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Additional file 2. Table S2: Pairwise comparison of the epigenomic data according to the staining and sorting results.

Additional file 3. Table S3: Pairwise comparison of the epigenomic data between donors and patients, ranked according to the staining and sorting results.

Additional file 1. Table S1: Comparison of the cumulated epigenomic data of the washed spermatozoa of semen donors with the cumulated epigenomic data of the washed spermatozoa of infertile patients, followed by stepwise analysis of the results.

Hearing loss is the most frequent sensory deficit at birth. Newborn hearing screening helps with early identification and clinical management of hearing deficits. A cochlear implantation is advised for profound hearing loss. Previously, an etiologic diagnosis was difficult to obtain, and many laboratory tests were required. Today, genetics has up to 60% success rate in etiologic diagnosis and is now part of the international pediatric ENT recommendations. The Centre Universitaire Romand des Implants Cochléaires (CURIC) follows children with cochlear implants. From 2015 to 2021, 26 implanted children received testing, with a 73% success rate. The genetic diagnosis helped guide their clinical management and helped to avoid unnecessary and costly clinical testing.Le déficit auditif (DA) est le déficit neurosensoriel le plus fréquent à la naissance. Le dépistage auditif permet l’identification et la prise en charge précoces des problèmes d’audition. Dans le cas de surdités profondes, une implantation cochléaire est conseillée. Auparavant, le diagnostic étiologique était difficile à poser malgré de nombreux examens complémentaires. Depuis 10 ans, la médecine génétique aboutit à un diagnostic étiologique dans 60% des cas et fait partie des recommandations internationales d’ORL pédiatrique. Le Centre universitaire romand des implants cochléaires prend en charge les enfants implantés. Entre 2015 et 2021, 26 enfants implantés ont eu une analyse génétique, dont 73% avec succès. Ceci permet d’orienter la prise en charge spécifiquement au profil génétique et diminue les examens complémentaires.

Hearing loss is the most frequent sensory deficit at birth. Newborn hearing screening helps with early identification and clinical management of hearing deficits. A cochlear implantation is advised for profound hearing loss. Previously, an etiologic diagnosis was difficult to obtain, and many laboratory tests were required. Today, genetics has up to 60% success rate in etiologic diagnosis and is now part of the international pediatric ENT recommendations. The Centre Universitaire Romand des Implants Cochléaires (CURIC) follows children with cochlear implants. From 2015 to 2021, 26 implanted children received testing, with a 73% success rate. The genetic diagnosis helped guide their clinical management and helped to avoid unnecessary and costly clinical testing.

International audience; At the present time, no viable treatment exists for cognitive and olfactory deficits in Down syndrome (DS). We show in a DS model (Ts65Dn mice) that these progressive nonreproductive neurological symptoms closely parallel a postpubertal decrease in hypothalamic as well as extrahypothalamic expression of a master molecule that controls reproduction—gonadotropin-releasing hormone (GnRH)—and appear related to an imbalance in a microRNA-gene network known to regulate GnRH neuron maturation together with altered hippocampal synaptic transmission. Epigenetic, cellular, chemogenetic, and pharmacological interventions that restore physiological GnRH levels abolish olfactory and cognitive defects in Ts65Dn mice, whereas pulsatile GnRH therapy improves cognition and brain connectivity in adult DS patients. GnRH thus plays a crucial role in olfaction and cognition, and pulsatile GnRH therapy holds promise to improve cognitive deficits in DS.

