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Illness46XX - disorders of sex development, differential diagnosis

Summary

Short information

A curated panel containing 13 core/core candidate genes and altogether 78 genes for the comprehensive analysis of the genetic causes of 46XX disorders of sex delopment; mutations in 13 genes cover the most frequent mutations.

ID
GP0071
Number of genes
75 Accredited laboratory test
Examined sequence length
16,8 kb (Core-/Core-canditate-Genes)
138,2 kb (Extended panel: incl. additional genes)
Analysis Duration
on request
Material
  • EDTA-anticoagulated blood (3-5 ml)
Diagnostic indications

NGS +

[Sanger]

 

Gene panel

Selected genes

NameExon Length (bp)OMIM-GReferenz-Seq.Heredity
BMP151179NM_005448.2XL
CYP11B11512NM_000497.4AR
CYP19A11512NM_031226.3AR
CYP21A21488NM_000500.9AR
FOXL21131NM_023067.4AD
HSD3B21119NM_000198.4AR
NR5A11386NM_004959.5AD
POR2043NM_001395413.1AR
RSPO1792NM_001038633.4AR
SOX101401NM_006941.4AD
SOX91530NM_000346.4AD
SRY615NM_003140.3YL
WNT41056NM_030761.5AR, AD
AMH1683NM_000479.5AR
AMHR21722NM_020547.3AR
ANOS12043NM_000216.4XLR
ATRX7479NM_000489.6XL
CHD78994NM_017780.4AD
CLPP834NM_006012.4AR
CYB5A297NM_001914.4AR
CYP11A11566NM_000781.3AR, AD
CYP17A11527NM_000102.4AR
DHCR71428NM_001360.3AR
DHH1191NM_021044.4AR
DUSP61146NM_001946.4AD
ESR21593NM_001437.3AD
FANCM6147NM_020937.4AR
FEZF11428NM_001024613.4AR
FGF17651NM_003867.4AD
FGF8735NM_033163.5AD
FGFR12469NM_023110.3AR
FSHB390NM_000510.4AR
FSHR2088NM_000145.4AR
GALT1140NM_000155.4AR
GATA41329NM_002052.5AD
GDF91365NM_005260.6AD, AR
GNRH1291NM_000825.3AR
GNRHR987NM_000406.3AR
HARS21521NM_012208.4AR
HFM14308NM_001017975.6AR
HOXA131167NM_000522.5AD
HSD17B3933NM_000197.2AR
HSD17B42211NM_000414.4AR
IL17RD2220NM_017563.5AR
KISS1R1197NM_032551.5AR
LARS22712NM_015340.4AR
LHB426NM_000894.3AR
LHCGR2100NM_000233.4AD, AR
MAMLD12325NM_005491.4XLR
MCM82523NM_032485.6AR
MCM93432NM_017696.3AR
MSH42811NM_002440.4AR
NOBOX2076NM_001080413.3AD
NOG699NM_005450.6AD
NR0B11413NM_000475.5XL
NSMF1587NM_015537.5AD
NUP1072778NM_020401.4AR
PMM2741NM_000303.3AR
POLG3720NM_002693.3AD, AR
POU5F11083NM_002701.6AD
PROK2390NM_001126128.2AD, AR, Oligo
PROKR21155NM_144773.4AD, AR
PSMC3IP654NM_016556.4AR
SAMD94770NM_001193307.2AD
SOHLH11164NM_001101677.2AR
SPRY4969NM_030964.5AD
SRD5A2764NM_000348.4AR
STAG33678NM_012447.4AR
STAR858NM_000349.3AR
TAC3366NM_013251.4AR
TACR31398NM_001059.3AR
TWNK2055NM_021830.5AR
WDR113675NM_018117.12AD
WT11569NM_024426.6AD, SMu
ZFPM23456NM_012082.4AD

