Reproductive longevity is associated with health outcomes. Early menopause, loss of ovarian function, and male infertility are linked to shorter lifespan and increased adverse health outcomes. Here we examined the extragonadal effects of whole animal loss of Sohlh1 gene in mice, a well-described mouse model of female and male infertility. Sohlh1 encodes a transcription factor that is primarily expressed in the male and female germline and regulates germline differentiation. The Sohlh1 knockout (KO) mouse model, just like human individuals with SOHLH1 loss of function, presents with hypergonadotropic hypogonadism and loss of ovarian function in females and impaired spermatogenesis in males, with a seemingly gonad restricted phenotype in both sexes. However, extragonadal phenotyping revealed that Sohlh1 deficiency leads to abnormal immune profiles in the blood and ovarian tissues of female animals, sex-specific alterations of metabolites, and behavior and cognition changes. Altogether, these results show that Sohlh1 deficiency impacts overall health in both male and female mice.
Purpose: Miscarriage, due to genetically heterogeneous etiology, is a common outcome of pregnancy. Preconception genetic carrier screening (PGCS) identifies at-risk partners for newborn genetic disorders; however, PGCS panels currently lack miscarriage-related genes. Here we assessed the theoretical impact of known and candidate genes on prenatal lethality and the PGCS among diverse populations. Methods: Human exome sequencing and mouse gene function databases were analyzed to define genes essential for human fetal survival (lethal genes), identify variants that are absent in a homozygous state in healthy human population, and to estimate carrier rates for known and candidate lethal genes. Results: Among 138 genes, potential lethal variants are present in the general population with a frequency of 0.5% or greater. Preconception screening for these 138 genes would identify from 4.6% (Finnish population) to 39.8% (East Asian population) of couples that are at-risk for miscarriage, explaining a cause for pregnancy loss for ~1.1-10% of conceptions affected by biallelic lethal variants. Conclusion: This study identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The diversity of these genes amongst the various ethnic groups highlights the importance of designing a pan-ethnic PGCS panel comprising miscarriage-related genes.
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