PT  - JOURNAL ARTICLE
AU  - Maram Arafat
AU  - Iris Har-Vardi
AU  - Avi Harlev
AU  - Eliahu Levitas
AU  - Atif Zeadna
AU  - Maram Abofoul-Azab
AU  - Victor Dyomin
AU  - Val C Sheffield
AU  - Eitan Lunenfeld
AU  - Mahmoud Huleihel
AU  - Ruti Parvari
TI  - Mutation in TDRD9 causes non-obstructive azoospermia in infertile men
AID  - 10.1136/jmedgenet-2017-104514
DP  - 2017 Sep 01
TA  - Journal of Medical Genetics
PG  - 633--639
VI  - 54
IP  - 9
4099  - http://jmg.bmj.com/content/54/9/633.short
4100  - http://jmg.bmj.com/content/54/9/633.full
SO  - J Med Genet2017 Sep 01; 54
AB  - Background Azoospermia is diagnosed when sperm cells are completely absent in the ejaculate even after centrifugation. It is identified in approximately 1% of all men and in 10%–20% of infertile males. Non-obstructive azoospermia (NOA) is characterised by the absence of sperm due to either a Sertoli cell-only pattern, maturation arrest, hypospermatogenesis or mixed patterns. NOA is a severe form of male infertility, with limited treatment options and low fertility success rates. In the majority of patients, the cause for NOA is not known and mutations in only a few genes were shown to be causative.Aim We investigated the cause of maturation arrest in five azoospermic infertile men of a large consanguineous Bedouin family.Methods and results Using whole genome genotyping and exome sequencing we identified a 4 bp deletion frameshift mutation in TDRD9 as the causative mutation with a Lod Score of 3.42. We demonstrate that the mutation results in a frameshift as well as exon skipping. Immunofluorescent staining with anti-TDRD9 antibody directed towards the N terminus demonstrated the presence of the protein in testicular biopsies of patients with an intracellular distribution comparable to a control biopsy. The mutation does not cause female infertility.Conclusion This is the first report of a recessive deleterious mutation in TDRD9 in humans. The clinical phenotype recapitulates that observed in the Tdrd9 knockout mice where this gene was demonstrated to participate in long interspersed element-1 retrotransposon silencing. If this function is preserved in human, our data underscore the importance of maintaining DNA stability in the human male germ line.