Informations about the disease

Clinical Comment

Phenotypic sex is the result of the differentiation of the internal ducts and external genitals under the hormonal influence of the differentiated gonad when the gonad has lost its bipotent state under the influence of sex-determining genes. Disorders of sexual development (DSDs) are defined as congenital conditions in which the development of chromosomal, gonadal and anatomical sex is atypical. Clinical classification in patients is difficult because phenotypes are similar or almost identical, although they may have several etiologies. These conditions can be identified at different lifetimes in foetuses or newborns with unclear external genitalia, gonadal dysgenesis and internal genitalia that are discordant in terms of sex chromosome constitution, and they can also be diagnosed subsequently in people with late puberty, unexpected virilization or gynecomastia, infertility or gonadal tumours. Occasionally DSDs can be part of a genetic syndrome, demonstrating the complexity of sexual development and the effect of multiple genes. DSDs are classified according to changes in the levels of sex determination: Genetic, chromosomal, gonadal, hormonal, ductal sex, external genitals, secondary characteristics, legally assigned sex and psychological characteristics. Molecular genetic analysis currently clarifies little more than half of the DSD problems. All inheritance patterns occur with variable expressivity. An inconspicuous genetic finding does not therefore mean that the clinical suspected diagnosis can be excluded with certainty.

Reference: https://www.karger.com/Article/FullText/499274

 

