Illness46XX infertility / sterility, differential diagnosis

NGS +

[Sanger]

Infertility is defined as a disease of the reproductive system characterized by the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse (WHO-ICMART). Accordingly, approximately 10% of women of reproductive age are unable to become pregnant or carry a pregnancy to term. Female factors alone account for at least one-third of all infertility cases and include a wide range of causes that affect ovarian development, oocyte maturation and fertilization competence as well as the potential of a fertilized oocyte for preimplantation development, implantation and fetal growth. Genetic abnormalities leading to infertility in women include chromosomal abnormalities, submicroscopic chromosomal deletions/duplications and DNA sequence variations in the many genes that control numerous biological processes involved in oogenesis, maintenance of ovarian reserve, hormonal signaling, anatomical and functional development of the female reproductive organs. The following genetic entities of disorders are included that are recurrent in infertility: Mosaic variegated aneuploidy syndrome, Mullerian aplasia in hyperandrogenism, oocyte maturation defects, ovarian dysgenesis, ovarian hyperstimulation syndrome, ovarian response to FSH stimulation, pregnancy loss, recurrent preimplantation embryo lethality, premature chromatid separation, premature ovarian failure and primary ovarian insufficiency. Yet, because very many cases of infertility are multifactorial, the molecular genetic yield is not precisely definable. An inconspicuous genetic finding does not mean exclusion of the suspected clinical diagnosis.

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

The FSHR polymorphism p.Asn680Ser may be relevant with regard to dose calculation prior to ovarian stimulation and is therefore reported if explicitly requested. doi: 10.1007/s00129-021-04785-6

• 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)