Abstract
PurposeTo develop a comprehensive genetic test for female and male infertility in support of medical decisions during assisted reproductive technology (ART) protocols.MethodsWe developed a next-generation sequencing (NGS) gene panel consisting of 87 genes including promoters, 5′ and 3′ untranslated regions, exons, and selected introns. In addition, sex chromosome aneuploidies and Y chromosome microdeletions were analyzed concomitantly using the same panel.ResultsThe NGS panel was analytically validated by retrospective analysis of 118 genomic DNA samples with known variants in loci representative of female and male infertility. Our results showed analytical accuracy of > 99%, with > 98% sensitivity for single-nucleotide variants (SNVs) and > 91% sensitivity for insertions/deletions (indels). Clinical sensitivity was assessed with samples containing variants representative of male and female infertility, and it was 100% for SNVs/indels, CFTR IVS8-5T variants, sex chromosome aneuploidies, and copy number variants (CNVs) and > 93% for Y chromosome microdeletions. Cost analysis shows potential savings when comparing this single NGS assay with the standard approach, which includes multiple assays.ConclusionsA single, comprehensive, NGS panel can simplify the ordering process for healthcare providers, reduce turnaround time, and lower the overall cost of testing for genetic assessment of infertility in females and males, while maintaining accuracy.
Highlights
It is estimated that 48 million couples were affected by infertility in 2010, and there has not been any significant improvement in infertility levels between 1990 and 2010 [1,2,3]
Male infertility accounts for 50% of infertility cases [5], with known genetic factors accounting for 15–30% of male infertility [6]
Genes were classified as Bdiagnostic^ when variants in them were reported to cause infertility across multiple populations, as supported by multiple publications from different laboratories, demonstrating a direct relationship with infertility
Summary
It is estimated that 48 million couples were affected by infertility in 2010, and there has not been any significant improvement in infertility levels between 1990 and 2010 [1,2,3]. A significant proportion of infertility cases are due to genetic defects. Chromosomal alterations [7], inversions [8], translocations [9], Y chromosome microdeletions [10], and gene mutations (for example single-nucleotide variants (SNVs) in CFTR [11]) are the main genetic variants causing male infertility. The two most common female factor conditions, ovulatory dysfunction (25%) and endometriosis (15%), have familial predisposition, suggesting a genetic basis [12]. Sex chromosome alterations [13] and several single gene mutations have been described impacting female fertility [14, 15], causing conditions like hypogonadotropic hypogonadism, premature ovarian insufficiency, endometriosis, and polycystic ovarian syndrome (reviewed in [12])
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