Description
Disorders of sex development inclusion criteria (36879)
46,XX disorder of sex development
•	Normal 46,XX karyotype following microarray testing, AND
•	Absence of SRY, AND
•	At least one of (a) genital ambiguity, (b) absence or anomaly of the Mullerian structures, or (c) gonadal dysgenesis

46,XY disorder of sex development
•	Normal 46,XY karyotype following microarray testing, AND
•	Presence of SRY, AND
•	At least one of (a) ambiguity of the external genitalia, (b) presence of Mullerian structures, or (c) gonadal dysgenesis

Disorders of sex development exclusion criteria (36879)
46,XX disorder of sex development
•	Antenatal history suggestive of non-genetic cause, e.g. maternal androgen exposure
•	Biochemical or genetic evidence of 21-hydroxylase deficiency, 11-hydroxylase deficiency, 3 beta hydroxysteroid dehydrogenase deficiency type 2, cytochrome P450 reductase (POR) related disorders and 17 alpha hydroxylase deficiency.

46,XY disorder of sex development
•	Isolated hypospadias
•	Biochemical or genetic evidence of 5 alpha reductase deficiency, 3 beta hydroxysteroid dehydrogenase deficiency type 2, cytochrome P450 reductase (POR) related disorders, aromatase deficiency and androgen insensitivity syndrome.

Prior genetic testing guidance (36879)
- Results should have been reviewed for all genetic tests undertaken, including disease-relevant genes in exome sequencing data. The patient is not eligible if they have a molecular diagnosis for their condition. 
- Genetic testing should continue according to routine local practice for this phenotype regardless of recruitment to the project; results of these tests must be submitted via the ‘Genetic investigations’ section of the data capture tool to allow comparison of WGS with current standard testing.  

PLEASE NOTE: The sensitivity of WGS compared to current diagnostic genetic testing has not yet been established. It is therefore important that tests which are clinically indicated under local standard practice continue to be carried out.

Disorders of sex development prior genetic testing genes (36879)
Testing of the following genes should be carried out PRIOR TO RECRUITMENT where this is in line with current local practice:

46,XX disorder of sex development
•	In situ study to exclude presence of SRY
•	Exclusion of CNV associated with 46 XX DSD
•	CYP21A2 and CYP11B1 if indicated by steroid biochemistry - steroid biochemistry to assess whether these disorders needed genetic testing would be a requirement before inclusion.

46,XY disorder of sex development
•	In situ study to prove presence of SRY
•	Exclusion of CNV associated with 46 XY DSD
•	Obligatory endocrinological assessment and steroid biochemistry (including testosterone, DHT) and where indicated from biochemical investigations analysis of HSD17B3, SRD5A2 and Androgen receptor)

Closing statement (36879)
These requirements will be kept under continual review during the main programme and may be subject to change.

5 reviewers

  • Ellen McDonagh (Genomics England Curator)

    Group: other
    Workplace: other

  • John Achermann (UCL Institute of Child Health)

    Group: GeCIP domain
    Workplace: Research lab

  • emma baple (Genomics England Curator)

    Group: NHS Genomic Medicine Centre
    Workplace: NHS clinical service

  • Sarah Leigh (Genomics England Curator)

    Group: Other
    Workplace: Other

  • Helen Brittain (Genomics England Curator)

