Whole-exome sequencing reveals SALL4 variants in premature ovarian insufficiency: an update on genotype–phenotype correlations

Premature ovarian insufficiency (POI) is a severe female disorder characterized by primary or secondary amenorrhea before 40 years of age. Genetic factors have been implicated in the pathogenesis of POI, but known POI-associated genes account for only a small fraction of heritability. Here, we performed whole-exome sequencing (WES) to explore pathogenic genes in Han Chinese subjects with POI. Intriguingly, we identified novel or rare heterozygous missense variants of SALL4 (spalt-like transcription factor 4) in 3 (6%) of 50 POI subjects. The SALL4 c.541G>A and c.2279C>T variants were paternally inherited, while c.1790A>G was inherited from an affected mother with early menopause. SALL4 encodes a transcription factor that is highly expressed in oocytes and early embryos. Our in vitro functional assays suggested that all of these SALL4 missense variants had significantly increased SALL4 protein expression with enhanced regulatory activity in regard to its downstream target POU5F1 compared to that of wild-type SALL4. Notably, previous studies demonstrated the genetic involvement of SALL4 loss-of-function variants in Okihiro syndrome and related syndromic developmental disorders. Through our analysis of genotype–phenotype correlations, we suggest that different variation types of SALL4 might have different effects on SALL4 activity, resulting in phenotypic variability. Our findings highlight the genetic contribution of SALL4 missense variants with enhanced regulatory activities to POI and underscore the importance of variant classification and evaluation for molecular diagnosis and genetic counseling.