Erkrankung46XY-Infertilität/-Sterilität, Differentialdiagnose

NGS +

[Sanger]

Unfruchtbarkeit ist definiert als die Unfähigkeit, innerhalb eines Jahres nach ungeschütztem Geschlechtsverkehr schwanger zu werden. Ungefähr 7% der männlichen Bevölkerung sind davon betroffen, was insgesamt die Unfruchtbarkeit bei der Hälfte aller betroffenen Paare erklärt. Die Ätiologie der männlichen Unfruchtbarkeit ist sehr komplex. Mindestens 15 % aller unfruchtbaren Männer zeigen genetische Auffälligkeiten. Zu den entscheidenden Ursachen für männliche Unfruchtbarkeit gehören die sexuelle Differenzierung, die Entwicklung des Urogenitalsystems und die Gametogenese. Anomalien der Geschlechtschromosomen spielen eine wichtige Rolle bei schweren Beeinträchtigungen der Spermatogenese, und mindestens 2 000 Gene sind an der Spermatogenese beteiligt. Beinahe ein Viertel der bekannten genetischen Faktoren, die zur männlichen Unfruchtbarkeit beitragen, führen zur Azoospermie. Autosomale Genmutationen verursachen vor allem zentralen Hypogonadismus, Teratozoospermie oder Asthenozoospermie, kongenitale obstruktive Azoospermie und familiäre Fälle von quantitativen Spermatogenese-Störungen. Die genetische Diagnostik beginnt mit Karyotypisierung, Deletionsanalysen des Azoospermie-Faktors (AZF) und der Mutationsanalyse im Gen des zystischen Fibrose-Transmembranleitfähigkeitsregulators (CFTR). Die molekulargenetische Diagnose kann derzeit bei etwa 5% der unfruchtbaren Männer mittels eines umfangreicheren Gen panels gesichert werden. Ein unauffälliger genetischer Befund bedeutet keinen Ausschluss der klinischen Verdachtsdiagnose.

