• A COMPOUND HETEROZYGOUS MISSENSE VARIANT IN DNAH5 GENE AND ITS CORRELATION WITH UNEXPLAINED MALE INFERTILITY
  • Maryam Afkari,1 Najmeh Salehi,2 Hesamoddin Sajadi,3 Marjan Sabbaghian2,4 Seyed Abolhassan Shahzadeh-Fazeli,5 Amir Amiri-Yekta,6,*
    1. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR
    2. School of Biological Science, Institute for Research in Fundamental Sciences (IPM),
    3. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR
    4. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR
    5. Department of Molecular and Cellular Biology, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, ACECR
    6. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR


  • Introduction: According to the World Health Organization, infertility is defined as the inability of couples to achieve pregnancy after one year of unprotected sexual intercourse. It affects approximately 50 million couples worldwide, with both men and women being equally affected. Male infertility is a complex issue with genetic factors playing a significant role. Conditions such as Klinefelter syndrome (XXY), Y Chromosome Microdeletions (YCMDs), and monogenic mutations can contribute to male infertility. Currently, hereditary factors account for 4% of male infertility cases, while the causes of 60-70% of cases remain unknown. Ongoing research aims to identify new genes and variants related to male fertility to improve diagnostic methods. It is believed that around 2000 genes are involved in preserving germ cells and ensuring normal meiosis, with more than 100 genes already identified concerning male infertility.
  • Methods: We assessed a patient with unexplained male infertility, who also had a brother with a similar issue. We used whole exome sequencing (WES) technology and analyzed the data through bioinformatics. Then we performed Sanger sequencing to confirm variations and segregation. We found that patients were carrying DNAH5 compound heterozygous variants (c.1121G>A and c.11437A>T).
  • Results: Genetic prediction databases such as Mutation Taster suggest that c.1121G>A and c.11437A>T may cause disease. The variations c.1121G>A and c.11437A>T may cause disease by bioinformatics prediction databases such as MutPred2, Project HOPE, mCSM, and Mutation taster. Each patient inherited one altered allele from their father and one from their mother. The parents underwent Sanger sequencing for the DNAH5 variants to determine whether the variants were present in a cis- or trans-presentation in the proband and his infertile brother. The variation (Chr5:13916533 A>G; c.1121G>A; p. I374T) was inherited paternally, while the variant (Chr5:13737379 G>A; c.11437A>T; p. R3813W) was inherited maternally. They may contribute to a risk of male infertility.
  • Conclusion: We investigated the potential correlation between DNAH5 mutations and unexplained male infertility. Changes in two amino acid properties - size, charge, and hydrophobicity - might affect the DNAH5 protein and lead to infertility. If this finding is confirmed in larger sample sizes and diverse racial populations, it could significantly improve the identification of male patients with unexplained infertility conditions.
  • Keywords: unexplained male infertility, bioinformatics analysis, Whole-exome sequencing, DNAH5