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International audience; We report on a phenotypically normal 41-year-old azoospermic man with a 45 chromosomes karyotype including one normal chromosome 21, one normal chromosome 22, and a der(22)ins(22;21). Array CGH showed a 1.8 Mb terminal deletion of bands 21pter to 21q21.1 and a 341 kb terminal deletion on band 21q22.3.

Thirty patients have been described with cytogenetically visible deletion of the short arm of chromosome 6. However, subtelomeric 6p deletion detected by subtelomeric specific probes has been reported only twice. We report two new patients with terminal 6p deletion detected by subtelomeric screening using fluorescence in situ hybridization (FISH). The two patients exhibited mental retardation, ocular abnormalities, hearing loss, and a characteristic facial appearance. Detailed FISH analyses with probes covering the distal 6p25 region estimated the size of the terminal deletions to approximately 5.5 Mb and approximately 4.8 Mb. Array-based comparative genomic hybridization (array CGH) was used to confirm the cryptic deletions. Most patients with subtelomeric defects lack a characteristic phenotype. However, some of the subtelomeric deletions result in a specific phenotype, which can direct the clinician towards the diagnosis. Submicroscopic 6p deletion appears to be a recognizable clinical phenotype, and this region should be thoroughly investigated with FISH probes, including at least a subtelomeric 6p probe and a probe covering FOXC1, for patients presenting with a characteristic facial appearance, ocular abnormalities, predominantly anterior-chamber eye defects, hearing loss, and mental retardation.

Le pronostic des cancers de l’homme jeune en âge de procreer s’est considerablement ameliore ces dernieres decades grâce aux progres therapeutiques. Les chimiotherapies et radiotherapies ont des effets bien connus sur la spermatogenese. Au dela de l’atteinte quantative et qualitative de la spermatogenese, des etudes realisees chez l’animal ont pu mettre en evidence des atteintes nucleaires (aneuploidie, presence d’adduits, fragmentation de l’ADN…) et parfois des atteintes au niveau des generations F1 et F2. Chez l’homme, l’etude des chromosomes des spermatozoides apres radiotherapie a mis en evidence une augmentation de la frequence des anomalies chromosomiques. Concernant la chimiotherapie, les premieres etudes utilisaient la technique de fecondation heterospecifique pour mettre en evidence les anomalies chromosomiques du spermatozoide. Plus recemment, la technique d’hybridation de sondes chromosomiques fluorescentes (FISH) permet d’etudier plusieurs chromosomes sur un grand nombre de spermatozoides. Les resultats des differentes etudes portant sur des effectifs reduits sont variables en fonction du protocole therapeutique administre et de la duree separant le prelevement de la fin du traitement. Nous avons etudie 5 patients ayant fait un prelevement de sperme 6 a 17 mois apres le protocole de chimiotherapie BEP (Bleomycin, Etoposide, Cisplatin). Nous avons mis en evidence une augmentation du taux de spermatozoides presentant une aneuploidie et une diploidie. Les resultats de notre etude et de celles du groupe de R. Martin [45, 47] evoquent la possibilite d’un effet transitoire de la chimiotherapie sur les chromosomes gametiques. Dans le cadre de la maladie de Hodgkin d’autres etudes ont mis en evidence l’aspect transitoire de l’effet sur l’aneuploidie. Au dela de l’atteinte chromosomique, l’action deletere des traitements pourrait avoir pour cible l’ADN du spermatozoide. Ainsi des etudes sur des effectifs importants, utilisant d’autres metodes d’analyse nous parraissent necessaires. Dans l’attente, il parait souhaitable de toujours conseiller l’autoconservation de sperme avant les traitements et d’adopter une grande prudence lors du conseil apporte aux patients desirant une grossesse, precocement, apres la fin des traitements.

