Microdeletions and microduplications linked to severe congenital disorders in infertile men

Abstract

Data on the clinical validity of DNA copy number variants (CNVs) in spermatogenic failure (SPGF) is limited. This study analyzed the genome-wide CNV profile in 215 men with idiopathic SPGF and 62 normozoospermic fertile men, recruited at the Andrology Clinic, Tartu University Hospital, Estonia. A two-fold higher representation of > 1 Mb CNVs was observed in men with SPGF (13%, n = 28) compared to controls (6.5%, n = 4). Seven patients with SPGF were identified as carriers of microdeletions (1q21.1; 2.4 Mb) or microduplications (3p26.3, 1.1 Mb; 7p22.3-p22.2, 1.56 Mb; 10q11.22, 1.42 Mb, three cases; Xp22.33; 2.3 Mb) linked to severe congenital conditions. Large autosomal CNV carriers had oligozoospermia, reduced or low-normal bitesticular volume (22-28 ml). The 7p22.3-p22.2 microduplication carrier presented mild intellectual disability, neuropsychiatric problems, and short stature. The Xp22.33 duplication at the PAR1/non-PAR boundary, previously linked to uterine agenesis, was detected in a patient with non-obstructive azoospermia. A novel recurrent intragenic deletion in testis-specific LRRC69 was significantly overrepresented in patients with SPGF compared to the general population (3.3% vs. 0.85%; χ² test, OR = 3.9 [95% CI 1.8-8.4], P = 0.0001). Assessment of clinically valid CNVs in patients with SPGF will improve their management and counselling for general and reproductive health, including risk of miscarriage and congenital disorders in future offspring.

Figure 1

The burden of copy number variants in the subgroups based on spermatogenic output. Y-axis shows the cumulative burden of all identified autosomal and X-chromosomal CNVs for every study subject (X-axis). Deletions and duplications larger than 1 Mb are indicated with color coding, and example variants are visualized with Genomestudio 2.0.5 (Illumina Inc.). Subjects with total burden of CNVs spanning over 2 Mb are indicated by numbering. Dotted lines refer to the median total span of CNVs in each subgroup.

Figure 2

Recurrent CNVs in men with spermatogenic failure. (A) Chromosomal distribution of recurrently detected deletions and duplications among 215 cases with spermatogenic failure (SPGF). The highlighted 13 CNVs represent the same type of copy number change (seven deletions, six duplications) encompassing protein-coding gene(s) and detected in at least four cases with SPGF and no normozoospermic fertile men (NORM). The number of encompassed genes, and the length and frequency of each variant in subjects with SPGF compared to the general population (pop; sources: DGV Gold, DECIPHER) are shown. Recurrent CNVs exceeding 1 Mb or disrupting only a single gene are highlighted. Intronic CSMD1 deletions (indicated by #) have been proposed as candidate contributors to male infertility, but in this study the detected prevalence in cases with SPGF was lower than reported in the general population. Details are presented in Supplementary Table S4. (B) The major protein-coding transcripts of the LRRC69 gene expressed in the human testis according to the GTEx database. The identified LRRC69 partial deletion is shown with a red box. Genomic coordinates of the minimal deleted region (52,375 bp) are chr8:92,128,840–92,181,214 (hg19). TPM, transcripts per million. (C) Statistically significant association between LRRC69 intragenic deletions among cases with SPGF compared to population-based participants in the Estonian Biobank (EstBB) cohort^,. A χ² test was used to test the difference between the two groups.