Deep learning predicts therapy-relevant genetics in acute myeloid leukemia from Pappenheim-stained bone marrow smears.

The detection of genetic aberrations is crucial for early therapy decisions in acute myeloid leukemia (AML) and recommended for all patients. Because genetic testing is expensive and time consuming, a need remains for cost-effective, fast, and broadly accessible tests to predict these aberrations in this aggressive malignancy. Here, we developed a novel fully automated end-to-end deep learning pipeline to predict genetic aberrations directly from single-cell images from scans of conventionally stained bone marrow smears already on the day of diagnosis.

Bi-allelic variants in INSL3 and RXFP2 cause bilateral cryptorchidism and male infertility.

Study Question: What is the impact of variants in the genes INSL3 (Insulin Like 3) and RXFP2 (Relaxin Family Peptide Receptor 2), respectively, on cryptorchidism and male infertility?

Summary Answer: Bi-allelic loss-of-function (LoF) variants in INSL3 and RXFP2 result in bilateral cryptorchidism and male infertility, whereas heterozygous variant carriers are phenotypically unaffected.

What Is Known Already: The small heterodimeric peptide INSL3 and its G protein-coupled receptor RXFP2 play a major role in the first step of the biphasic descent of the testes, and variants in the INSL3 and RXFP2 genes have long been implicated in inherited cryptorchidism. However, only one single homozygous missense variant in RXFP2 has clearly been linked to familial bilateral cryptorchidism, so the effects of bi-allelic variants in INSL3 and heterozygous variants in both genes on cryptorchidism and male infertility remain unclear.

Testicular Architecture of Men with 46,XX Testicular Disorders of Sex Development.

Background: A subtype of disorders of sex development (DSD) in individuals with a 46,XX karyotype who are phenotypically male is classified as testicular DSD (46,XX TDSD). These individuals develop testes but are infertile due to germ cell loss. However, little is known about their testicular architecture.

New developments and future trajectories in supernumerary sex chromosome abnormalities: a summary of the 2022 3rd International Workshop on Klinefelter Syndrome, Trisomy X, and XYY.

The 3rd International Workshop on Klinefelter Syndrome, Trisomy X, and 47,XYY syndrome was held in Leiden, the Netherlands, on September 12-14, 2022. Here, we review new data presented at the workshop and discuss scientific and clinical trajectories. We focus on shortcomings in knowledge and therefore point out future areas for research.

Functional assessment of DMRT1 variants and their pathogenicity for isolated male infertility.

Objective: To study the impact of Doublesex and mab-3-related transcription factor 1 (DMRT1) gene variants on the encoded protein's function and the variants' pathogenic relevance for isolated male infertility caused by azoospermia.

Design: This study established a novel luciferase assay for DMRT1 missense variants using 2 different target promotors and validated the assay by analyzing previously published variants associated with differences in sex development.

Setting: University genetics research institute and tertiary referral center for couples' infertility.

Transcriptome analyses in infertile men reveal germ cell-specific expression and splicing patterns.

The process of spermatogenesis-when germ cells differentiate into sperm-is tightly regulated, and misregulation in gene expression is likely to be involved in the physiopathology of male infertility. The testis is one of the most transcriptionally rich tissues; nevertheless, the specific gene expression changes occurring during spermatogenesis are not fully understood. To better understand gene expression during spermatogenesis, we generated germ cell-specific whole transcriptome profiles by systematically comparing testicular transcriptomes from tissues in which spermatogenesis is arrested at successive steps of germ cell differentiation.

Immune and spermatogenesis-related loci are involved in the development of extreme patterns of male infertility.

We conducted a genome-wide association study in a large population of infertile men due to unexplained spermatogenic failure (SPGF). More than seven million genetic variants were analysed in 1,274 SPGF cases and 1,951 unaffected controls from two independent European cohorts. Two genomic regions were associated with the most severe histological pattern of SPGF, defined by Sertoli cell-only (SCO) phenotype, namely the MHC class II gene HLA-DRB1 (rs1136759, P = 1.

A GWAS in Idiopathic/Unexplained Infertile Men Detects a Genomic Region Determining Follicle-Stimulating Hormone Levels.

Context: Approximately 70% of infertile men are diagnosed with idiopathic (abnormal semen parameters) or unexplained (normozoospermia) infertility, with the common feature of lacking etiologic factors. Follicle-stimulating hormone (FSH) is essential for initiation and maintenance of spermatogenesis. Certain single-nucleotide variations (SNVs; formerly single-nucleotide polymorphisms [SNPs]) (ie, FSHB c.

FSHB Genotype Identified as a Relevant Diagnostic Parameter Revealed by Cluster Analysis of Men With Idiopathic Infertility.

Introduction And Objectives: About 30-75% of infertile men are diagnosed with idiopathic infertility, thereby lacking major causative factors to explain their impaired fertility status. In this study, we used a large cohort of idiopathic infertile men to determine whether subgroups could be identified by an unbiased clustering approach and whether underlying etiologic factors could be delineated.

Patients And Methods: From our in-house database Androbase, we retrospectively selected patients (from 2008 to 2018) with idiopathic male infertility (azoo- to normozoospermia) who fit the following selection criteria: FSH ≥ 1 IU/l, testosterone ≥ 8 nmol/l, ejaculate volume ≥ 1.

Machine learning based prediction models in male reproductive health: Development of a proof-of-concept model for Klinefelter Syndrome in azoospermic patients.

