Male and Female Infertility via the FSHB Gene

Infertility affects 10-20% of couples worldwide and is generally attributed to males and females equally (Marchbanks et al. 1989). The follicle-stimulating hormone receptor signaling pathway is required for ovarian maturation and folliculogenesis in females and sperm production in males (reviewed in Layman & McDonough, 2000). The basic elements of this pathway include a follicle-stimulating hormone (FSH) ligand and an FSH receptor (FSHR). The FSH ligand is a heterodimer comprised of non-covalently joined α and β peptide chains. The α-subunit is encoded by the chorionic gonadotropin, alpha polypeptide (CGA) gene while the β-subunit is encoded by follicle-stimulating hormone, beta polypeptide (FSHB) gene. The CGA subunit is common to luteinizing hormone (LH), human chorionic gonadotropin (hCG), thyroid stimulating hormone (TSH) and FSH, but the FSHB subunit confers specificity of the hormone for FSHR. Binding of FSH to its receptor induces a cascade of events in ovarian granulosa cells and male Sertoli cells, which culminates in the transcription of genes required for folliculogenesis and spermatogenesis, respectively. Loss-of-function variants in either FSHB (OMIM 136530) or FSHR (OMIM 136435; see also the description for the FSHR test) lead to failed gametogenesis in both sexes. Women with variants in FSHB commonly display symptoms of delayed puberty, partial breast development and primary amenorrhea, while men with variants often undergo normal puberty but have azoospermia (Layman et al. 2002).

Infertility associated with FSHB variants is most often inherited in an autosomal recessive pattern, with the heterozygous family members exhibiting normal fertility (Layman et al. 1997; Phillip et al. 1998). However, in one reported case, the heterozygous mother of a child with primary amenorrhoea and infertility had been amenorrehoeic and infertile for six years prior to the unexpected conception of her child (Matthews et al. 1993), indicating that in some cases, FSHB haploinsufficiency may lead to a mild, subfertility phenotype. To date, five distinct pathogenic variants in the FSHB gene have been documented: two are missense variants (p.Cys51Gly and p.Cys82Arg), two are frameshifts (i.e. small deletions), and one is a nonsense variant (p.Tyr94*) (see www.hgmd.org).

The clinical sensitivity of this test is unknown at this time.

This test provides full coverage of all coding exons of the FSHB gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).