Disorders of Sex Development
Disorders of Sex Development (DSD), formerly termed intersex conditions, occur when there is a discrepancy between the appearance of the genitalia and the genetic makeup of an individual.
Overview
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Disorders of Sex Development (DSD), formerly termed intersex conditions, occur when there is a discrepancy between the appearance of the genitalia and the genetic makeup of an individual.
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These disorders can present from birth to adolescence. DSD can be mild or significant depending on the appearance of the genitalia and associated symptoms. DSD can be caused by changes at a chromosomal level and gene level thus the inheritance pattern of DSDs can be dominant, recessive or sex-linked. Additionally, DSDs can occur due to de novo changes in the DNA (for the first time in the affected individual).
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The Igenomix Disorders of Sex Development Precision Panel can be used to make a directed and accurate differential diagnosis of ambiguous genitalia ultimately leading to a better management and prognosis of the disease. It provides a comprehensive analysis of the genes involved in this disease using next-generation sequencing (NGS) to fully understand the spectrum of relevant genes involved.
Indication
The Igenomix Disorders of Sex Development Precision Panel is indicated for those patients with clinical suspicion of an intersex condition presenting with the following manifestations:
- Family history of genital ambiguity
- History of early death of infants
- Maternal drug ingestion
- Ambiguous genitalia
- Abnormal size and degree of differentiation of phallus
- Abnormal position of urethral meatus
- Separated labioscrotal folds
- Labioscrotal folds with increased pigmentation
Clinical Utility
The clinical utility of this panel is:
- The genetic and molecular confirmation for an accurate clinical diagnosis of a symptomatic patient.
- Early initiation of treatment with a multidisciplinary team for early surgical reconstruction, psychosocial aids and pharmacologic treatment.
- Risk assessment of asymptomatic family members according to the mode of inheritance.
Genes & Diseases
See all genes & diseases
| GENE | OMIM DISEASES | INHERITANCE* | % GENE COVERAGE (20X) | HGMD** |
| AKR1C2 | 46,XY Sex Reversal 8 | AR | 91.52% | 5 of 7 |
| AKR1C3 | Prostate Cancer, Endometrial Cancer, Breast Cancer, Skin Squamous Cell Carcinoma | – | 96.97% | 2 of 2 |
| AMH | Persistent Mullerian Duct Syndrome Types 1 and 2 | AR | 98.17% | 76 of 96 |
| AMHR2 | Persistent Mullerian Duct Syndrome Types 1 and 2 | AR | 100% | 87 of 95 |
| ANOS1 | Hypogonadotropic Hypogonadism 1 With Or Without Anosmia, Kallmann Syndrome, Normosmic Congenital Hypogonadotropic Hypogonadism, | X,XR,G | 96.86% | NA of NA |
| AR | Androgen Insensitivity Syndrome, X-linked Hypospadias, Kennedy Disease, Partial Androgen Insensitivity Syndrome, Prostate Cancer, Reifenstein Syndrome, X-linked Spinal And Bulbar Muscular Atrophy | AD,X,XR,G | 97.96% | NA of NA |
| ARX | Corpus Callosum Agenesis-Abnormal Genitalia Syndrome, Early Infantile Epileptic Encephalopathy, X-linked Lissencephaly With Abnormal Genitalia, X-linked Mental Retardation, Partington Syndrome, West Syndrome, X-linked Non-Syndromic Intellectual Disability, X-linked Spasticity-Intellectual Disability-Epilepsy Syndrome | X,XR,G | 81.92% | NA of NA |
| ATRX | Alpha-Thalassemia Myelodysplasia Syndrome, Carpenter-Waziri Syndrome, Chudley-Lowry-Hoar Syndrome, Holmes-Gang Syndrome, Juberg-Marsidi Syndrome, X-Linked Mental Retardation-Hypotonic Facies Syndrome, Neuroendocrine Tumor Of Stomach, Smith-Fineman-Myers Syndrome | X,XR,XD,G | 98.50% | NA of NA |