Purpose: The INTERMED instrument, which was developed to measure patient’s biopsychosocial (BPS) complexity, represents a powerful diagnostic and therapeutic tool. Epigenetic changes are the interface between signals from the environment and genetic modifications, affecting gene expression, in particular, by DNA methylation of CpG dinucleotides in promotor regions of the corresponding genes. The brain-derived neurotrophic factor (BDNF) gene plays a crucial role in the central sensitization (CS) of pain. In this study, we hypothesized that chronic pain modifies the methylation levels of the BDNF gene in a manner that is interconnected with the BPS status. Patients and Methods: Fifty-eight chronic musculoskeletal pain patients (CMSP) were enrolled in the study. DNA was extracted from blood samples, the methylation levels of 13 CpG sites in the BDNF promoter were measured by pyrosequencing, and association studies with various patient parameters and the INTERMED scores were performed. Results: Interestingly, a negative correlation (− 0.40) was found between the total INTERMED scores and the average CpG methylation values of the BDNF gene, but no correlation was observed with the severity of pain, degree of anxiety, depression, or kinesiophobia and catastrophism. Moreover, the association was independent of age, sex and level of comorbidities. Conclusion: This result shows that CMSP, in association with its biopsychosocial context, epigenetically decreases the degree of methylation of the BDNF promoter and should therefore increase the level of BDNF transcription. It also suggests a role of the INTERMED tool to detect a relationship between the BPS complexity and the epigenetic control of a target gene. The possible upregulation of BDNF expression might be, at least in part, the signal for chronic pain-induced central sensitization (CS). This could partly explain why patients with a higher level of complexity feel more pain than those with lower complexity.

Interpersonal violent (IPV) experiences when they begin in childhood and continue in various forms during adulthood often lead to chronic post-traumatic stress disorder (PTSD) that is associated in multiple studies with hypocortisolism and lower percentage of methylation of the promoter region of the gene coding for the glucocorticoid receptor (NR3C1). This prospective, longitudinal study examined the relationship of NR3C1 methylation among mothers with IPV-related PTSD and their toddlers and then looked at the relationship of maternal NR3C1 methylation and child psychopathology at school age.Forty-eight mothers were evaluated for life-events history and post-traumatic stress disorderLogistic regression models using child NR3C1 methylation as the dependent variable and maternal NR3C1 methylation and PTSD group status as predictors, as well as the interaction indicated that all three of these significantly predicted child NR3C1 methylation. These findings remained significant when controlling for child age, sex and maternal child abuse history. Overall, maternal NR3C1 methylation when children were toddlers was negatively and significantly associated with child externalizing behavior severity at school age.We found that correlations between mothers and their children of NR3C1 methylation levels overall and at all individual CpG sites of interest were significant only in the IPV-PTSD group. The latter findings support that NR3C1 methylation in mothers positively and statistically significantly correlates with NR3C1 methylation in their children only in presence of IPV-PTSD in the mothers. This maternal epigenetic signature with respect to this glucocorticoid receptor is significantly associated with child behavior that may well pose a risk for intergenerational transmission of violence and related psychopathology.

Introduction: Interpersonal violent (IPV) experiences when they begin in childhood and continue in various forms during adulthood often lead to chronic post-traumatic stress disorder (PTSD) that is associated in multiple studies with hypocortisolism and lower percentage of methylation of the promoter region of the gene coding for the glucocorticoid receptor (NR3C1). This prospective, longitudinal study examined the relationship of NR3C1 methylation among mothers with IPV-related PTSD and their toddlers and then looked at the relationship of maternal NR3C1 methylation and child psychopathology at school age. Methods: Forty-eight mothers were evaluated for life-events history and post-traumatic stress disorder via structured clinical interview when their children were ages 12-42 months (mean age 26.7 months, SD 8.8). Their children's psychopathology in terms of internalizing symptoms and externalizing behaviors was evaluated using the Child Behavior Checklist at ages 5-9 years (mean age 7 years, SD 1.1). Percentage of methylation for the NR3C1 gene promoter region was assessed from DNA extracted from maternal and child saliva using bisulfite pyrosequencing. Data analysis involved parametric and non-parametric correlations and multiple linear and logistic regression modeling. Results: Logistic regression models using child NR3C1 methylation as the dependent variable and maternal NR3C1 methylation and PTSD group status as predictors, as well as the interaction indicated that all three of these significantly predicted child NR3C1 methylation. These findings remained significant when controlling for child age, sex and maternal child abuse history. Overall, maternal NR3C1 methylation when children were toddlers was negatively and significantly associated with child externalizing behavior severity at school age. Discussion: We found that correlations between mothers and their children of NR3C1 methylation levels overall and at all individual CpG sites of interest were significant only in the IPV-PTSD group. The latter findings support that NR3C1 methylation in mothers positively and statistically significantly correlates with NR3C1 methylation in their children only in presence of IPV-PTSD in the mothers. This maternal epigenetic signature with respect to this glucocorticoid receptor is significantly associated with child behavior that may well pose a risk for intergenerational transmission of violence and related psychopathology.

