Researchers identifies a genetic abnormality linked with male infertility


At least one in five cases of infertility remain unexplained.

Male factors contribute to about half of these cases and, much of the time, men lack a specific causal diagnosis for their infertility.

Researchers estimate that genetics could explain up to 50 percent of these cases, but many of the genes involved in male infertility remain unknown.

A new study led by investigators at Brigham and Women’s Hospital identifies a genetic abnormality that may be at fault.

Investigators have found that a genetic rearrangement and variants affecting a gene known as SYCP2 are associated with low sperm count and report the first cases implicating the gene in four men with infertility.

The team’s findings are published in the American Journal of Human Genetics.

“We hope that our evidence will contribute to this gene being in panels for diagnosis of male infertility,” said corresponding author Cynthia Morton, PhD, medical geneticist at the Brigham. “Infertility is a big problem for young people, and 40 to 72 percent of men lack a diagnosis. This means that we have a lot of gene finding to do.

My lab has a longstanding interest in studying individuals who have a balanced chromosome rearrangement where two chromosome segments swap places. In this case, it led us to an important discovery.”

Morton, former graduate student and first author Samantha Schilit, PhD, and colleagues from Harvard Medical School and Wesleyan University began the work that would lead them to SYCP2 when a physician referred a case to them. Known as DGAP230, the subject was studied as part of the Developmental Genome Anatomy Project (DGAP), an initiative Morton began in 1999 to understand the genetic basis of birth defects and underlying molecular basis of development.

By age 28, DGAP230 had a two-year history of infertility and severely low sperm count. By analyzing his chromosomes, Schilit, Morton and colleagues found that the subject had a balanced chromosomal rearrangement on chromosomes 20 and 22.

The team discovered that this genetic abnormality led to a 20-fold increase in the activity of SYCP2. Through a series of elegant experiments involving yeast and cellular models, the researchers went about analyzing the impact of this change in SYCP2 activity.

“Balanced chromosomal rearrangements in infertile men are rarely followed up beyond reporting a risk for segregation of unbalanced gametes, which can lead to recurrent miscarriage.

This work shows that a chromosomal rearrangement may also disrupt or dysregulate genes important in fertility, and therefore should be considered,” said Schilit.

In addition, the researchers looked for other cases of SYCP2 contributing to male infertility. To do so, they collaborated with investigators at the University of Münster who had enrolled men with infertility in a separate study.

The team’s search revealed three men with loss-of-function variants in SYCP2. Disruptions in SYCP2 were far more frequent among men with infertility than in the general population.

The team discovered that this genetic abnormality led to a 20-fold increase in the activity of SYCP2. Through a series of elegant experiments involving yeast and cellular models, the researchers went about analyzing the impact of this change in SYCP2 activity.

Morton notes that while the discoveries about SYCP2 may help inform diagnosis, implications for treatment remain to be determined.

“A diagnosis can be therapeutic in itself — even if there isn’t something that can be done to correct it. It ends the search for the underlying issue and opens the door for enrolling in clinical trials,” said Morton.

“And I believe there is good reason to be optimistic; we now have better tools for discovery and can begin on the path toward therapy.”

Funding: This study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (F31HD090780), the National Institute of General Medical Sciences (P01GM061354, R15GM104827 and R15GM116109), and the National Science Foundation (DGE1144152).

Infertility is one of the most common disorders for men of reproductive age. To identify novel genetic etiologies, we studied a male with 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 disruption of the synaptonemal complex, a common cause of defective spermatogenesis in mammals. Exome sequencing of infertile males revealed three novel heterozygous SYCP2 frameshift variants in additional subjects with cryptozoospermia and azoospermia.

This study provides the first evidence of SYCP2-mediated male infertility in humans.

Infertility affects 10-15% of couples, making it one of the most common disorders for individuals between the ages of 20-45 years1. While many factors contribute to infertility including anatomical defects, gamete integrity, hormonal dysregulation, environmental exposures, age, and certain genetic syndromes, at least 1 in 5 cases of infertility are “unexplained”2.