Synonyms
  • Alias: DSD, disorders of sex determination; Genetic 46XX DSD
  • Alias: Genetic female pseudohermaphroditism
  • Alleic: Progressive external ophthalmoplegia, AR 1 (POLG)
  • Allelic: Acampomelic campomelic dysplasia (SOX9)
  • Allelic: Aldosteronism, glucocorticoid-remediable (CYP11B1)
  • Allelic: Alpha-thalassemia myelodysplasia syndrome, somatic (ATRX)
  • Allelic: Alpha-thalassemia/mental retardation syndrome (ATRX)
  • Allelic: Atrial septal defect 2 (GATA4)
  • Allelic: Atrioventricular septal defect 4 (GATA4)
  • Allelic: Beckwith-Wiedemann syndrome (CDKN1C)
  • Allelic: Blepharophimosis, epicanthus inversus, ptosis, type 1 (FOXL2)
  • Allelic: Blepharophimosis, epicanthus inversus, ptosis, type 2 (FOXL2)
  • Allelic: Brachydactyly, type B2 (NOG)
  • Allelic: Campomelic dysplasia (SOX9)
  • Allelic: Combined oxidative phosphorylation deficiency 5 (MRPS22)
  • Allelic: D-bifunctional protein deficiency (HSD17B4)
  • Allelic: Diaphragmatic hernia 3 (ZFPM2)
  • Allelic: Disordered steroidogenesis due to cytochrome P450 oxidoreductase (POR)
  • Allelic: Encephalocraniocutaneous lipomatosis, somatic mosaic (FGFR1)
  • Allelic: Galloway-Mowat syndrome 7 (NUP107)
  • Allelic: Guttmacher syndrome (HOXA13)
  • Allelic: Hartsfield syndrome (FGFR1)
  • Allelic: Hydrops, lactic acidosis + sideroblastic anemia (LARS2)
  • Allelic: Hypospadias 2, XL (MAMLD1)
  • Allelic: Jackson-Weiss syndrome (FGFR1)
  • Allelic: Leukoencephalopathy with vanishing white matter (EIF2B5)
  • Allelic: Leydig cell adenoma, somatic, with precocious puberty (LHCGR)
  • Allelic: Leydig cell hypoplasia with hypergonadotropic hypogonadism (LHCGR)
  • Allelic: Leydig cell hypoplasia with pseudohermaphroditism (LHCGR)
  • Allelic: Mental retardation-hypotonic facies syndrome, XL (ATRX)
  • Allelic: Mesothelioma, somatic (WT1)
  • Allelic: Mitochondrial DNA depletion syndrome 4A [Alpers type] (POLG)
  • Allelic: Mitochondrial DNA depletion syndrome 4B [MNGIE type] (POLG)
  • Allelic: Mitochondrial DNA depletion syndrome 7 [hepatocerebral type] (TWNK)
  • Allelic: Mitochondrial recessive ataxia syndrome [includes SANDO + SCAE] (POLG)
  • Allelic: Monosomy 7 myelodysplasia and leukemia syndrome 2 (SAMD9)
  • Allelic: Multiple synostoses syndrome 1 (NOG)
  • Allelic: Nephrotic syndrome, type 11 (NUP107)
  • Allelic: Nephrotic syndrome, type 4 (WT1)
  • Allelic: Non-obstructive azoospermia [panelapp] (MSH4)
  • Allelic: Osteoglophonic dysplasia (FGFR1)
  • Allelic: Ovarian hyperstimulation syndrome (FSHR)
  • Allelic: Ovarian response to FSH stimulation (FSHR)
  • Allelic: PCWH syndrome (SOX10)
  • Allelic: Pfeiffer syndrome (FGFR1)
  • Allelic: Precocious puberty, male (LHCGR)
  • Allelic: Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 3 (TWNK)
  • Allelic: Progressive external ophthalmoplegia, AR 1 (POLG)
  • Allelic: Pseudovaginal perineoscrotal hypospadias (SRD5A2)
  • Allelic: Spermatogenic failure 28 (FANCM)
  • Allelic: Spermatogenic failure 32 (SOHLH1)
  • Allelic: Spermatogenic failure 8 (NR5A1)
  • Allelic: Stapes ankylosis with broad thumbs + toes (NOG)
  • Allelic: Symphalangism, proximal, 1A (NOG)
  • Allelic: Tarsal-carpal coalition syndrome (NOG)
  • Allelic: Tetralogy of Fallot (GATA4)
  • Allelic: Tetralogy of Fallot (ZFPM2)
  • Allelic: Trigonocephaly 1 (FGFR1)
  • Allelic: Tumoral calcinosis, familial, normophosphatemic (SAMD9)
  • Allelic: Ventricular septal defect 1 (GATA4)
  • Allelic: Waardenburg syndrome, type 4C (SOX10)
  • Allelic: Wilms tumor, type 1 (WT1)
  • Allelic:Mitochondrial DNA depletion syndrome 4A, Alpers type (POLG)
  • 17,20-lyase deficiency, isolated (CYP17A1)
  • 17-alpha-hydroxylase/17,20-lyase deficiency (CYP17A1)
  • 46XX sex reversal 1 (SRY)
  • 46XX sex reversal 4 (NR5A1)
  • 46XY gonadal dysgenesis with minifascicular neuropathy (DHH)
  • 46XY sex reversal 1 (SRY)
  • 46XY sex reversal 2, dosage-sensitive (NR0B1)
  • 46XY sex reversal 3 (NR5A1)
  • 46XY sex reversal 5 (CBX2)
  • 46XY sex reversal 6 (MAP3K1)
  • 46XY sex reversal 7 (DHH)
  • 46XY sex reversal 8 (AKR1C2)
  • 46XY sex reversal 8, modifier of (AKR1C4)
  • 46XY sex reversal 9 (ZFPM2)
  • Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency (CYP11B1)
  • Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency (CYP21A2)
  • Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency (HSD3B2)
  • Adrenal hypoplasia, congenital (NR0B1)
  • Adrenal insufficiency, congenital, with 46XY sex reversal, partial/complete (CYP11A1)
  • Adrenocortical insufficiency (NR5A1)
  • Allelic: Charcot-Marie-Tooth disease, demyelinating, type 1I (POLR3B)
  • Allelic: Precocious puberty, central, 1 (KISS1R)
  • Allelic: Spastic paraplegia 39, AR (PNPLA6)
  • Antley-Bixler syndrome with genital anomalies + disordered steroidogenesis (POR)
  • Aromatase deficiency (CYP19A1)
  • Aromatase excess syndrome (CYP19A1)
  • Boucher-Neuhauser syndrome (PNPLA6)