Purpose: Hearing loss is characterized by an extensive genetic heterogeneity and remains a common disorder in children. Molecular diagnosis is of particular benefit in children, and permits the early identification of clinically-unrecognized hearing loss syndromes, which permits effective clinical management and follow-up, including genetic counselling. Methods: We performed whole-exome sequencing with the analysis of a panel of 189 genes associated with hearing loss in a prospective cohort of 61 children and 9 adults presenting mainly with isolated hearing loss. Results: The overall diagnostic rate using exome sequencing was 47.2% (52.5% in children, 22% in adults). In children with confirmed molecular results, 17/32 (53.2%) showed autosomal recessive inheritance patterns, 14/32 (43.75%) showed an autosomal dominant condition, and one case had X-linked hearing loss. In adults, the two patients showed an autosomal dominant inheritance pattern. Among the 32 children, 17 (53.1%) had nonsyndromic hearing loss and 15 (46.7%) had syndromic hearing loss. One adult was diagnosed with syndromic hearing loss and one with nonsyndromic hearing loss. The most common causative genes were STRC (5 cases), GJB2 (3 cases), COL11A1 (3 cases), and ACTG1 (3 cases). Conclusions: Exome sequencing has a high diagnostic yield in children with hearing loss and can reveal a syndromic hearing loss form before other organs/systems become involved, allowing the surveillance of unrecognized present and/or future complications associated with these syndromes.

Bi-allelic loss-of-function variants of OTOA are a well-known cause of moderate-to-severe hearing loss. Whereas non-allelic homologous recombination-mediated deletions of the gene are well known, gene conversions to pseudogene OTOAP1 have been reported in the literature but never fully described nor their pathogenicity assessed. Here, we report two unrelated patients with moderate hearing-loss, who were compound heterozygotes for a converted allele and a deletion of OTOA. The conversions were initially detected through sequencing depths anomalies at the OTOA locus after exome sequencing, then confirmed with long range polymerase chain reactions. Both conversions lead to loss-of-function by introducing a premature stop codon in exon 22 (p.Glu787*). Using genomic alignments and long read nanopore sequencing, we found that the two probands carry stretches of converted DNA of widely different lengths (at least 9 kbp and around 900 bp, respectively).

AIMS OF THE STUDY The European Society of Medical Oncology (ESMO) recommends that countries should have reference centres to provide adequate diagnosis and treatment of gestational trophoblastic disease. A trophoblastic disease centre in the French-speaking part of Switzerland was inaugurated in 2009. The objectives of this study were to report the activity of the centre during the last 10 years and analyse gestational trophoblastic disease outcomes. METHODS This was a retrospective study with data collected from all cases of gestational trophoblastic disease referred to the centre from 2009 to 2018. All histological specimens as well as data for treatment and follow-up of gestational trophoblastic disease and neoplasia were reviewed. Clinical features, including age, prognostic score and International Federation of Gynecology and Obstetrics (FIGO) stages (in the case of gestational trophoblastic neoplasia), human chorionic gonadotropin (hCG) follow-up, treatment and outcome were reported. RESULTS The centre registered 354 patients, and these patients presented 156 cases of partial hydatidiform moles, 163 cases of complete hydatidiform moles and 14 cases of gestational trophoblastic neoplasia. During follow-up, 35 gestational trophoblastic neoplasms were diagnosed after hCG persistence. After pathology review, the overall agreement rates between our centre and a participating provider hospital was 82%. Methotrexate was the first line of single-agent chemotherapy for most patients, with resistance rates of 23%. Multi-agent chemotherapy was used as first-line treatment for five patients. None of the patients followed up by the centre died from gestational trophoblastic disease. CONCLUSIONS This study reflects the activity of the Swiss trophoblastic disease centre from the French-speaking part of Switzerland created in 2009, and its role as local and national reference centre, in terms of global health, for women with gestational trophoblastic disease.

