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.
Kidney Diseases , Nephrology , Adult , Child , Humans , Kidney , Kidney Diseases/genetics , Kidney Diseases/therapy , Ambulatory Care Facilities , Hospitals, University , Rare Diseases/therapy
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.
Cochlear Implantation , Cochlear Implants , Deafness , Hearing Loss , Child , Deafness/diagnosis , Hearing Loss/diagnosis , Hearing Loss/genetics , Humans , Infant, Newborn , Molecular Biology , Switzerland
We studied a family in which the first-born child, a girl, had developmental delay, facial dysmorphism, and agenesis of the corpus callosum (ACC). The subsequent pregnancy was interrupted as the fetus was found to be also affected by ACC. Both cases were heterozygous for two KDM5B variants predicting p (Ala635Thr) and p (Ser1155AlafsTer4) that were shown to be in trans. KDM5B variants have been previously associated with moderate to severe developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and dysmorphism in a few individuals, but the pathogenetic mechanisms are not clear yet as patients with both monoallelic and biallelic variants have been observed. Interestingly, one individual has previously been reported with ACC and severe ID in association with biallelic KDM5B variants. Together with the observations in this family, this suggests that agenesis of the corpus callosum may be part of the phenotypic spectrum associated with KDM5B variants and that the KDM5B gene should be included in gene panels to clarify the etiology of ACC both in the prenatal and postnatal setting.
Agenesis of Corpus Callosum/genetics , Intellectual Disability/genetics , Jumonji Domain-Containing Histone Demethylases/genetics , Nuclear Proteins/genetics , Repressor Proteins/genetics , Abortion, Eugenic , Agenesis of Corpus Callosum/complications , Agenesis of Corpus Callosum/diagnosis , Child, Preschool , Developmental Disabilities/complications , Developmental Disabilities/genetics , Facial Asymmetry/complications , Facial Asymmetry/genetics , Family , Female , Fetal Diseases/diagnosis , Fetal Diseases/genetics , Heterozygote , Humans , Intellectual Disability/complications , Intellectual Disability/diagnosis , Mutation, Missense , Pedigree , Pregnancy , Siblings , Switzerland
MYH11 (myosin heavy chain 11) gene is involved in vascular contractility and several autosomal dominant mutations have been linked to thoracic aortic aneurysms. Three male members of the same family were found to carry a heterozygous missense variant in the MYH11 gene and all 3 individuals presented a thoracic aortic aneurysm/dilation. We identified a rare missense variant in the MYH11 gene predicted to be damaging and affecting a conserved amino acid in the myosin tail of the protein. This variant appears to be responsible for our familial case of thoracic aortic aneurysms, as the clinical expression reunited all features of genetic aneurysms.
Aortic Aneurysm, Thoracic/genetics , Mutation, Missense , Myosin Heavy Chains/genetics , Aged , Humans , Male
In Switzerland, since modifications of the law regulating reproductive medicine introduced the 1rst of September 2017, preimplantation genetic testing (PGT) has been legalised. Infertile couples undergoing in vitro fertilization (IVF) can benefit from this technology by detecting which embryos are aneuploid (ie abnormal number of chromosomes, PGT-A). This is performed in order to transfer euploid embryos (normal number of chromosomes) and to optimise success, though data are limited. Couples at risk of transmitting a severe monogenic disease or unbalanced translocation can undergo PGT for monogenic disease or chromosomal structural rearrangements (PGT-M/SR). These tests are subject to strict legal criteria. Their clinical application needs to be approved through a multidisciplinary approach taking into account legal and ethical issues while respecting the autonomy of the couples.
Depuis le 1er septembre 2017, les tests génétiques préimplantatoires (PGT) sont autorisés en Suisse suite aux modifications de la loi sur la procréation médicalement assistée (LPMA). Les couples infertiles qui effectuent une fécondation in vitro (FIV) peuvent bénéficier d'un PGT des aneuploïdies (PGT-A) dans le but de transférer des embryons euploïdes (nombre normal de chromosomes) et ainsi optimiser leurs chances de succès, sous réserve de données encore limitées. Les couples à risque de transmettre une maladie monogénique grave ou une translocation déséquilibrée peuvent avoir recours au PGT d'une anomalie d'un gène unique ou d'une anomalie de structure de chromosome (PGT-M/SR), dans les limites d'un cadre légal strict. Leur mise en pratique doit être décidée de manière pluridisciplinaire en tenant compte des enjeux légaux et éthiques dans le respect de l'autonomie des couples.
Genetic Testing/ethics , Genetic Testing/legislation & jurisprudence , Preimplantation Diagnosis/ethics , Aneuploidy , Female , Fertilization in Vitro , Genetic Testing/methods , Humans , Male , Pregnancy , Preimplantation Diagnosis/methods , Switzerland
PURPOSE: Women carrying BRCA1/BRCA2 germ-line mutations have an increased risk of developing breast/ovarian cancer. To minimize this risk, international guidelines recommend lifelong surveillance and preventive measures. This study explores the challenges that unaffected women genetically predisposed to breast/ovarian cancer face in managing their risk over time and the psychosocial processes behind these challenges. METHODS: Between 2011 and 2013, biographical qualitative interviews were conducted in Switzerland with 32 unaffected French- and Italian-speaking women carrying BRCA1/BRCA2 mutations. Their mutation status had been known for at least 3 years (mean, 6 years). Data were analyzed through constant comparative analysis using software for qualitative analysis. RESULTS: From the time these women received their positive genetic test results, they were encouraged to follow medical guidelines. Meanwhile, their adherence to these guidelines was constantly questioned by their social and medical environments. As a result of these contradictory pressures, BRCA1/BRCA2 mutation carriers experienced a sense of disorientation about the most appropriate way of dealing with genetic risk. CONCLUSION: Given the contradictory attitudes of health-care professionals in caring for unaffected BRCA1/BRCA2 mutation carriers, there is an urgent need to educate physicians in dealing with genetically at-risk women and to promote a shared representation of this condition among them.Genet Med 17 9, 726-732.
BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/genetics , Breast Neoplasms/prevention & control , Genes, BRCA1 , Genes, BRCA2 , Germ-Line Mutation , Adult , Attitude of Health Personnel , Breast Neoplasms/psychology , Female , Genetic Predisposition to Disease/psychology , Genetic Testing , Guideline Adherence , Humans , Interview, Psychological , Longitudinal Studies , Middle Aged , Retrospective Studies , Risk Factors
We report a 26-year-old female patient who was diagnosed within 4 years with chest sarcoma, lung adenocarcinoma, and breast cancer. While her family history was unremarkable, DNA sequencing of TP53 revealed a germline de novo non-sense mutation in exon 6 p.Arg213X. One year later, she further developed a contralateral ductal carcinoma in situ, and 18 months later a jaw osteosarcoma. This case illustrates the therapeutic pitfalls in the care of a young cancer patient with TP53 de novo germline mutations and the complications related to her first-line therapy. Suggestion is made to use the less stringent Chompret criteria for germline TP53 mutation screening. Our observation underlines the possibly negative effect of radiotherapy in generating second tumors in patients with a TP53 mutation. We also present a review of six previously reported cases, comparing their cancer phenotypes with those generally produced by TP53 mutations.
Neoplasms, Second Primary/etiology , Sarcoma/radiotherapy , Thoracic Neoplasms/genetics , Thoracic Neoplasms/radiotherapy , Thoracic Wall , Tumor Suppressor Protein p53/genetics , Adenocarcinoma/etiology , Adult , Breast Neoplasms/etiology , Female , Germ-Line Mutation , Humans , Lung Neoplasms/etiology
