Pathogenic Variants in ZSWIM7 Cause Primary Ovarian Insufficiency

Abstract

Context: Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers.

Objective: We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis.

Setting: Study subjects were recruited at academic centers.

Patients or other participants: Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected.

Research design: Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene.

Main outcome measure(s): Rare deleterious variants in known and candidate genes associated with POI.

Results: Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function.

Conclusions: Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions.

Keywords: ZSWIM7; DNA damage response; DNA repair; female infertility; primary ovarian insufficiency.

Figure 1.

Variants in the ZSWIM7 gene. (A, B) Family pedigrees. Affected females are shown in gray-filled circles. Both patients had normal 46,XX karyotype and no history of autoimmune or iatrogenic conditions as a cause of primary ovarian insufficiency. Double horizontal lines indicate consanguinity. The ZSWIM7 genotype is provided for each individual. The wild-type allele is indicated as WT. (C) Gene structure with known protein domains of the gene product. The ZSWIM7 (zinc finger SWIM domain-containing protein 7) gene is located on chromosome 17p12 (chr17:15,879,875_ 15,903,006; hg19) and composed of 5 exons. Exons are specified as green-colored boxes. In patient P20428, the ZSWIM7 homozygous missense c.38T > C variant occurs in exon 1. In TPOF-GII2, a homozygous frameshift c.231_232delAT variant is located in exon 4, encoding the zinc finger SWIM domain (purple-shaded box). ZSWIM7, a 140-amino acid protein, contains 2 β-strands, a zinc finger SWIM (ZF SWIM) domain, and an α-helix. (D) Protein sequence alignment of human ZSWIM7 and its homologs in Mus musculus, Danio reiro, Canis lupus, Pan troglodytes, Bos taurus, and Gallus gallus. The affected Leu13 residue (marked in red) is highly conserved among all shown organisms. Residues are shaded based on similarity. Symbols denote: (*) conserved residue; (;) conservation between groups of strongly similar properties (>0.5 in the Gonnet PAM 250 matrix); (.) conservation between groups of weakly similar properties (≤0.5 in the Gonnet PAM 250 matrix). (E) In silico modeling of amino acid substitutions in ZSWIM7. The WT and 2 altered protein structures are shown. The leucine to proline change at residue 13 (p.Leu13Pro) is predicted to “break” the N-terminal helix, dividing this helix into 2, whose central axes no longer align (red lines). This could reorganize the packing of the entire molecule, including the DNA-binding region. Furthermore, if the regions surrounding position 13 still were able to form helices, the smaller proline sidechain would destabilize its interaction with neighboring amino acids. The p.Cys78fs*21 frameshift change at residue 78 that truncates the protein after 21 residues would impact the β-sheet and helix integral to supporting the zinc finger fold.