[Management of genetic renal disorders: local experience and importance of the network]. / Prise en charge des maladies rénales génétiques : expérience locale et importance du réseau.

In nephrology, rare disorders are frequently encountered. In children, about 60% of the renal disorders are rare, with congenital abnormalities of the kidney and urinary tract disorders (CAKUT), being highly prevalent. In adults, about 22% of the disorders leading to renal replacement therapies are rare and include glomerulonephritis and genetic disorders. Rarity may preclude the rapid and extensive access to care for patients suffering of renal disorders, especially in Switzerland, which is small and fragmented. Only collaborative network and access to databases, shared resources and to specific competence may help patient management. Lausanne and Geneva University Hospitals have started specialized outpatient clinics for rare renal disorders several years ago and are part of national and international networks.

Dans le domaine des maladies rénales, la rareté est fréquente. Chez l'enfant, 60 % des maladies touchant les reins sont rares et les malformations de l'axe urinaire sont prépondérantes. Chez l'adulte, près de 22 % des pathologies qui mènent à la maladie rénale terminale sont rares et incluent les glomérulonéphrites et les maladies génétiques. La rareté de ces pathologies fait que les compétences médicales peuvent être difficiles à trouver et l'expérience locale insuffisante. Ainsi, seule la mise en réseau des données, des ressources et des compétences peut permettre d'améliorer la prise en charge de ces patients. Le CHUV et les HUG ont mis en place des consultations spécialisées pour les maladies rénales rares. Elles s'inscrivent dans un réseau national et international.

Increased Arterial Responsiveness to Angiotensin II in Mice Conceived by Assisted Reproductive Technologies.

Since the first report in 1978, the number of individuals conceived by Assisted Reproductive Technologies (ART) has grown incessantly. In parallel, with the recent emergence of possible underlying mechanisms of ART-induced epigenetic changes in the renin-angiotensin system, the cardiovascular repercussions of ART in mice and human offspring (including arterial hypertension, vascular dysfunction, and cardiac remodeling) have become increasingly recognized. Here, we hypothesized that ART may increase arterial responsiveness to angiotensin II (ANG II) by epigenetically modifying the expression of its receptors. To test this hypothesis, we assessed the vasoconstrictor responsiveness to ANG II in isolated aortas from ART and control mice. We also examined ANG II receptor (ATR) type 1 and 2 expression and the promoter methylation of the At1aR, At1bR and At2R genes. We found that the vasoconstrictor response to ANG II was markedly increased in ART mice compared to controls. This exaggerated vasoconstrictor responsiveness in ART mice correlated with a significant increase in the ANG II receptor (ATR) type 1 to ATR type 2 protein expression ratio in the aorta; this was mainly driven by an increase in AT1R expression, and by hypomethylation of two CpG sites located in the At1bR gene promoter leading to increased transcription of the gene. We conclude that in mice, ART increase the vasoconstrictor response to ANG II in the aorta by epigenetically causing an imbalance between the expression of vasoconstrictor (AT1R) and vasodilator (AT2R) ANG II receptors. Unbalanced expression of AT1R and AT2R receptors seems to be a novel mechanism contributing to ART-induced arterial hypertension in mice.

[Molecular genetic diagnosis in children with cochlear implants in the Western french speaking part of Switzerland]. / Diagnostic génétique moléculaire des enfants implantés cochléaires en Suisse romande.

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.

Molecular characterization of pathogenic OTOA gene conversions in hearing loss patients.

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).

LARS2-Perrault syndrome: a new case report and literature review.

BACKGROUND: Perrault syndrome is a rare recessive and genetically heterogeneous disorder characterized by sensorineural hearing loss in males and females and gonadal dysgenesis in females. Mutations in seven different genes have been identified: HARS2, HSD17B4, CLLP, C10orf, ERAL1, TWNK and LARS2. To date, 19 variants have been reported in 18 individuals with LARS2-Perrault syndrome. CASE PRESENTATION: Here we describe the case of an 8-year-old girl with compound heterozygous missense mutations in the LARS2 gene. We identified two missense mutations [c.457A > C, p.(Asn153His) and c.1565C > A, p.(Thr522Asn)] and subsequent familial segregation showed that each parent had transmitted a mutation. CONCLUSIONS: These results have implications for genetic counseling and provide insight into the functional role of LARS2. This case highlights the importance of an early diagnosis. Systematic genetic screening of children with hearing loss allows the early identification of a Perrault syndrome in order to ensure specific endocrinological surveillance and management to prevent secondary complications. Clinical data are compared with the other cases reported in the literature.