Background: Due to the highly variable clinical phenotype, Klinefelter Syndrome is underdiagnosed.

Objective: Assessment of supervised machine learning based prediction models for identification of Klinefelter Syndrome among azoospermic patients, and comparison to expert clinical evaluation.

Materials And Methods: Retrospective patient data (karyotype, age, height, weight, testis volume, follicle-stimulating hormone, luteinizing hormone, testosterone, estradiol, prolactin, semen pH and semen volume) collected between January 2005 and June 2019 were retrieved from a patient data bank of a University Centre.

Pituitary response to GnRH stimulation tests in different FSHB-211 G/T genotypes.

Study Question: Does pituitary response to a GnRH stimulation test differ according to the different FSHB-211 G/T genotypes?

Summary Answer: The promoter polymorphism FSHB-211 G > T affects the pituitary response to exogenous GnRH stimulation by reducing FSH and increasing LH outputs.

What Is Known Already: The FSHB-211 G > T single nucleotide polymorphism (SNP) is known to affect pituitary FSH output by impairing the transcriptional activity of FSHB.

Study Design, Size, Duration: This was a cross-sectional, retrospective study on 67 male subjects (mean age: 24.

Healthy ageing and spermatogenesis.

Delayed family planning and increased parental age increase the risk for infertility and impaired offspring health. While the impact of ageing on oogenesis is well studied, this is less understood on spermatogenesis. Assessing ageing effects on the male germline presents a challenge in differentiating between the effects of ageing-associated morbidities, infertility and 'pure' ageing.

Testicular blood supply is altered in the 41,XX* Klinefelter syndrome mouse model.

Hypergonadotropic hypogonadism is a major feature of Klinefelter syndrome (KS), assumed to be caused by testicular hormone resistance. It was previously shown that intratesticular testosterone levels in vivo and Leydig cell function in vitro seem to be normal indicating other functional constraints. We hypothesized that impaired testicular vascularization/blood flow could be a co-factor to the observed hypergonadotropic hypogonadism.

The Male Fertility Gene Atlas: a web tool for collecting and integrating OMICS data in the context of male infertility.

Study Question: How can one design and implement a system that provides a comprehensive overview of research results in the field of epi-/genetics of male infertility and germ cells?

Summary Answer: Working at the interface of literature search engines and raw data repositories, the newly developed Male Fertility Gene Atlas (MFGA) provides a system that can represent aggregated results from scientific publications in a standardized way and perform advanced searches, for example based on the conditions (phenotypes) and genes related to male infertility.

What Is Known Already: PubMed and Google Scholar are established search engines for research literature. Additionally, repositories like Gene Expression Omnibus and Sequence Read Archive provide access to raw data.

Testicular Microlithiasis Is Associated with Impaired Spermatogenesis in Patients with Unexplained Infertility.

Introduction: Testicular microlithiasis (TML) was shown to be associated with an increased risk of infertility. However, the association of TML with spermatogenesis in patients with unexplained infertility is still unknown. In this study, we therefore investigated the effect of TML on hormones and sperm parameters in a large cohort of infertile men without major factors for impaired fertility and azoospermic men serving for comparison.

Molecular Aging Markers in Patients with Klinefelter Syndrome.

Molecular aging markers provide the opportunity for biological age determination in humans and to study factors, such as genetic determinants, affecting the ageing process. In males with Klinefelter syndrome (KS, non-mosaic karyotype 47, XXY), which is the most common sex chromosome aneuploidy, age-related morbidity and mortality are increased, and a significantly reduced life span has been observed. The aim of this study was to investigate whether Klinefelter patients exhibit molecular signs of premature ageing.

41,XX * male mice: An animal model for Klinefelter syndrome.

Klinefelter syndrome (KS, 47,XXY) is the most frequent male chromosomal aneuploidy resulting in a highly heterogeneous clinical phenotype associated with hormonal dysbalance, increased rate of co-morbidities, and reduced lifespan. Two hallmarks of KS-affecting testicular functions are consistently observed: Hypergonadotropic hypogonadism and germ cell (GC) loss resulting in infertility. Although KS is being studied for decades, the underlying mechanisms for the observed pathophysiology are still unclear.

Does the FSHB c.-211G>T polymorphism impact Sertoli cell number and the spermatogenic potential in infertile patients?

Background: A genetic variant within the FSHB gene can deviate FSH action on spermatogenesis. The c.-211G>T FSHB single nucleotide polymorphism impacts FSHB transcription and biosynthesis due to interference with the LHX3 transcription factor binding.

Ageing in men with normal spermatogenesis alters spermatogonial dynamics and nuclear morphology in Sertoli cells.

Background: Ageing in men is believed to be associated with fertility decline and elevated risk of congenital disorders for the offspring. The previous studies also reported reduced germ and Sertoli cell numbers in older men. However, it is not clear whether ageing in men with normal spermatogenesis affects the testis and germ cell population dynamics in a way sufficient for transmitting adverse age effects to the offspring.

Pharmacogenetics of FSH Action in the Male.

Male infertility is a major contributor to couple infertility, however in most cases it remains "idiopathic" and putative treatment regimens are lacking. This leads to a scenario in which intra-cytoplasmic spermatozoa injection (ICSI) is widely used in idiopathic male infertility, though the treatment burden is high for the couple and it entails considerable costs and risks. Given the crucial role of the Follicle-stimulating hormone (FSH) for spermatogenesis, FSH has been used empirically to improve semen parameters, but the response to FSH varied strongly among treated infertile men.