A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature

Abstract

Primary ovarian insufficiency (POI) refers to an etiologically heterogeneous disorder characterized by hypergonadotropic hypogonadism that represents a major cause of infertility in women under 40 years of age. Most cases are apparently sporadic, but about 10-15% have an affected first-degree relative, indicating a genetic etiology. Pathogenic variations in genes involved in development, meiosis and hormonal signaling have been detected in the hereditary form of the disorder. However, most cases of POI remain unsolved even after exhaustive investigation. A 19-year-old Senegalese female affected by non-syndromic POI presented with primary amenorrhoea and answered well to the hormonal induction of puberty. In order to investigate the presence of a genetic defect, aCGH-SNP analysis was performed. A 13.5 Mb long contiguous stretch of homozygosity (LCSH) was identified on chromosome 7q21.13-q22.1 where the exome sequencing revealed a novel homozygous 4-bp deletion (c.3381_3384delAGAA) in STAG3. Pathogenic variants in this gene, encoding for a meiosis-specific protein, have been previously reported as the cause of POI in only eight families and recently as the cause of infertility in a male. The here-identified mutation leads to the truncation of the last 55 amino acids, confirming the important role in meiosis of the STAG3 C-terminal domain.

Keywords: LCSH; STAG3; exome sequencing; primary ovarian insufficiency.

Figure 1

Magnetic resonance before and after estrogen replacement therapy. Panels “a”,“b” show uterine hypoplasia (continuous white arrows) in sagittal (panel “a”) and transversal plane (panel “b”). Reduced uterine thickness, consistent with pre-pubertal morphology, is evidenced in panel “a” (dashed arrow). In panels “c”,“d”, continuous white arrows indicate the uterine development after 24 months of estrogen therapy both in sagittal (panel “c”) and transversal (panel “d”) planes. Endometrial development and increase in uterine thickness are evident in panel “c” (dashed arrow).

Figure 2

CGH-SNP array and sequencing results. (A) Array-CGH-SNP results: the LCSH on chromosome 7q21.13-q22.1 is indicated by a blue arrow. (B) The partial sequencing electropherogram is shown including the novel homozygous mutation identified in STAG3 (NM_001282716.1:c.3381_3384del); the corresponding wild-type sequence is shown below with a dashed rectangle showing the deleted bases.

Figure 3

Schematic representation of STAG3 and protein structure with pathogenic variants reported in POI patients. The exon-intron structure of STAG3 (transcript NM_001282716.1) is displayed in the lower part of the figure. The scheme of STAG3 protein consisting of 1225 amino acids (aa) (protein domains for ENSP00000400359.1) is reported in the middle part of the figure with colored rectangles indicating the STAG domain (174–283 aa; PF08514 Pfam database), an Armadillo-type fold domain (ARM-type fold) (303–813 aa; SSF48371 Superfamily database) and a Stromalin conservative domain (SCD) (309–394 aa; PS51425 Prosite profiles). The pathogenetic variants identified in previous studies in females are shown in blue boxes whereas the variant identified in this study is shown in the red box. The pathogenetic variants identified in males are shown in green boxes.