  • CHARGE syndrome (CHD7)
  • CHARGE syndrome (SEMA3E)
  • Campomelic dysplasia with autosomal sex reversal (SOX9)
  • Cerebellar ataxia and hypogonadotropic hypogonadism (RNF216)
  • Congenital disorder of glycosylation, type Ia (PMM2)
  • Denys-Drash syndrome (WT1)
  • Disorders of sex development [panelapp] (ATRX)
  • Frasier syndrome (WT1)
  • Galactosemia (GALT)
  • Gordon-Holmes syndrome [GeneReviews] (OTUD4, PNPLA6, RNF216, STUB1)
  • Hand-foot-uterus syndrome (HOXA13)
  • Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency (CYP21A2)
  • Hypogonadotropic hypogonadism 1 with/-out anosmia; Kallmann syndrome 1 (ANOS1)
  • Hypogonadotropic hypogonadism 10 with/-out anosmia (TAC3)
  • Hypogonadotropic hypogonadism 11 with/-out anosmia (TACR3)
  • Hypogonadotropic hypogonadism 12 with/-out anosmia (GNRH1)
  • Hypogonadotropic hypogonadism 13 with/-out anosmia (KISS1)
  • Hypogonadotropic hypogonadism 14 with/-out anosmia (WDR11)
  • Hypogonadotropic hypogonadism 15 with/-out anosmia (HS6ST1)
  • Hypogonadotropic hypogonadism 16 with/-out anosmia (SEMA3A)
  • Hypogonadotropic hypogonadism 16 with/-out anosmia (SEMA3A)
  • Hypogonadotropic hypogonadism 17 with/-out anosmia (SPRY1)
  • Hypogonadotropic hypogonadism 18 with/-out anosmia (IL17RD)
  • Hypogonadotropic hypogonadism 19 with/-out anosmia (DUSP6)
  • Hypogonadotropic hypogonadism 2 with/-out anosmia (FGFR1)
  • Hypogonadotropic hypogonadism 20 with/-out anosmia (FGF17)
  • Hypogonadotropic hypogonadism 21 with anosmia (FLRT3)
  • Hypogonadotropic hypogonadism 22, with/-out anosmia (FEZF1)
  • Hypogonadotropic hypogonadism 23 with/-out anosmia (LHB)
  • Hypogonadotropic hypogonadism 24 without anosmia (FSHB)
  • Hypogonadotropic hypogonadism 3 with/-out anosmia (PROKR2)
  • Hypogonadotropic hypogonadism 4 with/-out anosmia (PROK2)
  • Hypogonadotropic hypogonadism 5 with/-out anosmia (CHD7)
  • Hypogonadotropic hypogonadism 6 with/-out anosmia (FGF8)
  • Hypogonadotropic hypogonadism 7 without anosmia (GNRHR)
  • Hypogonadotropic hypogonadism 8 with/-out anosmia (KISS1R)
  • Hypogonadotropic hypogonadism 9 with/-out anosmia (NSMF)
  • IMAGE syndrome (CDKN1C)
  • Isolated gonadotropin-releasing hormone deficiency [GeneReviews] (AXL, CCDC141)
  • Laurence-Moon syndrome (PNPLA6)
  • Leukodystrophy, hypomyelinating, 8, +/- oligodontia +/- hypogonadotropic hypogonadism (POLR3B)
  • Lipoid adrenal hyperplasia (STAR)
  • Luteinizing hormone resistance, female (LGCGR)
  • MIRAGE syndrome (SAMD9)
  • Marinesco-Sjogren syndrome (SIL1)
  • Mayer-Rokitansky-Kuster-Hauser syndrome (LHX1)
  • Meacham syndrome (WT1)
  • Mental retardation, XL, with isolated growth hormone deficiency (SOX3)
  • Methemoglobinemia + ambiguous genitalia (CYB5A)
  • Mullerian aplasia + hyperandrogenism (WNT4)
  • Oliver-McFarlane syndrome (PNPLA6)
  • Ovarian dysgenesis 1 (FSHR)
  • Ovarian dysgenesis 2 (BMP15)
  • Ovarian dysgenesis 3 (PSMC3IP)
  • Ovarian dysgenesis 4 (MCM9)
  • Ovarian dysgenesis 5 (SOHLH1)
  • Ovarian dysgenesis 6 (NUP107)
  • Ovarian dysgenesis 7 (MRPS22)
  • Ovarian dysgenesis 8 (ESR2)
  • Ovarioleukodystrophy (EIF2B5)
  • Palmoplantar hyperkeratosis + true hermaphroditism (RSPO1)
  • Palmoplantar hyperkeratosis, squamous cell carcinoma of skin, sex reversal (RSPO1)
  • Panhypopituitarism, XL (SOX3)
  • Perrault syndrome 1 (HSD17B4)
  • Perrault syndrome 2 (HARS2)
  • Perrault syndrome 3 (CLPP)
  • Perrault syndrome 4 (LARS2)
  • Perrault syndrome 5 (TWNK)
  • Perrault syndrome 6 (ERAL1)
  • Persistent Mullerian duct syndrome, type I (AMH)
  • Persistent Mullerian duct syndrome, type II (AMHR2)
  • Premature ovarian failure 10 (MCM8)
  • Premature ovarian failure 14 (GDF9)
  • Premature ovarian failure 15 (FANCM)
  • Premature ovarian failure 2A (DIAPH2)
  • Premature ovarian failure 3 (FOXL2)
  • Premature ovarian failure 4 (BMP15)
  • Premature ovarian failure 5 (NOBOX)
  • Premature ovarian failure 7 (NR5A1)
  • Premature ovarian failure 8 (STAG3)
  • Premature ovarian failure 9 (HFM1)
  • Primary ovarian failure [MONDO:0005387] (MSH4)
  • Primary ovarian insufficiency (POU5F1)
  • Primary ovarian insufficiency (SOHLH2)
  • Primary ovarian insufficiency [panelapp] (NANOS3)
  • Primary ovarian insufficiency [panelapp] (NOG)
  • Primary ovarian insufficiency [panelapp] (POLG)
  • Pseudohermaphroditism, male, with gynecomastia (HSD17B3)
  • SERKAL syndrome: 46,XX SEx Reversal with dysgenesis of Kidney, Adrenals, Lungs (WNT4)
  • Smith-Lemli-Opitz syndrome (DHCR7)
  • Spinocerebellar ataxia 48 (STUB1)
  • Spinocerebellar ataxia, AR 16 (STUB1)
  • Testicular anomalies with/-out congenital heart disease (GATA4)
  • Waardenburg syndrome, type 2E, with/-out neurologic involvement (SOX10)
  • Woodhouse-Sakati syndrome (DCAF17)
Heredity, heredity patterns etc.
  • AD
  • AR
  • Oligo
  • SMu
  • XL
  • XLR
  • YL
OMIM-Ps
  • Multiple OMIM-Ps
ICD10 Code

