Abstract
Infertility is a multifactorial disorder that affects approximately 12% of couples of childbearing ages worldwide. Few studies have been conducted to understand the genetic causes of infertility in depth. The synaptonemal complex (SC), which is essential for the progression of meiosis, is a conserved tripartite structure that binds homologous chromosomes together and is thus required for fertility. This study investigated genetic causes of infertility in a Pakistani consanguineous family containing two patients suffering from non-obstructive azoospermia (NOA). We performed whole-exome sequencing, followed by Sanger sequencing, and identified a novel pathogenic variant (c.7G > A [p.D3N]) in the SC coding gene C14orf39, which was recessively co-segregated with NOA. In silico analysis revealed that charges on wild-type residues were lost, which may result in loss of interactions with other molecules and residues, and a reduction in protein stability occurred, which was caused by the p.D3N mutation. The novel variant generated the mutant protein C14ORF39D3N, and homozygous mutations in C14orf39 resulted in NOA. The transcriptome profile of C14ORF39 shows that it is specifically expressed in early brain development, which suggests that research in this area is required to study other functions of C14ORF39 in addition to its role in the germline. This research highlights the conserved role of C14orf39/SIX6OS1 in assembly of the SC and its indispensable role in facilitating genetic diagnosis in patients with infertility, which may enable the development of future treatments.
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Data availability
The variation data reported in this paper have been deposited in the Genome Variation Map (Song et al. 2018) in BIG Data Center (BIGDC 2017), Beijing Institute of Genomics (BIG), Chinese Academy of Sciences, under accession number GVM000307 that can be publicly accessible at (http://bigd.big.ac.cn/gvm/getProjectDetail?project=PRJCA008169).
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Acknowledgements
The present study was financially supported by the National Key Research and Developmental Program of China (2018YFC1004700 and 2016YFC1000600), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB19000000), the National Natural Science Foundation of China (31890780, 31630050 and 31871514), the Major Program of Development Foundation of Hefei Centre for Physical Science and Technology (2018ZYFX005), and the Fundamental Research Funds for the Central Universities (YD2070002006).
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HA, AU, and SD wrote the manuscript, MZ, and AH collected the patient’s samples and performed semen analysis. HA and AU performed the bioinformatics analysis. HA, AU, and SD, FU, IK analyzed the data; Qinghua Shi modified the manuscript and supervised the study.
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Supplementary file1 (PDF 457 KB) Figure S1. The logarithm of the odds scores; Genome-wide logarithm of the odds scores using WES-derived genotypes for the family. LOD, the logarithm of the odds
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Supplementary file3 (PDF 138 KB) Figure S3. Developmental stages and Transcriptomic profile of C14ORF39 in other organisms
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Ali, H., Unar, A., Zubair, M. et al. In silico analysis of a novel pathogenic variant c.7G > A in C14orf39 gene identified by WES in a Pakistani family with azoospermia. Mol Genet Genomics 297, 719–730 (2022). https://doi.org/10.1007/s00438-022-01876-4
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DOI: https://doi.org/10.1007/s00438-022-01876-4