Case report: a 58 -year -old man with small kidneys and elevated liver enzymes.

BACKGROUND: The conjunction of hepatitis and renal disease can be seen in several clinical context, including karyomegalic nephritis (KIN). Karyomegalic nephritis (KIN) is a rare genetic disease, with less than 50 cases reported, which incidence is probably underestimated. We report here an unusual case presentation of KIN with obtention of several organ biopsies and a novel mutation leading to the disease. CASE PRESENTATION: A 58 year old Caucasian without relevant family history presents with advanced chronic kidney disease, elevated liver enzymes and recurrent pulmonary infection. Familial history was negative. Renal biopsy revealed a chronic tubulo-intertsitial nephritis with enlarged and irregular hyperchromatic nuclei. Karyomegalic nephritis (KIN) was confirmed by genetic testing with a non-sense mutation and a deletion in the Fanconi anemia associated nuclease 1 (FAN1) gene. CONCLUSIONS: KIN is rare disease to be suspected in the presence of renal disease, biological hepatitis and recurrent pulmonary infections, even without a familial history. Diagnosis of this condition is crucial to perform family screening, avoid progression factors, and adapt post transplantation immunosuppression. Finally, avoiding familial heterozygote donors appears of major importance in this condition.

[Trimethylaminuria†: a perhaps not so uncommon case]. / Triméthylaminurie†: un cas pas forcément si rare.

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.

[Genes and sex : which determination ?] / Entre gènes et sexe :quelle détermination ?

Relations between sex and genes are well understood in regards to the pathways that control sex differentiation and leading to phenotypic sex. However, the question of the role of genes in gender identity, sexual and affective orientation, or sexual function remains elusive. If the role of steroid hormones on brain development is established, their role on gender identity or sexual orientation is still hypothetical. Concerning sexual function, the attempts to define which genes are potentially involved, have only pointed to genes associated to neurotransmission, but no breakthrough discovery has been made.

Les relations entre génétique et sexe sont bien étudiées et admises en ce qui concerne le rôle des chromosomes, des gènes et des voies biologiques qui déterminent le sexe gonadique, ainsi que celles menant au sexe phénotypique. Le lien entre génétique et identité de genre, orientation affective et sexuelle, voire fonction sexuelle est lui, encore mal compris. Si l'influence des hormones stéroïdiennes sur le développement cérébral semble établie, le rôle de celles-ci dans l'identité de genre ou l'orientation sexuelle reste hypothétique. Quant à l'exploration des déterminants génétiques de la fonction sexuelle, elle permet de pointer certains gènes candidats, en lien avec la neurotransmission, sans toutefois de découverte sensationnelle à ce jour.

[Preimplantation genetic testing]. / Gynécologie-obstétrique: Tests préimplantatoires de l'embryonen médecine de reproduction.

Preimplantation genetic testing avoids the transmission of monogenic diseases or structural chromosome abnormality to the offspring in fertile couples. Furthermore, it allows screening for aneuploidies (PGT-A, Preimplantation genetic testing for aneuploidy), with the aim of selecting one euploid embryo before transfer in infertile couples undergoing in vitro fertilization (IVF). Indeed, aneuploidies are frequent and explain most IVF failures and early miscarriages. The indications for PGT-A remain controversial, due to the lack of clear evidence of improved outcomes after IVF. Cost-effectiveness studies and follow-up of neonatal outcomes are needed. Finally, each situation requires counseling taking into account ethical considerations.

Les tests préimplantatoires permettent à un couple fertile d'éviter la transmission d'une maladie monogénique ou d'une anomalie chromosomique structurelle à sa descendance. Mais ils peuvent également dépister des aneuploïdies (PGT-A, Preimplantation genetic testing for aneuploidy), avec pour but la sélection d'un embryon euploïde avant transfert in utero pour les couples infertiles réalisant une fécondation in vitro (FIV). En effet, les aneuploïdies, très fréquentes, sont à l'origine de la majorité des échecs d'implantation après FIV et des avortements spontanés précoces. Les indications du PGT-A restent néanmoins controversées en l'absence de preuve évidente d'une amélioration des résultats en FIV. Des études coût/efficacité et un suivi des issues néonatales sont nécessaires. Enfin, chaque situation nécessite un counseling en intégrant les aspects éthiques.