Genetic defects may be responsible for many of these idiopathic cases. Indeed, mutations in over 600 genes have been shown to decrease fertility in animal models, and yet few genetic causes of infertility have been validated in humans3,4.

This results in part from the decreased reproductive fitness of infertile individuals which reduces the number of large families available for genetic analysis in humans as well as the genetic heterogeneity of the disorder5,6.

Male factors contribute to about half of all infertility cases, and 40-72% of men lack a specific causal diagnosis5,7,8.

Given that 30-50% of these cases are estimated to have genetic etiologies, searching for genes involved in unexplained infertility is a rich endeavor5,7. Uncovering these novel causes not only informs an understanding of mechanisms regulating fertility, but also provides clinical information to support diagnosis, genetic counseling, and therapeutic intervention.

Currently, the most common genetic testing for male infertility in the clinic involves sequencing of the cystic fibrosis transmembrane conductance regulator (CFTR) gene (pathogenic variants found in 80-90% of cases of congenital bilateral absence of the vas deferens), assessing Y chromosome microdeletions (accounting for 5-15% of men with severe oligozoospermia [<5M/ml] or nonobstructive azoospermia), and karyotype analysis (revealing Klinefelter syndrome in 14% of azoospermic men)3,7,9,10.

In 0.5-1% of severe oligozoospermic or azoospermic men, a karyotype may reveal an apparently balanced reciprocal translocation11. While balanced reciprocal translocations may cause subfertility by doubling the risk of miscarriage, the mechanism for how such chromosomal abnormalities may lead to low sperm counts has not been rigorously investigated12,13.

We hypothesize that a chromosomal rearrangement may disrupt or dysregulate genes important for fertility in the immediate vicinity of rearrangement breakpoints. By using the well-established Developmental Genome Anatomy Project (DGAP) infrastructure, we initiated a study aimed at identifying new genes important for fertility and exploring an additional explanation for how balanced reciprocal translocations reduce fertility.


Male infertility is a common disorder among reproductive-aged couples and the majority of subjects lack a specific etiologic diagnosis5. Understanding the precise causes of male infertility may directly inform therapies for infertile couples. For example, an azoospermic male with a complete deletion of AZFc has a 50% success rate for obtaining sperm by testicular sperm extraction (TESE), while TESE would not be recommended or successful for a man with a complete deletion of AZFa7.

Identifying genetic etiologies for human male infertility has been hindered by smaller pedigrees inherent to decreased reproductive fitness and genetic heterogeneity of the disorder. In addition, some genetic evidence of a disorder may not be investigated deeply. For example, balanced reciprocal translocations identified by karyotype in infertile men are rarely followed up beyond reporting a risk for segregation of unbalanced gametes. As a result, a deep investigation into single case studies is critical for uncovering novel genetic etiologies for male infertility.

In this study, we identified a balanced reciprocal translocation in a severe oligozoospermic male designated DGAP230. While it is generally thought that balanced reciprocal translocations may reduce fertility due to production of unbalanced gametes13 or meiotic silencing of unsynapsed chromatin45, this does not account for the specific phenotype of severe oligozoospermia or azoospermia because the majority of men with balanced reciprocal translocations have normal sperm counts46. In addition, men with low sperm counts and a balanced reciprocal translocation have rearrangement breakpoints that sometimes cluster in distinct genomic regions, suggesting that as opposed to a nonspecific mechanism of meiotic segregation, there may be something intrinsic to these genomic regions important for fertility47,48.

In the case of DGAP230, the structural rearrangement leads to dysregulation of SYCP2, which resides distal to one of the rearrangement breakpoints. This cytogenomic influence on gene expression supports the finding that translocation breakpoints can influence gene expression by dysregulating genes residing within the same TAD30. As a result, in men with balanced chromosomal rearrangements and a phenotype of infertility, pathogenesis by specific breakpoints should be considered as an alternative etiology to that of segregation of unbalanced gametes.

