Premature Ovarian Failure/Ovarian Dysgenesis via the SOHLH1 Gene

Premature Ovarian Failure (POF), also known as primary ovarian insufficiency, is a genetically and phenotypically heterogeneous disorder characterized by primary amenorrhea or loss of menstrual function before the age of 40. Patients with POF often have elevated levels of follicle-stimulating hormone (FSH) and decreased levels of estrogen (Nelson. 2009. PubMed ID: 19196677). POF, in the most severe form, is a result of ovarian dysgenesis in which pubertal development is also severely affected. POF is a major cause of infertility and affects 1% of women before the age of 40. Approximately 50% of patients have varying and unpredictable ovarian function, and 5 to 10% of patients with POF may conceive without treatment (Nelson. 2009. PubMed ID: 19196677). There are several causes of premature ovarian failure, including chromosomal abnormalities, pathogenic sequence variants, autoimmune disorder, and environmental factors. POF can be isolated or part of a genetic syndrome (Kovanci and Schutt. 2015. PubMed ID: 25681846).

Approximately 10-30% of POF cases have familial inheritance (Vegetti et al. 1998. PubMed ID: 9740426; van Kasteren et al. 1999. PubMed ID: 10527968). The inheritance can be autosomal recessive, dominant or X-linked. To date, defects in at least 21 genes, including SOHLH1, have been documented to cause POF (Bouilly et al. 2016. PubMed ID: 27603904; Patiño et al. 2017. PubMed ID: 28505269).

SOHLH1 is a basic helix-loop-helix (bHLH) transcription factor that is expressed during oogenesis and plays a critical role in early folliculogenesis. It is also expressed during early testis development and is an important regulator of spermatogenesis (Kumar. PubMed ID: 28504648). Bi-allelic loss-of-function variants (nonsense, missense, splicing and small frameshift deletions) in SOHLH1 have been reported as causative for autosomal recessive POF (Bayram et al. 2015. PubMed ID: 25774885; Bouilly et al. 2016. PubMed ID: 27603904).

Several pathogenic variants in SOHLH1 have been documented. In a cohort of 100 patients with premature ovarian failure, three pathogenic variants in SOHLH1 were identified (Bouilly et al. 2016. PubMed ID: 27603904).

No large deletions or duplications involving SOHLH1 have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the SOHLH1 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).