[Genetics of hearing disorders in children]. / Génétique des troubles auditifs chez l'enfant.

The majority of early hearing disorders are of genetic origin. In view of the genetic heterogeneity, high-throughput sequencing analysis of a panel of genes involved in hearing loss is the most effective and economical approach, providing a diagnostic yield of around 40 % today. The determination of a molecular diagnosis makes it possible to: i) adapt the audiological care; ii) to search for possible somatic problems associated with so-called syndromic hearing loss; (iii) to avoid unnecessary additional examinations in isolated hearing loss; (iv) to establish accurate genetic counseling for relatives, or even to provide early diagnosis; and (v) to lay the foundation for potential future molecular hearing loss therapies in selected cases.

La majorité des troubles auditifs précoces est d'origine génétique. La détection rapide et la prise en charge adaptée limitent l'impact développemental; de même, un diagnostic étiologique précis améliore le suivi des patients. Au vu de l'hétérogénéité génétique des troubles auditifs, l'analyse par séquençage à haut débit d'un panel de gènes constitue l'approche la plus efficace et économique avec un rendement actuel d'environ 40 %. Le diagnostic moléculaire permet: 1) d'adapter la prise en charge audiologique; 2) de rechercher d'éventuels problèmes somatiques associés; 3) d'éviter des examens complémentaires inutiles dans les déficits auditifs isolés; 4) d'établir un conseil génétique pour les apparentés, voire de proposer un diagnostic précoce; 5) d'établir les bases d'une éventuelle thérapie génique future.

Novel NEXMIF pathogenic variant in a boy with severe autistic features, intellectual disability, and epilepsy, and his mildly affected mother.

Intellectual disability (ID) and autism spectrum disorders are complex neurodevelopmental disorders occurring among all ethnic and socioeconomic groups. Pathogenic variants in the neurite extension and migration factor (NEXMIF) gene (formerly named KIAA2022) on the X chromosome are responsible for ID, autistic behavior, epilepsy, or dysmorphic features in males. Most affected females described had a milder phenotype or were asymptomatic obligate carriers. We report here for the first time mother-to-son transmission of a novel NEXMIF truncating variant without X-inactivation skewing in the blood. Truncating gene variant leads to symptomatic mother to severely affected son transmission. Our findings emphasize that NEXMIF sequencing should be strongly considered in patients with unexplained autism spectrum disorder, ID, and epilepsy, irrespective of gender. Such testing could increase our knowledge of the pathogenicity of NEXMIF variants and improve genetic counseling.

Intergenerational Transmission of DNA Methylation Signatures Associated with Early Life Stress.

Early life stress in humans (i.e. maltreatment, violence exposure, loss of a loved one) and in rodents (i.e. disrupted attachment or nesting, electric shock, restraint, predator odor) occurs during critical steps of neural circuit formation. ELS in humans is associated with increased risk for developmental psychopathology, including anxious and depressive phenotypes. The biological mechanisms underlying these potentially persistent maladaptive changes involve long-term epigenetic modifications, which have been suggested to be potentially transmissible to subsequent generations. DNA methylation is an epigenetic mechanism that modifies gene expression patterns in response to environmental challenges and influences mutation rates. It remains to be seen whether a functionally relevant fraction of DNA methylation marks can escape genome-wide erasures that occur in primordial germ cells and after fertilization within the zygote. Early life-stress-triggered changes in epigenetic mediated transmission of acquired behavioral traits among humans have been assessed mainly by targeting genes involved in the hypothalamic-pituitary-adrenal (HPA) axis, such as NR3C1 and FKBP5. Recently, researchers examining epigenetic transmission have begun to apply genome-wide approaches. In humans, reduced representation bisulfite sequencing (RRBS) was performed on peripheral samples that were obtained from individuals who were prenatally exposed to the "Dutch Hunger Winter", resulting in two Differentially Methylated Regions (DMRs) in INSR and CPTIA genes that were functionally, biologically and technically validated, and significantly associated with birth weights and LDL cholesterol levels in offspring. In rodents, non-genomic intergenerational transmission of anxiety which was associated with differentially methylated enhancers that were putatively involved in lipid signaling and synaptic/neurotransmission in hippocampal granule cells, was discovered also using RRBS. Finally, transgenerational transmission of altered behaviors was associated with sperm-derived microRNAs produced by ELS male mice. The field of epigenetic transmission is just beginning to enter the epigenomic era by using genome-wide analyses. Such approaches remain of strong interest to human studies, first in order to help to assess the relevance of the previous targeted studies, and second to discover new important epigenetic modifications of potential clinical importance. New discoveries may help to assess how transmittable the negative impact of stress may be to offspring. The latter may open doors for future treatments and resilience-promoting interventions, as well as new approaches to treat the effects of childhood trauma before the onset of psychiatric disorder.