Referenzen: https://pubmed.ncbi.nlm.nih.gov/29622783/

https://doi.org/10.1093/humrep/dez022

https://pubmed.ncbi.nlm.nih.gov/31347970/

• Allelic: Acampomelic campomelic dysplasia (SOX9)
• Allelic: Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency (CYP21A2)
• Allelic: Aldosteronism, glucocorticoid-remediable (CYP11B1)
• Allelic: Atrial septal defect 2 (GATA4)
• Allelic: Atrioventricular septal defect 4 (GATA4)
• Allelic: Campomelic dysplasia (SOX9)
• Allelic: Cystic fibrosis (CFTR)
• Allelic: Deafness, AD 34, with/-out inflammation (NLRP3)
• Allelic: Dyslexia, susceptibility to, 1 (DNAAF4)
• Allelic: Encephalitis/encephalopathy, mild, with reversible myelin vacuolization (MYRF)
• Allelic: Familial cold inflammatory syndrome 1 (NLRP3)
• Allelic: Hydrocephalus, normal pressure, 1 (CFAP43)
• Allelic: Hypertrypsinemia, neonatal (CFTR)
• Allelic: Keratoendothelitis fugax hereditaria (NLRP3)
• Allelic: Leber congenital amaurosis 10 (CEP290)
• Allelic: Mesothelioma, somatic (WT1)
• Allelic: Nephrotic syndrome, type 4 (WT1)
• Allelic: Ovarian dysgenesis 1 (FSHR)
• Allelic: Ovarian hyperstimulation syndrome (FSHR)
• Allelic: Ovarian response to FSH stimulation (FSHR)
• Allelic: Pancreatitis, hereditary (CFTR)
• Allelic: Premature ovarian failure 15 (FANCM)
• Allelic: Premature ovarian failure 17 (XRCC2)
• Allelic: Primary ovary insufficiency [panelapp] (IGSF10)
• Allelic: Prostate cancer, susceptibility to (AR)
• Allelic: Spinal + bulbar muscular atrophy of Kennedy (AR repeat)
• Allelic: Sweat chloride elevation without CF (CFTR)
• Allelic: Tetralogy of Fallot (GATA4)
• Allelic: Ventricular septal defect 1 (GATA4)
• Allelic: Wilms tumor, type 1 (WT1)
• 17,20-lyase deficiency, isolated (CYP17A1)
• 17-alpha-hydroxylase/17,20-lyase deficiency (CYP17A1)
• 46XY sex reversal 11 (DHX37)
• Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency (CYP11B1)
• Adrenal insufficiency, congenital, with 46XY sex reversal, partial or complete (CYP11A1)
• Allelic: Pregnancy loss, recurrent, 4 (SYCP3)
• Amyloidosis, 3 or more types (APOA1)
• Androgen insensitivity (AR)
• Androgen insensitivity, partial, with/-out breast cancer (AR)
• Anosmic hypogonadotropic hypogonadism [panelapp] (CCDC141)
• Aromatase deficiency (CYP19A1)
• Aromatase excess syndrome (CYP19A1)
• Bardet-Biedl syndrome 14 (CEP290)
• Bronchiectasis with/-out elevated sweat chloride 1, modifier of (CFTR)
• CINCA syndrome (NLRP3)
• Campomelic dysplasia with autosomal sex reversal (SOX9)
• Cardiac-urogenital syndrome (MYRF)
• Ciliary dyskinesia, primary, 10 (DNAAF2)
• Ciliary dyskinesia, primary, 14 (CCDC39)
• Ciliary dyskinesia, primary, 15 (CCDC40)
• Ciliary dyskinesia, primary, 25 (DNAAF4)
• Ciliary dyskinesia, primary, 3, with/-out situs inversus (DNAH5)
• Ciliary dyskinesia, primary, 32 (RSPH3)
• Ciliary dyskinesia, primary, 36, XL (DNAAF6)
• Ciliary dyskinesia, primary, 37 (DNAH1)
• Ciliary dyskinesia, primary, 7, with/-out situs inversus (DNAH11)
• Congenital bilateral absence of vas deferens (CFTR)
• Congenital hypogonadotropic hypogonadism [MONDO:0015770] (CCDC141)
• Cryptorchidism (INSL3)
• Deafness, AR 32, with/-out immotile sperm /CDC14A)
• Deafness, autosomal recessive 32, with or without immotile sperm (CDC14A)
• Delayed puberty [panelapp] (IGSF10)
• Denys-Drash syndrome (WT1)
• Fanconi anemia compelmentation group A (FANCA)
• Fanconi anemia, complementation group U (XRCC2)
• Frasier syndrome (WT1)
• Heterotaxy, visceral, 9, autosomal, with male infertility (MNS1)
• Hydatidiform mole, recurrent, 3 (MEI1)
• Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency (CYP21A2)
• Hypoalphalipoproteinemia, primary, 2 (APOA1)
• Hypoalphalipoproteinemia, primary, 2, intermediate (APOA1)
• Hypogonadotropic hypogonadism 1 with/-out anosmia; Kallmann syndrome 1 (ANOS1)
• Hypogonadotropic hypogonadism 11 with/-out anosmia (TACR3)
• Hypogonadotropic hypogonadism 12 with/-out anosmia (GNRH1)
• Hypogonadotropic hypogonadism 14 with/-out anosmia (WDR11)
• Hypogonadotropic hypogonadism 15 with/-out anosmia (HS6ST1)
• Hypogonadotropic hypogonadism 16 with/-out anosmia (SEMA3A)
• Hypogonadotropic hypogonadism 18 with/-out anosmia (IL17RD)
• Hypogonadotropic hypogonadism 2 with/-out anosmia (FGFR1)
• Hypogonadotropic hypogonadism 20 with/-out anosmia (FGF17)
• 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 6 with/-out anosmia (FGF8)
• Hypogonadotropic hypogonadism 7 without anosmia (GNRHR)
• Hypogonadotropic hypogonadism [panelapp] (IGSF10)
• Hypospadias 2, XL (MAMLD1)
• Infertility, male [jte-titled from lit.] (DDX3Y)
• Intellectual developmental disorder, XL, with isolated growth hormone deficiency (SOX3)
• Joubert syndrome 5 (CEP290)
• Lipoid adrenal hyperplasia (STAR)
• Lower urinary tract obstruction, congenital (BNC2)
• Meacham syndrome (WT1)
• Meckel syndrome 4 (CEP290)
• Microphthalmia, syndromic 3 (SOX2)
• Microphthalmia, syndromic 6 (BPM4)
• Muckle-Wells syndrome (NLRP3)
• Neurodevelopmental disorder with brain anomalies with/-out vertebral/cardiac anomalies (DHX37)
• Optic nerve hypoplasia + abnormalities of the central nervous system (SOX2)
• Orofacial cleft 11 (BPM4)
• Palmoplantar hyperkeratosis + true hermaphroditism (RSPO1)
• Palmoplantar hyperkeratosis with squamous cell carcinoma of skin + sex reversal (RSPO1)
• Panhypopituitarism, XL (SOX3)
• Pituitary hormone deficiency, combined or isolated, 1 (POU1F1)
• Pituitary hormone deficiency, combined, 2 (PROP1)
• Polycystic kidney disease 1 (PKD1)
• Pseudovaginal perineoscrotal hypospadias (SRD5A2)
• Senior-Loken syndrome 6 (CEP290)
• Spermatogenic failure (HSF2)
• Spermatogenic failure 1 (SYCP2)
• Spermatogenic failure 10 (SEPTIN12)
• Spermatogenic failure 11 (KLHL10)
• Spermatogenic failure 16 (SUN5)
• Spermatogenic failure 17 (PLCZ1)
• Spermatogenic failure 18 (DNAH1)
• Spermatogenic failure 19 (CFAP43)
• Spermatogenic failure 20 (CFAP44)
• Spermatogenic failure 23 (TEX14)
• Spermatogenic failure 24 (CFAP69)
• Spermatogenic failure 25 (TEX15)
• Spermatogenic failure 26 (TSGA10)
• Spermatogenic failure 28 (FANCM)
• Spermatogenic failure 31 (PMFBP1)
• Spermatogenic failure 33 (CFAP251)
• Spermatogenic failure 34 (FSIP2)
• Spermatogenic failure 35 (QRICH2)
• Spermatogenic failure 38 (ARMC2)
• Spermatogenic failure 39 (DNAH17)
• Spermatogenic failure 4 (SYCP3)
• Spermatogenic failure 40 (CFAP65)
• Spermatogenic failure 42 (TTC29)
• Spermatogenic failure 43 (SPEF2)
• Spermatogenic failure 48 (M1AP)
• Spermatogenic failure 50 (XRCC2)
• Spermatogenic failure 51 (CFAP91)
• Spermatogenic failure 6 (SPATA16)
• Spermatogenic failure, XL 2 (TEX11)
• Testicular anomalies with/-out congenital heart disease (GATA4)