| BCOR | Acute Promyelocytic Leukemia, Lenz Type Microphthalmia, Oculofaciocardiodental Syndrome | X,XD,G | 99.87% | NA of NA |
| CBX2 | 46,XY Complete Gonadal Dysgenesis,46XY Sex Reversal | AR | 100% | 6 of 6 |
| CDK9 | Primary Immunodeficiency, Multiple Myeloma, NUT Midline Carcinoma | 82.69% | 2 of 2 | |
| CDKN1C | Beckwith-Wiedemann Syndrome, IMAGE Syndrome, Intrauterine Growth Restriction-Short Stature-Early Adult-Onset Diabetes Syndrome, Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia Congenita, And Genital Anomalies | AD | 73.58% | 55 of 76 |
| CEP41 | Joubert Syndrome | AR | 100% | 17 of 17 |
| CHD7 | CHARGE Syndrome, Hypogonadotropic Hypogonadism With Or Without Anosmia, Kallmann Syndrome, Normosmic Congenital Hypogonadotropic Hypogonadism, Omenn Syndrome | AD | 96.25% | 823 of 896 |
| CITED4 | Adult Oligodendroglioma, Breast Cancer | 65.14% | NA of NA | |
| CREBBP | Menke-Hennekam Syndrome, Rubinstein-Taybi Syndrome | AD | 100% | 318 of 318 |
| CYB5A | 46,XY Disorder Of Sex Development Due To Isolated 17,20-Lyase Deficiency, Hereditary Methemoglobinemia And Ambiguous Genitalia | AR | 100% | 5 of 5 |
| CYP11A1 | 46,XY Disorder Of Sex Development-Adrenal Insufficiency Due To Cyp11a1 Deficiency | 100% | 39 of 39 | |
| CYP11B1 | Congenital Adrenal Hyperplasia Due To Steroid 11-Beta-Hydroxylase Deficiency, Familial Hyperaldosteronism Type I, Glucocorticoid-Remediable Aldosteronism | AD,AR | 100% | 144 of 144 |
| CYP17A1 | 46,XY Disorder Of Sex Development Due To Isolated 17,20-Lyase Deficiency, Congenital Adrenal Hyperplasia Due To 17-Alpha-Hydroxylase Deficiency | AR | 100% | 127 of 127 |
| CYP19A1 | Aromatase Deficiency, Aromatase Excess Syndrome | AD,AR | 100% | 33 of 35 |
| CYP21A2 | Congenital Adrenal Hyperplasia Due To 21-Hydroxylase Deficiency | AR | 99.98% | 278 of 280 |
| DHCR7 | Smith-Lemli-Opitz Syndrome | AR | 100% | 217 of 217 |
| DHH | 46,XY Complete Gonadal Dysgenesis | AR | 99.85% | 21 of 21 |
| DYNC2H1 | Jeune Syndrome, Short Rib-Polydactyly Syndrome, X,Short-Rib Thoracic Dysplasia With Or Without Polydactyly | AR,MU,D | 99.78% | 214 of 221 |
| EMX2 | Schizencephaly | 100% | 5 of 5 | |
| ERCC3 | Trichothiodystrophy, Xeroderma Pigmentosum-Cockayne Syndrome Complex | AR | 99.98% | 24 of 24 |
| FEZF1 | Hypogonadotropic Hypogonadism With Or Without Anosmia, Kallmann Syndrome | AR | 99.95% | 3 of 3 |
| FGF8 | Alobar Holoprosencephaly, Hypogonadotropic Hypogonadism With Or Without Anosmia, Kallmann Syndrome | AD | 98.36% | 38 of 38 |
| FGFR1 | Encephalocraniocutaneous Lipomatosis, Hartsfield Syndrome, Isolated Trigonocephaly, Jackson-Weiss Syndrome, Kallmann Syndrome, Lobar Holoprosencephaly,Microform Holoprosencephaly, Normosmic Congenital Hypogonadotropic Hypogonadism, Oligodontia, Osteoglophonic Dysplasia, Pfeiffer Syndrome, Septo-Optic Dysplasia Spectrum, Nonsyndromic Trigonocephaly | AD | 100% | 279 of 280 |
| FIG4 | Amyotrophic Lateral Sclerosis, Bilateral Parasagittal Parieto-Occipital Polymicrogyria, Charcot-Marie-Tooth Disease, Cleidocranial Dysplasia With Micrognathia, Absent Thumbs And Distal, Polymicrogyria, Bilateral Temporooccipital, Yunis-Varon Syndrome | AD,AR | 99.92% | 72 of 72 |
| FOXL2 | Blepharophimosis, Ptosis, And Epicanthus Inversus, Premature Ovarian Failure | AD | 89.36% | 136 of 201 |
| FRAS1 | Fraser Syndrome | AR | 98.73% | 57 of 58 |
| GNRH1 | Hypogonadotropic Hypogonadism With Or Without Anosmia, Normosmic Congenital Hypogonadotropic Hypogonadism | AR | 100% | 12 of 12 |
| GNRHR | Hypogonadotropic Hypogonadism Without Anosmia, Normosmic Congenital Hypogonadotropic Hypogonadism | AR | 100% | 59 of 59 |
