Klinische Fragestellung46XX-Infertilität/-Sterilität, Differentialdiagnose

NGS +

[Sanger]

Unfruchtbarkeit ist definiert als Erkrankung des Fortpflanzungssystems, die durch das Ausbleiben einer klinischen Schwangerschaft nach 12 Monaten oder mehr mit regelmäßigem ungeschütztem Geschlechtsverkehr definiert wird (WHO-ICMART). Etwa 10% der Frauen im fortpflanzungsfähigen Alter sind demgemäß nicht in der Lage, schwanger zu werden bzw. eine Schwangerschaft auszutragen. Weibliche Faktoren allein sind für mindestens ein Drittel aller Unfruchtbarkeitsfälle verantwortlich und umfassen ein breites Spektrum von Ursachen, die die Entwicklung der Eierstöcke, die Reifung der Eizellen und die Befruchtungskompetenz sowie das Potenzial einer befruchteten Eizelle für die Präimplantationsentwicklung, die Implantation und das fetale Wachstum beeinflussen. Genetische Anomalien, die zu Unfruchtbarkeit bei Frauen führen, umfassen Chromosomenanomalien, submikroskopische Chromosomen-Deletionen/-Duplikationen und DNA-Sequenzvariationen in den vielen Genen, die zahlreiche biologische Prozesse steuern, die in der Oogenese, der Aufrechterhaltung der Eierstockreserve, der hormonellen Signalübertragung sowie der anatomischen und funktionellen Entwicklung der weiblichen Fortpflanzungsorgane eine Rolle spielen. Folgende genetische Entitäten von Störungen sind eingeschlossen, die bei Unfruchtbarkeit immer wieder auftreten: „Mosaic variegated aneuploidy“ Syndrom, Mullerian-Aplasie bei Hyperandrogenismus, Oozyten-Reifungsdefekte, Ovarialdysgenese, ovarielles Hyperstimulationssyndrom, ovarielle Reaktion auf FSH-Stimulation, Schwangerschaftsverlust, rezidivierende Präimplantations-Embryonen-Letalität, prämature Chromatid-Separation, vorzeitiges Ovarialversagen und primäre Ovarialinsuffizienz. Da allerdings sehr viele Fälle von Sterilität multifaktoriell bedingt sind, ist die molekulargenetische Ausbeute nicht genau definierbar. Ein unauffälliger genetischer Befund bedeutet keinen Ausschluss der klinischen Verdachtsdiagnose.

