DDx Infertility

· Inability to achieve conception, or the inability to sustain a pregnancy through to live birth (infecundity)

· 15% of couples affected

· Female causes:

· Fallopian tube obstruction / adhesion

· Anatomic abnormalities of the genital tract

· Ovulation disorders

· Hypothalamic

· Pituitary

· Ovarian

· Most cytogenetic abnormalities fall into this category

· Endometriosis

· A fraction is genetically determined

· A minority of those with demonstrable chromosomal causes

· Male:

· XXY (or XXY/XY)

· Typically azoospermia and occasionally severe oligospermia

· Yq microdeletion (azoospermia typically)

· AZF (azoospermia factor) regions in Yq11

· Important genes in spermatogenesis

· AZFc region most common (Yq11.23)

· DAZ multigene family

· Doesn’t necessarily cause infertility

· AZFa and AZFb region deletions are more severe in their effects as a rule

· Mostly not detectable cytogenetically

· Structural gonosomal abnormalities

· Y-autosome translocation (rare)

· XX male (rare)

· Small isodicentric 15

· Prader-Willi

· Female:

· Turner (45,X) and its variants, including mosaicism

· X structural abnormalities

· X Deletions

· Xp11.2 (ovarian failure or menstrual irregularities and infertility)

· Xq13 -26 (critical region for Xq deletions)

· More distal Xq deletions associated with milder phenotype

· Gonosomal marker chromosome

· Autosomal causes infrequently

· 47,XXX (uncommon association)

· Fragile X permutation heterozygote

· XY female (rare)

· Both:

· Autosomal causes infrequently (male > female)

· Reciprocal translocation

· Especially involving an acrocentric

· Robertsonian translocation (most often male)

· (infrequently causes severe hypospermatogenesis and moderate to severe oligospermia)

· Inversion

· (infrequently causes severe hypospermatogenesis and moderate to severe oligospermia)

· X-autosome translocation (almost always infertile)

· Complex rearrangements and rings

· Typically azoospermia, less often female oogenesis affected

· markers

· Low-level trisomy 21 mosaicism (infecundity)

· Other (non-chromosomal) genetic causes of infertility:

· Male:

· Persistent Mullerian duct syndrome

· Testosterone synthesis defects

· 5-alpha-reductase deficiency

· Kennedy disease

· Luteinizing hormone receptor defect

· Idiopathic hypogonadotropic hypogonadism

· Cystic fibrosis

· Congenital bilateral (and some unilateral) absence of the vas deferens (CBAVD)

· Primary ciliary dyskinesia

· Kartagener syndrome

· Bardet-Biedl syndrome

· Noonan syndrome

· Myotonic dystrophy

· Kallman syndrome

· Prader-Willi syndrome (due to UPD or imprinting defect)

· Female:

· Ovarian function:

· FMR1 mutation (Xq27.3) – Fragile X syndrome

· SRY mutation (Yp11.3) – Swyer syndrome

· FSHR mutation (2p21-p16)

· LHR mutation (2p21)

· CYP17 (10q24.2) – 17-Hydroxylase deficiency

· CYP19 (15q21.1) – aromatase deficiency

· AIRE (21q22.3) – autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

· FTZF1 (SF1) (9q33)

· GALT (9p13)

· Hyothalamic function:

· KAL (Xp22.3) – Kallman syndrome

· AHC (Xp21)

· Leptin (7q31.3)

· Leptin receptor (1p31)

· Pituitary function:

· GNHR (4q21.2)

· HESX1 (3p21.1-21.2)

· LH (19q13.3)

· FSH (5q)

· HESX1 (3p21.1-21.2)

· Uterine development:

· AR (Xq11q12) – androgen insensitivity syndrome

· HOXA13 – hand-foot-uterus syndrome

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References:

· Gardner RJM & Sutherland G. Chromosom Abnormalities and Genetic Counselling, 3^rd ed. Oxford University Press (2004)

· Gersen et al. The Principles of Clinical Cytogenetics, 2^nd ed. Humana, New Jersey, 2005.

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