| HSD17B3 | 46,XY Disorder Of Sex Development Due To 17-Beta-Hydroxysteroid Dehydrogenase Deficiency, Male Pseudohermaphroditism With Gynecomastia | AR | 100% | 61 of 61 |
| HSD3B2 | Congenital Adrenal Hyperplasia Due To 3-Beta-Hydroxysteroid Dehydrogenase Deficiency, Congenital Adrenal Hyperplasia Due To 3-Beta-Hydroxysteroid Dehydrogenase Deficiency | AR | 100% | 70 of 70 |
| IL17RD | Hypogonadotropic Hypogonadism With Or Without Anosmia, Kallmann Syndrome | AD,AR | 99.95% | 17 of 17 |
| IRF6 | Autosomal Dominant Popliteal Pterygium Syndrome, Cleft Lip And Alveolus, Cleft Lip/Palate, Isolated Cleft Lip, Oligodontia, Orofacial Cleft, Van Der Woude Syndrome | AD,MU,P | 99.98% | 325 of 335 |
| KISS1 | Hypogonadotropic Hypogonadism With Or Without Anosmia, Normosmic Congenital Hypogonadotropic Hypogonadism | AR | 100% | 9 of 10 |
| KISS1R | Hypogonadotropic Hypogonadism With Or Without Anosmia, Kallmann Syndrome, Normosmic Congenital Hypogonadotropic Hypogonadism, Central Precocious Puberty | AD,AR | 99.41% | 42 of 43 |
| LHB | Hypogonadotropic Hypogonadism Without Anosmia | AR | 100% | 11 of 11 |
| LHCGR | Familial Male-Limited Precocious Puberty, Hypergonadotropic Hypogonadism, Precocious Puberty, Male-limited | AD,AR | 100% | 75 of 75 |
| LHX9 | Gonadal Agenesis, 46 XY Sex Reversal | 99.65% | 1 of 1 | |
| MAMLD1 | X-linked Hypospadias, X-linked Myotubular Myopathy-Abnormal Genitalia Syndrome | X,XR,G | 99.87% | NA of NA |
| MAP3K1 | 46,XY Complete Gonadal Dysgenesis, 46 XY Partial Gonadal Dysgenesis, 46 XY Sex Reversal | AD | 96.50% | 31 of 32 |
| MKRN3 | Prader-Willi Syndrome, Central Precocious Puberty | AD,ADWMI | 99.98% | 39 of 41 |
| MKS1 | Bardet-Biedl Syndrome, Joubert Syndrome, Meckel Syndrome | AR | 99.98% | 49 of 49 |
| NR0B1 | 46,XX Testicular Disorder Of Sex Development, 46XY Complete Gonadal Dysgenesis, 46XY Partial Gonadal Dysgenesis, Congenital Adrenal Hypoplasia, Dosage-Sensitive Sex Reversal | X,XR,G | 99.87% | NA of NA |
| NR5A1 | 46,XX Gonadal Dysgenesis, 46 XX Ovotesticular Disorder Of Sex Development,46 XX Sex Reversal, 46 XX Testicular Disorder Of Sex Development,46 XY Complete Gonadal Dysgenesis, 46 XY Partial Gonadal Dysgenesis, 46 XY Sex Reversal, Male Infertility With Azoospermia Or Oligozoospermia Due To Single Gene Mutation, Premature Ovarian Failure, Spermatogenic Failure | AD | 99.97% | 222 of 224 |
| POR | Antley-Bixler Syndrome With Genital Anomalies And Disordered Steroidogenesis, Congenital Adrenal Hyperplasia Due To Cytochrome P450 Oxidoreductase Deficiency, Disordered Steroidogenesis Due To Cytochrome P450 Oxidoreductase | AD,AR | 99.98% | 67 of 68 |
| PROK2 | Hypogonadotropic Hypogonadism With Or Without Anosmia, Kallmann Syndrome, Normosmic Congenital Hypogonadotropic Hypogonadism | AD | 100% | 20 of 20 |
| PROKR2 | Hypogonadotropic Hypogonadism With Or Without Anosmia, Kallmann Syndrome, Normosmic Congenital Hypogonadotropic Hypogonadism, Pituitary Stalk Interruption Syndrome, Septo-Optic Dysplasia Spectrum | AD | 100% | 64 of 64 |
| RSPO1 | Palmoplantar Hyperkeratosis With Squamous Cell Carcinoma Of Skin, 46 XX Sex Reversal, Palmoplantar Keratoderma | AR | 100% | 6 of 7 |
| SAMD9 | Mirage Syndrome, Familial Normophosphatemic Tumoral Calcinosis | AD,AR | 99.72% | 45 of 46 |
| SGPL1 | Nephrotic Syndrome | AR | 98.96% | 18 of 18 |
| SOX10 | Kallmann Syndrome, Peripheral Demyelinating Neuropathy-Central Dysmyelinating Leukodystrophy, Waardenburg Syndrome, Hirschsprung Disease, Peripheral Demyelinating Neuropathy, Central Dysmyelination | AD | 99.74% | 139 of 147 |
| SOX13 | Metastatic Cancer Disease | 100% | 1 of 1 | |