Bioinformatics and clinical interpretation

Test-Stärken

  • DAkkS-akkreditiertes Labor
  • EU-Richtlinie für IVD in Umsetzung
  • Qualitäts-kontrolliert arbeitendes Personal
  • Leistungsstarke Sequenzierungstechnologien, fortschrittliche Target-Anreicherungsmethoden und Präzisions-Bioinformatik-Pipelines sorgen für überragende analytische Leistung
  • Sorgfältige Kuratierung klinisch relevanter und wissenschaftlich begründeter Gen-Panels
  • eine Vielzahl nicht Protein-kodierender Varianten, die in unseren klinischen NGS-Tests mit erfasst werden
  • unser strenges Variantenklassifizierungsschema nach ACMG-Kriterien
  • unser systematischer klinischer Interpretations-Workflow mit proprietärer Software ermöglicht die genaue und nachvollziehbare Verarbeitung von NGS-Daten
  • unsere umfassenden klinischen Aussagen

Testeinschränkungen

  • Gene mit eingeschränkter Abdeckung werden gekennzeichnet
  • Gene mit kompletten oder partiellen Duplikationen werden gekennzeichnet
  • es wird angenommen, dass ein Gen suboptimal abgedeckt ist, wenn >90% der Nukleotide des Gens bei einem Mapping-Qualitätsfaktor von >20 (MQ>20) nicht abgedeckt sind
  • die Sensitivität der Diagnostik zur Erkennung von Varianten mit genannten Testeinschränkungen ist möglicherweise begrenzt bei:
  • Gen-Konversionen
  • komplexe Inversionen
  • Balancierte Translokationen
  • Mitochondriale Varianten
  • Repeat-Expansionen, sofern nicht anders dokumentiert
  • nicht kodierende Varianten, die Krankheiten verursachen, die von diesem Panel nicht mit abgedeckt werden
  • niedriger Mosaik-Status
  • Repeat-Blöcke von Mononukleotiden
  • Indels >50bp (Insertionen-Deletionen)
  • Deletionen oder Duplikationen einzelner Exons
  • Varianten innerhalb von Pseudogenen
  • die analytische Sensitivität kann geringer ausfallen werden, wenn die DNA nicht von amedes genetics extrahiert wurde

Laboratory requirement

  • Die in grün gezeigten Gene sind kuratiert und werden als Gen-Panel untersucht. Eine Erweiterung des Panels (blau gezeigte Gene, jeweils ebenfalls kuratiert) kann auf Anfrage erfolgen. Sofern unter "Erweitertes Panel" ein Minuszeichen angezeigt wird, sind nur Core-/Basis-Gene verfügbar.

  • Für die Anforderung einer genetischen Untersuchung senden Sie uns bitte die Krankheits-ID auf einem Überweisungsschein. Bitte die Material-Angabe beachten.

  • Für privat versicherte Patienten empfehlen wir einen Antrag auf Kostenübernahme bei der Krankenversicherung.

  • Die Untersuchung wird auch für Selbstzahler angeboten.