While it is known that many different SC proteins have intrinsic ability to self-assemble into polycomplexes when overexpressed, mutated, or expressed in mitotic cells4953, this study demonstrates the first observation of Red1 overexpression leading to its polycomplex formation. We predict that aggregation may be mediated by misexpression before formation of meiotic chromosomes and expression of other axial element proteins as well as the presence of a coiled-coil domain, which facilitates protein complex interactions. Red1 overexpression in budding yeast also decreases double-strand break formation and meiotic recombination initiation, a requirement for SC assembly in budding yeast and most mammals54. The resulting asynapsis phenocopies red1 mutants in S. cerevisiae as well as coiled-coil domain-deficient Sycp2 mice, suggesting that synaptonemal complex formation is sensitive to dosage of axial elements36,55.

We believe that our finding of asynapsis resulting from axial element misexpression is directly related to severe oligozoospermia, because asynapsis triggers checkpoint-mediated apoptosis of spermatocytes during spermatogenesis41,56,57, which reduces sperm count and has been shown to lead to male-specific infertility36. Therefore, DGAP230’s phenotype of severe oligozoospermia and infertility is likely due to asynapsis-triggered cell death in spermatocytes.

The identification of three novel frameshift variants in SYCP2 from men with cryptozoospermia and meiotic arrest further supports the role of SYCP2 in human male fertility. All variants are extremely rare consistent with the inability to segregate these mutations in the general population due to a phenotype of infertility. This is also supported by the maternal inheritance of the variant in participant M1581, as SYCP2-mediated pathogenicity has been shown to cause male infertility but not female infertility in a mouse model36.

Stop codons resulting from the three frameshift variants reside upstream of the coiled-coil domain, which is critical for functionality of the protein36. It is important to note, however, that all cases represent heterozygous LoF variants which would support an autosomal dominant disease model. This is discordant with the SYCP2 knockout mouse model that only demonstrates a male infertility phenotype in homozygotes36. However, haploinsufficiency discordance has been observed between human and mouse for the male infertility gene SYCP3, the other mammalian axial element in the synaptonemal complex as well as numerous other mouse models58,59SYCP2’s pLI > 0.9 and oe <0.35 also support a haploinsufficient model, as extreme intolerance to LoF according to constraint analysis is strongly correlated with haploinsufficiency42. While less common than autosomal recessive forms of male infertility, autosomal dominant forms have been identified for pathogenic variants in HIWI60, KLHL1061 PLK462, SYCP358, SPINK263, NR5A164, and DMRT165.

Another potential concern is that the phenotypes of severe oligozoospermia, cryptozoospermia and meiotic arrest are distinctive from each other. It is possible that the differences reflect variable expressivity, as has been observed in the male infertility genes DBY (Sertoli cell-only syndrome and severe hypospermatogenesis), KLHL10 (severe oligozoospermia and oligozoospermia), TAF4B (azoospermia and oligozoospermia), TDRD9 (azoospermia and cryptozoospermia), and TEX11 (complete meiotic arrest and mixed testicular atrophy)61,6670.

It is well known that homologous chromosome synapsis is critical for spermatogenesis. Indeed, several genes implicated in human male infertility encode proteins that are members of the synaptonemal complex (SYCP3 and SYCE1) or are otherwise required for synapsis (SPO11, MEIOB, TEX11, and TEX15)6,58,67,7073. Before this study, SYCP2 was considered a strong candidate gene for human male infertility because it encodes a protein that interacts directly with protein products of the human male infertility genes SYCP3 and TEX11, serves as an axial element in the synaptonemal complex, and is required for male fertility in the mouse36,37,74. DGAP230 and the three participants from the Münster cohort represent the first cases of putative SYCP2-mediated male infertility in humans.

Research link

Brigham and Women’s Hospital
Media Contacts:
Elaine St Peter – Brigham and Women’s Hospital
Image Source:
The image is in the public domain.

Original Research: Closed access
“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, and others.
American Journal of Human Genetics doi:10.1016/j.ajhg.2019.11.013.


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