SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility

Samantha L P Schilit; Shreya Menon; Corinna Friedrich; Tammy Kammin; Ellen Wilch; Carrie Hanscom; Sizun Jiang; Sabine Kliesch; Michael E Talkowski; Frank Tüttelmann; Amy J MacQueen; Cynthia C Morton

doi:10.1016/j.ajhg.2019.11.013

SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility

Am J Hum Genet. 2020 Jan 2;106(1):41-57. doi: 10.1016/j.ajhg.2019.11.013. Epub 2019 Dec 19.

Authors

Affiliations

¹ Program in Genetics and Genomics and Certificate Program in Leder Human Biology and Translational Medicine, Biological and Biomedical Sciences Program, Graduate School of Arts and Sciences, Harvard University, Cambridge, MA 02138, USA; Harvard Medical School, Boston, MA 02115, USA.
² Harvard College, Harvard University, Cambridge, MA 02138, USA.
³ Institute of Human Genetics, University of Münster, 48149 Münster, Germany.
⁴ Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁵ Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Baxter Laboratory for Stem Cell Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ Centre of Reproductive Medicine and Andrology, Department of Clinical and Surgical Andrology, University Hospital Münster, 48149 Münster, Germany.
⁸ Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA 02115, USA; Departments of Neurology, Psychology, and Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁹ Institute of Human Genetics, University of Münster, 48149 Münster, Germany. Electronic address: frank.tuettelmann@ukmuenster.de.
¹⁰ Department of Molecular Biology and Biochemistry, Wesleyan University, Middletown, CT 06459, USA.
¹¹ Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Manchester Academic Health Science Centre, University of Manchester, Manchester M13 9NT, UK. Electronic address: cmorton@bwh.harvard.edu.

Abstract

Unexplained infertility affects 2%-3% of reproductive-aged couples. One approach to identifying genes involved in infertility is to study subjects with this clinical phenotype and a de novo balanced chromosomal aberration (BCA). While BCAs may reduce fertility by production of unbalanced gametes, a chromosomal rearrangement may also disrupt or dysregulate genes important in fertility. One such subject, DGAP230, has severe oligozoospermia and 46,XY,t(20;22)(q13.3;q11.2). We identified exclusive overexpression of SYCP2 from the der(20) allele that is hypothesized to result from enhancer adoption. Modeling the dysregulation in budding yeast resulted in disrupted structural integrity of the synaptonemal complex, a common cause of defective spermatogenesis in mammals. Exome sequencing of infertile males revealed three heterozygous SYCP2 frameshift variants in additional subjects with cryptozoospermia and azoospermia. In sum, this investigation illustrates the power of precision cytogenetics for annotation of the infertile genome, suggests that these mechanisms should be considered as an alternative etiology to that of segregation of unbalanced gametes in infertile men harboring a BCA, and provides evidence of SYCP2-mediated male infertility in humans.

Keywords: balanced reciprocal translocation; male infertility; meiosis; molecular cytogenetics; reproductive genetics; topologically associating domain.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Cell Cycle Proteins / genetics*
Chromosome Aberrations*
DNA-Binding Proteins / genetics*
Female
Frameshift Mutation*
Humans
Infertility, Male / etiology*
Infertility, Male / pathology
Karyotyping
Male
Oligospermia / etiology*
Oligospermia / pathology
Pedigree
Phenotype
Translocation, Genetic

Substances

Cell Cycle Proteins
DNA-Binding Proteins
SYCP2 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding