down turnaround times. In the future, larger multi-disorder panels, whole-exome and even whole-genomeapproaches might be used as first-line investigations,with the initial bioinformatics analysis restricted only toDSD-related genes. In most places, however, these ap-proaches are still limited by cost and capacity, and so inthe meantime specific targeted panels have a lot to offer.AbbreviationsCAH: Congenital adrenal hyperplasia; CHH: Central hypogonadotropichypogonadism; DSD: Disorders/differences of sex development; FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; NGS: Next-generationsequencing; WES: Whole-exome sequencingAcknowledgmentsFB and JCA co-authored the manuscript.FundingJCA is a Wellcome Trust Senior Research Fellow in Clinical Science (grantnumber 098513/Z/12/Z) with support from the National Institute for HealthResearch Biomedical Research Centre at Great Ormond Street Hospital forChildren NHS Foundation Trust and University College London.Authors’ contributionBoth authors read and approved the final manuscript.Competing interestsFB and JCA have received educational support from Agilent to attend TheFestival of Genomics meeting in London, in 2016, but this has notinfluenced the content of this article.References1. Koopman P, Sinclair A, Lovell-Badge R. Of sex and determination: marking25 years of Randy, the sex-reversed mouse. Development. 2016;143:1633–7.2. Achermann JC, Domenice S, Bachega TA, Nishi MY, Mendonca BB. Disordersof sex development: effect of molecular diagnostics. Nat Rev Endocrinol.2015;11:478–88.3. Suntharalingham JP, Buonocore F, Duncan AJ, Achermann JC. DAX-1(NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. BestPract Res Clin Endocrinol Metab. 2015;29:607–19.4. Baxter RM, Arboleda VA, Lee H, Barseghyan H, Adam MP, Fechner PY, et al.Exome sequencing for the diagnosis of 46, XY disorders of sexdevelopment. J Clin Endocrinol Metab. 2015;100:E333–44.5. Eggers S, Sadedin S, van den Bergen J, Robevska G, Ohnesorg T, Hewitt J,et al. Disorders of sex development: insights from targeted genesequencing of a large patient cohort. Genome Biol. 2016;17:243.6. Arboleda VA, Lee H, Sánchez FJ, Délot EC, Sandberg DE, Grody WW, et al.Targeted massively parallel sequencing provides comprehensive geneticdiagnosis for patients with disorders of sex development. Clin Genet.2013;83:35–43.7. Dong Y, Yi Y, Yao H, Yang Z, Hu H, Liu J, et al. Targeted next-generationsequencing identification of mutations in patients with disorders of sexdevelopment. BMC Med Genet. 2016;17:23.8. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards andguidelines for the interpretation of sequence variants: a joint consensusrecommendation of the American College of Medical Genetics andGenomics and the Association for Molecular Pathology. Genet Med.2015;17:405–24.9. De Franco E, Flanagan SE, Houghton JA, Lango Allen H, Mackay DJ, TempleIK, et al. The effect of early, comprehensive genomic testing on clinical carein neonatal diabetes: an international cohort study. Lancet. 2015;386:957–63.10. Guran T, Buonocore F, Saka N, Nuri Ozbek M, Aycan Z, Bereket A, et al. Rarecauses of primary adrenal insufficiency: Genetic and clinical characterizationof a large nationwide cohort. J Clin Endocrinol Metab. 2016;101:284–92.

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