The key developmental steps in the male germ cell lineage include the epigenetic reprogramming of the primordial germ cells, the large-scale replacement of histone by protamine in spermatids and some degree of apoptosis. In past experiments, we prenatally exposed mice to di(2-ethylhexyl)phthalate (DEHP, CAS number 117-81-7). At adulthood, the exposed mice were characterized by reduced anogenital distance (AGD), poor semen quality, and epigenomic abnormalities in their gametes’ DNA. However, the phenotype heavily depended on the genetic background of the mouse strain. We identified SNP-dependent binding motifs for sex hormones signaling pathways varying between the susceptible and the resistant mouse strains. These SNP-dependent motifs were located in the genes that were the most affected one by DEHP, at both DNA methylation and RNA transcription levels. We then tried to replicate these observations into human. We selected 6 infertile patients with short AGD and 5 fertile sperm donors. Testicular volume was significantly reduced in infertile men with shorter AGD. Sub-populations of spermatozoa were FACS-sorted using the chromomycin A3 dye (protamine vs. histone) and with the YO-PRO-1 dye (apoptotic vs. non-apoptotic). In the four sorted sperm populations, we analyzed the epigenomes through reduced-representation bisulfite sequencing (RRBS). The results demonstrated both lower CpG methylation and higher DNA fragmentation in infertile patients. Interestingly, numerous de-methylated regions localized within families of Alu repeats containing estrogen response elements (ERE). We are now in the process of replicating the entire study with a new cohort of five infertile patients and five fertile controls. The aim is to understand if there is a relationship between these epigenomic alterations within Alu repeats containing ERE and fertility, and whether exposures to anti-androgenic endocrine disruptors may alter methylation marks within these Alu-ERE repeats.

Introduction: The effects of acupuncture treatment in patients suffering from burnout may imply an epigenetic control mediated by DNA methylation changes. In this observational study, a genome-wide characterization of epigenetic changes in blood DNA, before and after acupuncture treatment, was performed in a cohort of 11 patients suffering from burnout. Methods: Burnout was assessed using the Maslach Burnout Inventory (MBI) and DNA was extracted from blood samples and analyzed by Illumina EPIC BeadChip. Results: Before acupuncture, all patients suffered of emotional exhaustion (EE) (MBI-EE score, 44 ± 6), 81% suffered of depersonalization (DP) (MBI-DP score, 16 ± 6), and 72% of low feelings of personal accomplishment (PA) (MBI-PA score, 29 ± 9). After acupuncture, all MBI dimensions improved significantly (EE, 16 ± 11 [p = 1.5 × 10–4]; DP, 4 ± 5 [p = 5.3 × 10–4]; and PA, 40 ± 6 [p = 4.1 × 10–3]). For each patient, both methylomes obtained before and after acupuncture co-clustered in the multidimensional scaling plot, indicating a high level of similarity. Genes corresponding to the 10 most differentially methylated CpGs showed enrichment in the brain dopaminergic signaling, steroid synthesis and in the insulin sensitivity pathways. Conclusion: Acupuncture treatment was found to be highly effective on all burnout dimensions and the epigenetic targets identified were involved in some major disturbances of this syndrome.

Patients come in consultation with a variety of complaints, some of which are unusual. We present here the case of a patient consulting for nauseating body odors for whom a diagnosis of trimethylaminuria could be found. This pathology, not very well known, may have important psychiatric and social repercussions. Genetics play a major role in diagnosis, while treatment consists essentially of various palliative measures.Les patients se présentent en consultation avec des plaintes variées, dont certaines sont peu communes. Nous présentons ici le cas d’un patient consultant pour des odeurs corporelles nauséabondes chez lequel un diagnostic de triméthylaminurie a pu être posé. Cette pathologie, peu connue, peut avoir des répercussions psychiatriques et sociales importantes. La génétique joue un rôle prépondérant dans le diagnostic, tandis que le traitement consiste essentiellement en diverses mesures palliatives.