| SOX3 | 46, XX Testicular Disorder Of Sex Development, X-linked Mental Retardation With Isolated Growth Hormone Deficiency, Non-Acquired Panhypopituitarism, X-linked Panhypopituitarism, Septo-Optic Dysplasia Spectrum | X,G | 92.88% | NA of NA |
| SOX9 | 46,XX Ovotesticular Disorder Of Sex Development, 46 XX Testicular Disorder Of Sex Development, 46 XY Complete Gonadal Dysgenesis, 46XY Partial Gonadal Dysgenesis, Campomelic Dysplasia, Isolated Pierre Robin Syndrome | AD | 97.28% | 87 of 95 |
| SRD5A2 | 46,XY Disorder Of Sex Development Due To 5-Alpha-Reductase Deficiency, Pseudovaginal Perineoscrotal Hypospadias | AR | na | na |
| SRY | 45X/46 XY Mixed Gonadal Dysgenesis,46 XX Ovotesticular Disorder Of Sex Development, 46XX Testicular Disorder Of Sex Development, 46XY Complete Gonadal Dysgenesis, 46XY Partial Gonadal Dysgenesis, 46XX Sex Reversal, 46XY Sex Reversal | X,XD,Y,G | 45% | NA of NA |
| STAR | Familial Glucocorticoid Deficiency, Lipoid Congenital Adrenal Hyperplasia | AR | 100% | 80 of 80 |
| TAC3 | Hypogonadotropic Hypogonadism With Or Without Anosmia, Normosmic Congenital Hypogonadotropic Hypogonadism | AR | 100% | 10 of 10 |
| TACR3 | Hypogonadotropic Hypogonadism With Or Without Anosmia, Kallmann Syndrome, Normosmic Congenital Hypogonadotropic Hypogonadism | AR | 99.97% | 40 of 40 |
| TOE1 | Pontocerebellar Hypoplasia | AR | 99.98% | 12 of 12 |
| TSPYL1 | Sudden Infant Death With Dysgenesis Of The Testes Syndrome | AR | 99.92% | 8 of 8 |
| WDR11 | Hypogonadotropic Hypogonadism With Or Without Anosmia, Kallmann Syndrome, Normosmic Congenital Hypogonadotropic Hypogonadism, Pituitary Stalk Interruption Syndrome | AD,AR | 100% | 19 of 19 |
| WT1 | 46 XY Complete Gonadal Dysgenesis, 46 XY Partial Gonadal Dysgenesis, Aniridia, Denys-Drash Syndrome, Desmoplastic Small Round Cell Tumor, Frasier Syndrome, Meacham Syndrome, Mesothelioma, Malignant, Nephroblastoma, Nephrotic Syndrome, WAGR Syndrome, Wilms Tumor, Aniridia, Genitourinary Anomalies, And Mental Retardation Syndrome Chromosome 11p13 Deletion Syndrome | AD | 98.92% | 178 of 185 |
| ZFPM2 | 46 XY Partial Gonadal Dysgenesis, 46 XY Sex Reversal, Congenital Diaphragmatic Hernia, Tetralogy Of Fallot | AD | 99.40% | 44 of 46 |
*Inheritance: AD: Autosomal Dominant; AR: Autosomal Recessive; X: X linked; XLR: X linked Recessive; Mi: Mitochondrial; Mu: Multifactorial.
**Number of clinically relevant mutations according to HGMD
References
Witchel S. F. (2018). Disorders of sex development. Best practice & research. Clinical obstetrics & gynaecology, 48, 90–102. https://doi.org/10.1016/j.bpobgyn.2017.11.005
Lee, P. A., Nordenström, A., Houk, C. P., Ahmed, S. F., Auchus, R., Baratz, A., Baratz Dalke, K., Liao, L. M., Lin-Su, K., Looijenga, L. H., 3rd, Mazur, T., Meyer-Bahlburg, H. F., Mouriquand, P., Quigley, C. A., Sandberg, D. E., Vilain, E., Witchel, S., & Global DSD Update Consortium (2016). Global Disorders of Sex Development Update since 2006: Perceptions, Approach and Care. Hormone research in paediatrics, 85(3), 158–180. https://doi.org/10.1159/000442975
Houk, C., & Lee, P. (2012). Update on disorders of sex development. Current Opinion In Endocrinology & Diabetes And Obesity, 19(1), 28-32. doi: 10.1097/med.0b013e32834edacb
Hughes, I., Houk, C., Ahmed, S., & Lee, P. (2006). Consensus statement on management of intersex disorders. Journal Of Pediatric Urology, 2(3), 148-162. doi: 10.1016/j.jpurol.2006.03.004
Yatsenko, S. A., & Witchel, S. F. (2017). Genetic approach to ambiguous genitalia and disorders of sex development: What clinicians need to know. Seminars in perinatology, 41(4), 232–243. https://doi.org/10.1053/j.semperi.2017.03.016
