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Journal of Assisted Reproduction and Genetics

Erschienen in:

18.07.2022 | Genetics

Genomic testing for copy number and single nucleotide variants in spermatogenic failure

verfasst von: J. Hardy, N. Pollock, T. Gingrich, P. Sweet, A. Ramesh, J. Kuong, A. Basar, H. Jiang, K. Hwang, J. Vukina, T. Jaffe, M. Olszewska, M. Kurpisz, A. N. Yatsenko

Erschienen in: Journal of Assisted Reproduction and Genetics | Ausgabe 9/2022

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Abstract

Purpose

To identify clinically significant genomic copy number (CNV) and single nucleotide variants (SNV) in males with unexplained spermatogenic failure (SPGF).

Materials and methods

Peripheral blood DNA from 97/102 study participants diagnosed with oligozoospermia, severe oligozoospermia, or non-obstructive azoospermia (NOA) was analyzed for CNVs via array comparative genomic hybridization (aCGH) and SNVs using whole-exome sequencing (WES).

Results

Of the 2544 CNVs identified in individuals with SPGF, > 90% were small, ranging from 0.6 to 75 kb. Thirty, clinically relevant genomic aberrations, were detected in 28 patients (~ 29%). These included likely diagnostic CNVs in 3/41 NOA patients (~ 7%): 1 hemizygous, intragenic TEX11 deletion, 1 hemizygous DDX53 full gene deletion, and 1 homozygous, intragenic STK11 deletion. High-level mosaicism for X chromosome disomy (~ 10% 46,XY and ~ 90% 47,XXY) was also identified in 3 of 41 NOA patients who previously tested normal with conventional karyotyping. The remaining 24 CNVs detected were heterozygous, autosomal recessive carrier variants. Follow-up WES analysis confirmed 8 of 27 (30%) CNVs (X chromosome disomy excluded). WES analysis additionally identified 13 significant SNVs and/or indels in 9 patients (~ 9%) including X-linked AR, KAL1, and NR0B1 variants.

Conclusion

Using a combined genome-wide aCGH/WES approach, we identified pathogenic and likely pathogenic SNVs and CNVs in 15 patients (15%) with unexplained SPGF. This value equals the detection rate of conventional testing for aneuploidies and is considerably higher than the prevalence of Y chromosome microdeletions. Our results underscore the importance of comprehensive genomic analysis in emerging diagnostic testing of complex conditions like male infertility.

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Titel: Genomic testing for copy number and single nucleotide variants in spermatogenic failure
verfasst von: J. Hardy
N. Pollock
T. Gingrich
P. Sweet
A. Ramesh
J. Kuong
A. Basar
H. Jiang
K. Hwang
J. Vukina
T. Jaffe
M. Olszewska
M. Kurpisz
A. N. Yatsenko
Publikationsdatum: 18.07.2022
Verlag: Springer US
Erschienen in: Journal of Assisted Reproduction and Genetics / Ausgabe 9/2022
Print ISSN: 1058-0468
Elektronische ISSN: 1573-7330
DOI: https://doi.org/10.1007/s10815-022-02538-5

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Genomic testing for copy number and single nucleotide variants in spermatogenic failure