[Intellectual disability: contribution of genetic studies to the etiological diagnosis]. / Handicap intellectuel : apport de la génétique pour le diagnostic étiologique.

The multidiscipinary care of patients with intellectual disability requires a structured and systematic etiological process. Today, advances in technology make it possible to perform diagnostic genetic analyzes that are highly contributive in this process. The CGH-array (Comparative Genomic Hybridization array) makes it possible to search for chromosomal anomalies with a very high level of resolution; high throughput sequencing can detect gene abnormalities on the whole exome or on a panel of genes. For the patient the detection of genetic anomalies aims to improve the quality of care; for related parties, genetic counseling is systematically offered.

La prise en charge multidisciplinaire des patients présentant un handicap intellectuel impose la mise en œuvre d'une démarche étiologique structurée et systématique. Les avancées technologiques permettent aujourd'hui la réalisation d'analyses génétiques diagnostiques très contributives. Le CGH-array (puce d'hybridation génomique comparative) permet de rechercher des anomalies chromosomiques avec un très haut niveau de résolution; le séquençage à haut débit permet de détecter des anomalies géniques sur l'exome entier ou sur un panel de gènes. Pour le patient, la détection d'anomalies génétiques a pour objectif d'améliorer la qualité de la prise en charge; pour les apparentés, un conseil génétique est systématiquement proposé.

METHYLATION OF SEROTONIN RECEPTOR 3A IN ADHD, BORDERLINE PERSONALITY, AND BIPOLAR DISORDERS: LINK WITH SEVERITY OF THE DISORDERS AND CHILDHOOD MALTREATMENT.

BACKGROUND: Serotonin 3A receptor (5-HT3A R) is associated at the genetic and epigenetic levels with a variety of psychiatric disorders and interacts with early-life stress such as childhood maltreatment. We studied the impact of childhood maltreatment on the methylation status of the 5-HT3A R and its association with clinical severity outcomes in relation with a functional genetic polymorphism. METHODS: Clinical severity indexes of 346 bipolar, borderline personality, and adult attention deficit hyperactivity disorders patients were tested for association with the DNA methylation status of eight 5-HT3A R gene CpGs. Relationship between the functional variant rs1062613 (C > T) and methylation status on severity of the disorders were also assessed. RESULTS: Childhood maltreatment was associated with higher severity of the disease (higher number of mood episodes, history of suicide attempts, hospitalization, and younger age at onset) across disorders and within each individual disorder. This effect was mediated by two 5-HT3A R CpGs. Compared to T allele carriers, CC carriers had higher methylation status at one CpG located 1 bp upstream of this variant. CONCLUSIONS: This study shows that epigenetic modification of the 5-HT3A R is involved in the mechanism underlying the relationship between maltreatment in childhood and the severity of several psychiatric disorders in adulthood.

[Genetic kidney diseases: new perspectives on diagnosis]. / Maladies génétiques rénales: perspectives diagnostiques.

Suspected renal inherited disorders are regularly evaluated in nephrology consultations both in adults and children. A positive family history and/or a typical phenotype should lead to genetic investigations. A confirmatory diagnosis integrated in a multidisciplinary genetic counseling approach gives patient guidance for further pregnancy. It also allows physician to better stratify disease risk and indicates treatment in some cases. The time to diagnosis and costs have been dramatically reduced thanks to next generation sequencing in several cases of complex inherited nephrologic syndromes.