    Group: Other
    Workplace: Other

52 Entities

51 reviewed, 33 green

List Entity Reviews Mode of inheritance Details
52 Entitiess
Green Green List (high evidence)
11p13 (WAGR syndrome) region Loss
ISCA-37401-Loss
Region
0 reviews
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • ClinGen
  • Expert Review Green
Phenotypes
  • Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome
  • 194072
Tags
Green Green List (high evidence)
AR
3 reviews
1 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Gender Assignment Gene Panel UKGTN
  • Androgen insensitivity,300068
  • Androgen insensitivity,partial,with/without breast cancer,312300
  • Hypospadias 1,X-linked,300633
Tags
Green Green List (high evidence)
ARX
1 review
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Corpus Callosum, Agenesis Of, With Abnormal Genitalia, Proud syndrome 300004
  • ARX-related Disorders
  • Lissencephaly, X-linked 2 300215
Tags
Green Green List (high evidence)
ATRX
2 reviews
1 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Mental retardation-hypotonic facies syndrome, X-linked 309580
Tags
Green Green List (high evidence)
CDKN1C
1 review
MONOALLELIC, autosomal or pseudoautosomal, paternally imprinted (maternal allele expressed)
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • IMAGE syndrome, 614732
  • Beckwith-Wiedemann syndrome 130650
  • Disproportionate Short Stature and Wilms Tumor: Sequencing Panels (Emory)
Tags
Green Green List (high evidence)
CHD7
1 review
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • OMIM
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • CHARGE syndrome, 214800
Tags
Green Green List (high evidence)
CUL4B
1 review
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Mental retardation, X-linked, syndromic 15 (Cabezas type), 300354
  • XLMR with Short Stature, Small Testes, Muscle Wasting, and Tremor
Tags
Green Green List (high evidence)
CYB5A
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Green
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • 46,XY underandrogenization with biochemistry similar to isolated 17,20-lyase deficiency
  • Methemoglobinemia, type I, 250790
Tags
Green Green List (high evidence)
CYP11A1
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
  • Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete, 613743
Tags
Green Green List (high evidence)
CYP11B1
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
  • Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency, 202010
Tags
Green Green List (high evidence)
CYP17A1
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
  • Endocrine disorders including disorders of sexual development (Emory)
  • congenital adrenal hyperplasia
  • 17,20-lyase deficiency, isolated 202110 and 17-alpha-hydroxylase/17,20-lyase deficiency 202110
Tags
Green Green List (high evidence)
CYP19A1
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Gender Assignment Gene Panel (UKGTN)
  • Endocrine disorders including disorders of sexual development
  • Aromatase deficiency, 613546
Tags
Green Green List (high evidence)
CYP21A2
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
  • Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency 201910
  • Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency, 201910
Tags
Green Green List (high evidence)
DHCR7
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
  • Smith-Lemli-Opitz syndrome, 270400
Tags
Green Green List (high evidence)
DHH
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • 46XY partial gonadal dysgenesis, with minifascicular neuropathy, 607080
  • 46XY sex reversal 7, 233420
Tags
Green Green List (high evidence)
HSD17B3
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Gender Assignment Gene Panel (UKGTN)
  • Pseudohermaphroditism, male, with gynecomastia, 264300
Tags
Green Green List (high evidence)
HSD3B2
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
  • Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency, 201810
Tags
Green Green List (high evidence)
LHCGR
2 reviews
1 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Gender Assignment Gene Panel (UKGTN)
  • Endocrine disorders including disorders of sexual development (Emory)
  • Leydic cell hypoplasia type 1, 238320
  • Precocious puberty, male, 176410
Tags
Green Green List (high evidence)
MAMLD1
2 reviews
1 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Gender Assignment Gene Panel (UKGTN)
  • Hypospadias 2, X-linked 300758
Tags
Green Green List (high evidence)
MAP3K1
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Green
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • 46XY sex reversal 6 613762
Tags
Green Green List (high evidence)
NR0B1
1 review
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • 6XY sex reversal 2, dosage-sensitive 300018
  • Adrenal hypoplasia, congenital 300200
Tags
Green Green List (high evidence)
NR5A1
2 reviews
1 green
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Emory Genetics Laboratory
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
  • Endocrine disorders including disorders of sexual development (Emory)
  • 46XY sex reversal 3, 612965
  • Premature ovarian failure 7, 612964
  • Spermatogenic failure 8, 613957
Tags
Green Green List (high evidence)
POR
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
  • Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis AR, 201750
  • Disordered steroidogenesis due to cytochrome P450 oxidoreductase, 613571
Tags
Green Green List (high evidence)
RPL10
1 review
1 green
X-LINKED: hemizygous mutation in males, biallelic mutations in females
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Mental retardation, X-linked, syndromic, 35 300998
