{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE343nnn/GSE343307/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE343307"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Compound heterozygous TDRD9 variants are associated with postmeiotic spermatid arrest and impaired LINE-1 suppression in a man with non-obstructive azoospermia","description":"Background: Biallelic variants in TDRD9, a component of the germline piRNA pathway, have been associated with male infertility, but the stage-specific consequences of partial TDRD9 dysfunction in humans remain unclear. Methods: We studied a 22-year-old man with idiopathic non-obstructive azoospermia and his unaffected parents. Exome sequencing and segregation analysis were integrated with minigene splicing and protein-stability assays, testicular histology, acrosomal staining, meiotic chromosome spreads, exploratory bulk RNA sequencing, transposable-element profiling, and LINE-1 open reading frame 1 protein immunofluorescence. Obstructive azoospermia samples with preserved spermatogenesis served as controls where indicated. Results: The proband carried a paternal splice-acceptor variant, c.1714-1G>C, and a maternal missense variant, c.2402A>C (p.Gln801Pro), in TDRD9. The splice variant caused exon 16 skipping and was predicted to generate p.Val572ArgfsTer5; p.Gln801Pro accelerated protein decay and was associated with reduced testicular TDRD9 abundance. Histology and acrosomal staining showed round-spermatid arrest, abnormal acrosome formation, and rare late spermatids. In the spermatocytes examined, chromosome-axis formation, synapsis, and sex-body formation showed no overt abnormalities. Exploratory transcriptomic findings were concordant with depletion of late spermiogenic programs. Evolutionarily young LINE-1 features were enriched among upregulated transposable-element features, and LINE-1 open reading frame 1 protein accumulated in spermatids. Conclusions: This deeply phenotyped case supports an association between compound heterozygous TDRD9 variants, postmeiotic spermatogenic failure, and impaired LINE-1 suppression. The data are compatible with residual TDRD9 activity permitting meiotic progression in the cells examined, but larger genotype-phenotype cohorts and direct piRNA analyses are required to test this model and assess clinical utility.","dates":{"publication":"2026/08/13"},"accession":"GSE343307","cross_references":{"GSM":["GSM9949117","GSM9949116","GSM9949115","GSM9949114","GSM9949113","GSM9949112"],"GPL":["24676"],"GSE":["343307"],"taxon":["Homo sapiens"]}}