Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia

Manon S. Oud, Liliana Ramos, Moira K. O'Bryan, Robert I. McLachlan, Ozlem Okutman, Stephane Viville, Petra F. de Vries, Dominique F.C.M. Smeets, Dorien Lugtenberg, Jayne Y. Hehir-Kwa, Christian Gilissen, Maartje van de Vorst, Lisenka E.L.M. Vissers, Alexander Hoischen, Aukje M. Meijerink, Kathrin Fleischer, Joris A. Veltman, Michiel J. Noordam

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

Abstract

Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY) and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations (CNVs) affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified 5 patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11–17 patients (1-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared to currently used methods.
Original languageEnglish
Pages (from-to)1592-1605
Number of pages14
JournalHuman Mutation
Volume38
Issue number11
DOIs
Publication statusPublished - Nov 2017

Keywords

  • male infertility
  • smMIPs
  • targeted sequencing
  • diagnostics
  • CFTR
  • CBAVD
  • azoospermia
  • oligozoospermia
  • reproduction

Cite this

Oud, Manon S. ; Ramos, Liliana ; O'Bryan, Moira K. ; McLachlan, Robert I. ; Okutman, Ozlem ; Viville, Stephane ; de Vries, Petra F. ; Smeets, Dominique F.C.M. ; Lugtenberg, Dorien ; Hehir-Kwa, Jayne Y. ; Gilissen, Christian ; van de Vorst, Maartje ; Vissers, Lisenka E.L.M. ; Hoischen, Alexander ; Meijerink, Aukje M. ; Fleischer, Kathrin ; Veltman, Joris A. ; Noordam, Michiel J. / Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia. In: Human Mutation. 2017 ; Vol. 38, No. 11. pp. 1592-1605.
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abstract = "Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY) and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations (CNVs) affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified 5 patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11–17 patients (1-1.5{\%}), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared to currently used methods.",
keywords = "male infertility, smMIPs, targeted sequencing, diagnostics, CFTR, CBAVD, azoospermia, oligozoospermia, reproduction",
author = "Oud, {Manon S.} and Liliana Ramos and O'Bryan, {Moira K.} and McLachlan, {Robert I.} and Ozlem Okutman and Stephane Viville and {de Vries}, {Petra F.} and Smeets, {Dominique F.C.M.} and Dorien Lugtenberg and Hehir-Kwa, {Jayne Y.} and Christian Gilissen and {van de Vorst}, Maartje and Vissers, {Lisenka E.L.M.} and Alexander Hoischen and Meijerink, {Aukje M.} and Kathrin Fleischer and Veltman, {Joris A.} and Noordam, {Michiel J.}",
year = "2017",
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doi = "10.1002/humu.23312",
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Oud, MS, Ramos, L, O'Bryan, MK, McLachlan, RI, Okutman, O, Viville, S, de Vries, PF, Smeets, DFCM, Lugtenberg, D, Hehir-Kwa, JY, Gilissen, C, van de Vorst, M, Vissers, LELM, Hoischen, A, Meijerink, AM, Fleischer, K, Veltman, JA & Noordam, MJ 2017, 'Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia', Human Mutation, vol. 38, no. 11, pp. 1592-1605. https://doi.org/10.1002/humu.23312

Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia. / Oud, Manon S.; Ramos, Liliana; O'Bryan, Moira K.; McLachlan, Robert I.; Okutman, Ozlem; Viville, Stephane; de Vries, Petra F.; Smeets, Dominique F.C.M.; Lugtenberg, Dorien; Hehir-Kwa, Jayne Y.; Gilissen, Christian; van de Vorst, Maartje; Vissers, Lisenka E.L.M.; Hoischen, Alexander; Meijerink, Aukje M.; Fleischer, Kathrin; Veltman, Joris A.; Noordam, Michiel J.

In: Human Mutation, Vol. 38, No. 11, 11.2017, p. 1592-1605.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Validation and application of a novel integrated genetic screening method to a cohort of 1,112 men with idiopathic azoospermia or severe oligozoospermia

AU - Oud, Manon S.

AU - Ramos, Liliana

AU - O'Bryan, Moira K.

AU - McLachlan, Robert I.

AU - Okutman, Ozlem

AU - Viville, Stephane

AU - de Vries, Petra F.

AU - Smeets, Dominique F.C.M.

AU - Lugtenberg, Dorien

AU - Hehir-Kwa, Jayne Y.

AU - Gilissen, Christian

AU - van de Vorst, Maartje

AU - Vissers, Lisenka E.L.M.

AU - Hoischen, Alexander

AU - Meijerink, Aukje M.

AU - Fleischer, Kathrin

AU - Veltman, Joris A.

AU - Noordam, Michiel J.

PY - 2017/11

Y1 - 2017/11

N2 - Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY) and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations (CNVs) affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified 5 patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11–17 patients (1-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared to currently used methods.

AB - Microdeletions of the Y chromosome (YCMs), Klinefelter syndrome (47,XXY) and CFTR mutations are known genetic causes of severe male infertility, but the majority of cases remain idiopathic. Here we describe a novel method using single molecule Molecular Inversion Probes (smMIPs), to screen infertile men for mutations and copy number variations (CNVs) affecting known disease genes. We designed a set of 4,525 smMIPs targeting the coding regions of causal (n = 6) and candidate (n = 101) male infertility genes. After extensive validation, we screened 1,112 idiopathic infertile men with non-obstructive azoospermia or severe oligozoospermia. In addition to five chromosome YCMs and six other sex chromosomal anomalies, we identified 5 patients with rare recessive mutations in CFTR as well as a patient with a rare heterozygous frameshift mutation in SYCP3 that may be of clinical relevance. This results in a genetic diagnosis in 11–17 patients (1-1.5%), a yield that may increase significantly when more genes are confidently linked to male infertility. In conclusion, we developed a flexible and scalable method to reliably detect genetic causes of male infertility. The assay consolidates the detection of different types of genetic variation while increasing the diagnostic yield and detection precision at the same or lower price compared to currently used methods.

KW - male infertility

KW - smMIPs

KW - targeted sequencing

KW - diagnostics

KW - CFTR

KW - CBAVD

KW - azoospermia

KW - oligozoospermia

KW - reproduction

U2 - 10.1002/humu.23312

DO - 10.1002/humu.23312

M3 - Article

VL - 38

SP - 1592

EP - 1605

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 11

ER -