Tags
Green Green List (high evidence)
RSPO1
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Palmoplantar hyperkeratosis and true hermaphroditism 610644
  • Palmoplantar hyperkeratosis with squamous cell carcinoma of skin and sex reversal 610644
Tags
Green Green List (high evidence)
SAMD9
1 review
1 green
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • MIRAGE syndrome 617053
Tags
  • missense
Green Green List (high evidence)
SOX10
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Waardenburg syndrome, type 4C 613266
Tags
Green Green List (high evidence)
SOX9
2 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Gender Assignment & Genital Anomalies and Suspected Adrenal Problems Gene Panels (UKGTN)
  • Campomelic dysplasia with autosomal sex reversal, 114290
Tags
Green Green List (high evidence)
SRD5A2
3 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Eligibility statement prior genetic testing
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Other
  • UKGTN
Phenotypes
  • Pseudovaginal perineoscrotal hypospadias 264600
Tags
Green Green List (high evidence)
SRY
3 reviews
1 green
Other - please specifiy in evaluation comments
Sources
  • Eligibility statement prior genetic testing
  • Emory Genetics Laboratory
  • Expert Review Green
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Testicular dysgenesis/Swyers syndrome
  • 46XX sex reversal 1 400045
  • 46XY sex reversal 1 400044
Tags
  • y-chromosome
Green Green List (high evidence)
STAR
2 reviews
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
  • Lipoid adrenal hyperplasia, 201710
Tags
Green Green List (high evidence)
TOE1
1 review
1 green
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
Phenotypes
  • Pontocerebellar hypoplasia, type 7 614969
Tags
Green Green List (high evidence)
WT1
3 reviews
1 green
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Denys-Drash syndrome 194080
  • Frasier syndrome 136680
  • Meacham syndrome 608978
Tags
Green Green List (high evidence)
ZFPM2
2 reviews
1 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Green
  • Other
Phenotypes
  • 46XY sex reversal 9 616067
Tags
Amber Amber List (moderate evidence)
SGPL1
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Nephrotic syndrome 14 617575
Tags
Red Red List (low evidence)
AKR1C2
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Expert list
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • 46XY sex reversal 8 614279
Tags
Red Red List (low evidence)
ATP6V0A4
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Genital Anomalies and Suspected Adrenal Problems Gene Panel (UKGTN)
  • Renal tubular acidosis, distal, autosomal recessive, 602722
Tags
Red Red List (low evidence)
CBX2
3 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Other
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Gender Assignment Gene Panel (UKGTN)
  • 46XY sex reversal 5, 613080
Tags
Red Red List (low evidence)
DGKQ
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • UKGTN
Tags
Red Red List (low evidence)
DMRT1
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • UKGTN
Phenotypes
  • Gender Assignment Gene Panel (UKGTN)
Tags
Red Red List (low evidence)
ERAL1
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Literature
Phenotypes
  • Perrault syndrome 6 617565
Tags
  • founder-effect
Red Red List (low evidence)
GATA4
2 reviews
2 red
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • ?Testicular anomalies with or without congenital heart disease 615542
Tags
Red Red List (low evidence)
GLI2
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Emory Genetics Laboratory
  • Expert Review Red
  • Illumina TruGenome Clinical Sequencing Services
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Culler-Jones syndrome, 615849
  • Holoprosencephaly-9, 610829
Tags
Red Red List (low evidence)
HHAT
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review
  • Expert Review Red
Phenotypes
  • 46,XY DSD with chondrodysplasia
Tags
Red Red List (low evidence)
HSD17B2
2 reviews
1 red
Unknown
Sources
  • Expert Review Red
  • UKGTN
Phenotypes
  • Gender Assignment Gene Panel (UKGTN)
Tags
Red Red List (low evidence)
INPP5E
1 review
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Radboud University Medical Center, Nijmegen
  • UKGTN
Phenotypes
  • Mental retardation, truncal obesity, retinal dystrophy, and micropenis, 610156
Tags
Red Red List (low evidence)
MCM5
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Literature
Phenotypes
  • ?Meier-Gorlin syndrome 8 617564
Tags
Red Red List (low evidence)
PAX6
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Emory Genetics Laboratory
  • Expert Review Red
  • Illumina TruGenome Clinical Sequencing Services
  • UKGTN
Phenotypes
  • Not relevant to this panel
Tags
Red Red List (low evidence)
SEMA3E
1 review
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert list
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • CHARGE syndrome 214800
Tags
Red Red List (low evidence)
TAF4B
1 review
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Other
Phenotypes
  • Spermatogenic failure 13 615841
Tags
Red Red List (low evidence)
TSPYL1
2 reviews
1 red
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Red
  • Expert list
  • Other
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Sudden infant death with dysgenesis of the testes syndrome 608800
Tags
Red Red List (low evidence)
TWIST2
1 review
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Radboud University Medical Center, Nijmegen
Phenotypes
  • Barber-Say syndrome 209885
  • Focal facial dermal dysplasia 3, Setleis type 227260
Tags

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