[Patients with variations of sex development : an example of interdisciplinary care]. / Patients avec variation du développement sexuel : un exemple de prise en charge interdisciplinaire.

The medical, psychological and social aspects of disorders of sex development (DSD) represent a challenge for the management of these patients. However, advances in our understanding of the etiology and genetics of this condition, novel surgical approaches and the growing influence of patient groups as well as wider recognition of ethical issues have helped improve the care of patients with a DSD. Importantly, a multidisciplinary approach involving specialists is crucial for understanding and treating such rare and complex cases. According to the recommendations of the Swiss National Ethical Commission, we shall use the term « Variation of Sex Development ¼ rather than « Disorder of Sex Development ¼ in this publication. This article addresses the care of DSD patients throughout development from the point of view of specialists in complementary fields.

La prise en charge des personnes avec une variation du développement sexuel (VDS) (disorder of sex development, DSD) est un défi tant sur le plan médical, psychologique que social. L'amélioration des connaissances étiologiques et génétiques, les nouvelles approches chirurgicales et l'influence tant des groupes de patients que de la Commission d'éthique suisse ont considérablement modifié la vision de la prise en charge de ces personnes durant ces dernières décennies. Une approche pluridisciplinaire et spécialisée est cruciale pour appréhender ces situations rares et souvent complexes. Le point de vue des différents spécialistes impliqués au long de la vie dans la prise en charge d'une VDS est abordé dans cet article.

Prevention of vascular dysfunction and arterial hypertension in mice generated by assisted reproductive technologies by addition of melatonin to culture media.

Assisted reproductive technologies (ART) induce vascular dysfunction in humans and mice. In mice, ART-induced vascular dysfunction is related to epigenetic alteration of the endothelial nitric oxide synthase (eNOS) gene, resulting in decreased vascular eNOS expression and nitrite/nitrate synthesis. Melatonin is involved in epigenetic regulation, and its administration to sterile women improves the success rate of ART. We hypothesized that addition of melatonin to culture media may prevent ART-induced epigenetic and cardiovascular alterations in mice. We, therefore, assessed mesenteric-artery responses to acetylcholine and arterial blood pressure, together with DNA methylation of the eNOS gene promoter in vascular tissue and nitric oxide plasma concentration in 12-wk-old ART mice generated with and without addition of melatonin to culture media and in control mice. As expected, acetylcholine-induced mesenteric-artery dilation was impaired (P = 0.008 vs. control) and mean arterial blood pressure increased (109.5 ± 3.8 vs. 104.0 ± 4.7 mmHg, P = 0.002, ART vs. control) in ART compared with control mice. These alterations were associated with altered DNA methylation of the eNOS gene promoter (P < 0.001 vs. control) and decreased plasma nitric oxide concentration (10.1 ± 11.1 vs. 29.5 ± 8.0 µM) (P < 0.001 ART vs. control). Addition of melatonin (10(-6) M) to culture media prevented eNOS dysmethylation (P = 0.005, vs. ART + vehicle), normalized nitric oxide plasma concentration (23.1 ± 14.6 µM, P = 0.002 vs. ART + vehicle) and mesentery-artery responsiveness to acetylcholine (P < 0.008 vs. ART + vehicle), and prevented arterial hypertension (104.6 ± 3.4 mmHg, P < 0.003 vs. ART + vehicle). These findings provide proof of principle that modification of culture media prevents ART-induced vascular dysfunction. We speculate that this approach will also allow preventing ART-induced premature atherosclerosis in humans.

Recurrent spontaneous pneumothorax in an NF1 patient with a novel causative variant: broadening genotype-phenotype correlations.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance, most commonly known to affect the skin and eyes. Although lung involvement in the form of cysts and bullae occurs in up to 20% of adults, the seemingly intuitive association of NF1 and spontaneous pneumothorax is not widely recognised among clinicians. Here, we report the second case of recurring spontaneous pneumothorax in the context of NF1 with a confirmed molecular diagnosis. In both cases, the NF1 variants featured a premature stop codon in the C-terminal protein domain. Interestingly, our patient had mild skin symptoms, suggesting that spontaneous pneumothorax may not be correlated with cutaneous disease severity. More genotype-phenotype correlation studies are needed for NF1 in general and for its link to spontaneous pneumothorax in particular.