Referenz: https://doi.org/10.1093/biolre/ioz084

• Allelic: 46XX sex reversal 4 (NR5A1)
• Allelic: 46XY sex reversal 2, dosage-sensitive (NR0B1)
• Allelic: 46XY sex reversal 3 (NR5A1)
• Allelic: Acromesomelic dysplasia, Demirhan type (BMPR1B)
• Allelic: Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency (CYP21A2)
• Allelic: Adrenocortical insufficiency (NR5A1)
• Allelic: Brachydactyly, type A1, D (BMPR1B)
• Allelic: Brachydactyly, type A2 (BMPR1B)
• Allelic: Breast cancer, somatic (ESR1)
• Allelic: Budd-Chiari syndrome (F5)
• Allelic: Cerebrooculofacioskeletal syndrome 1 (ERCC6)
• Allelic: Cockayne syndrome, type B (ERCC6)
• Allelic: Colorectal cancer, somatic (BUB1B)
• Allelic: Combined oxidative phosphorylation deficiency 5 (MRPS22)
• Allelic: Combined oxidative phosphorylation deficiency 8 (AARS2)
• Allelic: Congenital bilateral absence of vas deferens (CFTR)
• Allelic: Cystic fibrosis (CFTR)
• Allelic: D-bifunctional protein deficiency (HSD17B4)
• Allelic: De Sanctis-Cacchione syndrome (ERCC6)
• Allelic: Dysprothrombinemia (F2)
• Allelic: Factor V deficiency (F5)
• Allelic: Fragile X syndrome (FMR1 repeat)
• Allelic: Fragile X tremor/ataxia syndrome (FMR1 repeat)
• Allelic: Galloway-Mowat syndrome 7 (NUP107)
• Allelic: Holoprosencephaly 9 (GLI2)
• Allelic: Hydrops, lactic acidosis + sideroblastic anemia (LARS2)
• Allelic: Hypertrypsinemia, neonatal (CFTR)
• Allelic: Hypoprothrombinemia (F2)
• Allelic: Hypospadias 1, X-linked (AR)
• Allelic: IVIC syndrome (SALL4)
• 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: Lung cancer, susceptibility to (ERCC6)
• Allelic: Macular degeneration, age-related, susceptibility to, 5 (ERCC6)
• Allelic: Migraine, susceptibility to (ESR1)
• Allelic: Mitochondrial DNA depletion syndrome 7, hepatocerebral type (TWNK)
• Allelic: Mitochondrial recessive ataxia syndrome, SANDO + SCAE (POLG)
• Allelic: Multiple fibroadenomas of the breast (PRLR)
• Allelic: Myocardial infarction, susceptibility to (ESR1)
• Allelic: Nephrotic syndrome, type 11 (NUP107)
• Allelic: Neutropenia, severe congenital 3, AR (HAX1)
• Allelic: PCWH syndrome (SOX10)
• Allelic: Pancreatitis, hereditary (CFTR)
• Allelic: Precocious puberty, male (LHCGR)
• Allelic: Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 3 (TWNK)
• Allelic: Progressive external ophthalmoplegia, AD 1 (POLG)
• Allelic: Progressive external ophthalmoplegia, AR 1 (POLG)
• Allelic: Prostate cancer, susceptibility to (AR)
• Allelic: SERKAL syndrome (WNT4)
• Allelic: Spermatogenic failure 2 (MSH4)
• Allelic: Spermatogenic failure 32 (SOHLH1)
• Allelic: Spermatogenic failure 4 (SYCP3)
• Allelic: Spermatogenic failure 8 (NR5A1)
• Allelic: Spinal + bulbar muscular atrophy of Kennedy (AR repeat)
• Allelic: Stroke, ischemic, susceptibility to (F2, F5)
• Allelic: Sweat chloride elevation without CF (CFTR)
• Allelic: Thrombophilia due to activated protein C resistance (F5)
• Allelic: Thrombophilia due to thrombin defect (F2)
• Allelic: Thrombophilia, susceptibility to, due to factor V Leiden (F5)
• Allelic: UV-sensitive syndrome (ERCC6)
• Allelic: Waardenburg syndrome, type 2E, with/-out neurologic involvement (SOX10)
• Allelic: Waardenburg syndrome, type 4C (SOX10)
• "Fertility stabilizer" (PGRMC1)
• 17,20-lyase deficiency, isolated (CYP17A1)
• 17-alpha-hydroxylase/17,20-lyase deficiency (CYP17A1)
• Adrenal hypoplasia, congenital (NR0B1)
• Androgen insensitivity (AR)
• Androgen insensitivity, partial, with/-out breast cancer (AR)
• Bronchiectasis with/-out elevated sweat chloride 1, modifier of (CFTR)
• Congenital disorder of glycosylation, type Ia (PMM2)
• Culler-Jones syndrome (GLI2)
• Duane-radial ray syndrome (SALL4)
• Estrogen resistance (ESR1)
• Galactosemia (GALT)
• Growth hormone deficiency with pituitary anomalies (HESX1)
• Hydatidiform mole, recurrent, 1 (NLRP7)
• Hydatidiform mole, recurrent, 2 (KHDC3L)
• Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency (CYP21A2)
• Hyperprolactinemia (PRLR)
• 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 or without anosmia (HS6ST1)
• Hypogonadotropic hypogonadism 16 with/-out anosmia (SEMA3A)
• Hypogonadotropic hypogonadism 17 with/-out anosmia (SPRY4)
• 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)
• Leukoencephalopathy with vanishing white matter 5 +/- ovarian failure (EIF2B5)
• Leukoencephalopathy, progressive, with ovarian failure (AARS2)
• Luteinizing hormone resistance, female (LHCGR)
• Mitochondrial DNA depletion syndrome 4A, Alpers type (POLG)
• Mitochondrial DNA depletion syndrome 4B, MNGIE type (POLG)
• Mosaic variegated aneuploidy syndrome 1 (BUB1B)
• Mosaic variegated aneuploidy syndrome 3 (TRIP13)
• Mullerian aplasia + hyperandrogenism (WNT4)
• Muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome (GGPS1)
• Obesity, morbid, due to leptin deficiency (LEP)
• Obesity, morbid, due to leptin receptor deficiency (LEPR)
• Oocyte maturation defect 1 (ZP1)
• Oocyte maturation defect 9 (TRIP13)
• 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)
• Ovarian hyperstimulation syndrome (FSHR)
• Ovarian response to FSH stimulation (FSHR)
• Perrault syndrome 1 (HSD17B4)
• Perrault syndrome 2 (HARS2)
• Perrault syndrome 3 (CLPP)
• Perrault syndrome 4 (LARS2)
• Perrault syndrome 5 (TWNK)
• Pituitary hormone deficiency, combined, 2 (PROP1)
• Pituitary hormone deficiency, combined, 5 (HESX1)
• Pregnancy loss, recurrent, 4 (SYCP3)
• Pregnancy loss, recurrent, susceptibility to, 1 (F5)
• Pregnancy loss, recurrent, susceptibility to, 2 (F2)
• Pregnancy loss, recurrent, susceptibility to, 3 (ANXA5)
• Preimplantation embryonic lethality (TLE6)
• Preimplantation embryonic lethality 2 (PADI6)
• Premature chromatid separation trait (BUB1B)
• Premature ovarian failure 1 (FMR1 repeat)
• Premature ovarian failure 10 (MCM8)
• Premature ovarian failure 11 (ERCC6)
• Premature ovarian failure 13 (MSH5)
• Premature ovarian failure 14 (GDF9)
• Premature ovarian failure 20 (NSH4)
• Premature ovarian failure 2A (DIAPH2)
• Premature ovarian failure 2B (POF1B)
• Premature ovarian failure 3 (FOXL2)
• Premature ovarian failure 4 (BMP15)
• Premature ovarian failure 5 (NOBOX)
• Premature ovarian failure 6 (FIGLA)
• Premature ovarian failure 7 (NR5A1)
• Premature ovarian failure 8 (STAG3)
• Premature ovarian failure 9 (HFM1)
• Primary ovarian insufficiency (SOHLH2)
• Primary ovarian insufficiency (SOX8)
• Primary ovarian insufficiency [panelapp] (SOHLH2)
• Rickets, vitamin D-resistant, type IIA (VDR)
• Septooptic dysplasia (HESX1)
• Spermatogenic failure, XL, 2 (TEX11)