Testicular cancer is the most common neoplasia occurring in the young male population. The PEB (cisplatin, etoposide and bleomycin) adjuvant chemotherapy usually proposed after orchidectomy in non seminomatous tumours, and in metastatic seminomas, has improved the long-term survival of these patients. Following an azoospermic period, sperm cell recovery is generally observed after treatment delivery, but little is known about the genetic consequences on these new spermatozoa. To estimate the chromosomal consequences of this chemotherapy on sperm cells during the period of recovery of spermatogenesis, sperm cell aneuploidy was studied in testicular cancer patients, at 6-18 months after PEB adjuvant chemotherapy delivery, using fluorescence in-situ hybridization (FISH) of chromosomes 7, 16, 18, X and Y with specific DNA probes. A significant increase in the frequency of diploidy and disomy for chromosomes 16, 18 and XY was observed in treated patients compared with a healthy control group. Spermatozoa aneuploidy occurring during the spermatogenesis recovery period might be a possible side effect of the PEB regimen. Thus, practitioners should be advised to provide counselling about the need for an appropriate duration of contraception. Moreover, genetic counselling should be offered in cases of pregnancy occurring soon after the end of chemotherapy.

International audience; SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.

International audience; Background: Mutations in the gene encoding mito- fusin 2 (MFN2) cause Charcot-Marie-Tooth disease type 2 (CMT2), with heterogeneity concerning severity and associated clinical features. Objective: To describe MFN2 mutations and associ- ated phenotypes in patients with hereditary motor and sensory neuropathy (HMSN). Design: Direct sequencing of the MFN2 gene and clini- cal investigations of patients with MFN2 mutations. Setting: Molecular genetics laboratory of a university hospital and the LimogesNational Referral Center for Rare Peripheral Neuropathies. Patients: One hundred fifty index patients with HMSN and amedianmotor nerve conduction velocity of 25m/s or greater and without mutations in the genes encoding connexin 32 and myelin protein zero. Main Outcome Measures: Results of genetic analy- ses and phenotypic observations. Results: Twenty different missense mutations were identified in 20 index patients. Mutation frequency was 19 of 107 (17.8%) in patients with CMT2 and 1 of 43 (2.3%) in patients with a median motor nerve conduc- tion velocity less than 38 m/s. Four patients had proven de novo mutations, 8 families had autosomal dominant inheritance, and 3 had autosomal recessive inheritance. The remaining 5 patients were sporadic cases with het- erozygous mutations. Phenotypes varied from mild forms to early-onset severe forms. Additional features were encountered in 8 patients (32%). Six patients un- derwent sural nerve biopsy: electronic microscopy showed prominent mitochondrial abnormalities on longitudinal sections. Conclusions: MFN2 mutations are a frequent cause of CMT2, with variable severity and either dominant or recessive inheritance. MFN2 gene testing must be a first-line analysis in axonal HMSN irrespective of the mode of inheritance or the severity of the peripheral neuropathy.

Thirty patients have been described with cytogenetically visible deletion of the short arm of chromosome 6. However, subtelomeric 6p deletion detected by subtelomeric specific probes has been reported only twice. We report two new patients with terminal 6p deletion detected by subtelomeric screening using fluorescence in situ hybridization (FISH). The two patients exhibited mental retardation, ocular abnormalities, hearing loss, and a characteristic facial appearance. Detailed FISH analyses with probes covering the distal 6p25 region estimated the size of the terminal deletions to approximately 5.5 Mb and approximately 4.8 Mb. Array-based comparative genomic hybridization (array CGH) was used to confirm the cryptic deletions. Most patients with subtelomeric defects lack a characteristic phenotype. However, some of the subtelomeric deletions result in a specific phenotype, which can direct the clinician towards the diagnosis. Submicroscopic 6p deletion appears to be a recognizable clinical phenotype, and this region should be thoroughly investigated with FISH probes, including at least a subtelomeric 6p probe and a probe covering FOXC1, for patients presenting with a characteristic facial appearance, ocular abnormalities, predominantly anterior-chamber eye defects, hearing loss, and mental retardation.