2. Academic Validation
  3. ZSWIM7 Is Associated With Human Female Meiosis and Familial Primary Ovarian Insufficiency

ZSWIM7 Is Associated With Human Female Meiosis and Familial Primary Ovarian Insufficiency

  • J Clin Endocrinol Metab. 2022 Jan 1;107(1):e254-e263. doi: 10.1210/clinem/dgab597.
Sinéad M McGlacken-Byrne 1 2,  Polona Le Quesne Stabej 3 4,  Ignacio Del Valle 1,  Louise Ocaka 3,  Andrey Gagunashvili 3,  Berta Crespo 5,  Nadjeda Moreno 5,  Chela James 3,  Chiara Bacchelli 3,  Mehul T Dattani 1,  Hywel J Williams 6,  Dan Kelberman 3,  John C Achermann 1,  Gerard S Conway 2
Affiliations

Affiliations

  • 1 Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • 2 Institute for Women's Health, University College London, London WC1N 1EH, UK.
  • 3 GOSgene, Genetics and Genomic Medicine, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • 4 Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
  • 5 Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • 6 Division of Cancer and Genetics, Genetic and Genomic Medicine, Cardiff University, Cardiff CF14 4AY, UK.
PMID: 34402903 DOI: 10.1210/clinem/dgab597
Abstract

Background: Primary ovarian insufficiency (POI) affects 1% of women and is associated with significant medical consequences. A genetic cause for POI can be found in up to 30% of women, elucidating key roles for these genes in human ovary development.

Objective: We aimed to identify the genetic mechanism underlying early-onset POI in 2 sisters from a consanguineous pedigree.

Methods: Genome sequencing and variant filtering using an autosomal recessive model was performed in the 2 affected sisters and their unaffected family members. Quantitative Reverse Transcriptase PCR (qRT-PCR) and RNA sequencing were used to study the expression of key genes at critical stages of human fetal gonad development (Carnegie Stage 22/23, 9 weeks post conception (wpc), 11 wpc, 15/16 wpc, 19/20 wpc) and in adult tissue.

Results: Only 1 homozygous variant cosegregating with the POI phenotype was found: a single nucleotide substitution in zinc finger SWIM-type containing 7 (ZSWIM7), NM_001042697.2: c.173C > G; resulting in predicted loss-of-function p.(Ser58*). qRT-PCR demonstrated higher expression of ZSWIM7 in the 15/16 wpc ovary compared with testis, corresponding to peak meiosis in the fetal ovary. RNA sequencing of fetal gonad samples showed that ZSWIM7 has a similar temporal expression profile in the developing ovary to other homologous recombination genes.

Main conclusions: Disruption of ZSWIM7 is associated with POI in humans. ZSWIM7 is likely to be important for human homologous recombination; these findings expand the range of genes associated with POI in women.

Keywords

NGS; delayed puberty; genetics; meiosis; ovary development; primary amenorrhea; primary ovarian insufficiency.

Figures