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Context:Premature ovarian insufficiency (POI) may be secondary to chemotherapy, radiotherapy, or environmental factors. Genetic causes are identified in 20–25% of cases, but most POI cases remain idiopathic.Objective:This study aimed to identify new genes involved in POI and to characterize the implication of CPEB1gene in POI.Design and Setting:This was a case report and cohort study replicate conducted in academic medical centers.Patients and Methods:A deletion including CPEB1gene was first identified in a patient with primary amenorrhea. Secondly, 191 sporadic POI cases and 68 familial POI cases were included. For each patient, karyotype was normal and FMR1premutation was excluded. Search for CPEB1deletions was performed by quantitative multiplex PCR of short fluorescent fragments or DNA microarray analysis. Gene sequencing of CPEB1was performed for 95 patients.Results:We identified three patients carrying a microdeletion in band 15q25.2. The proximal breakpoint, for the three patients, falls within a low-copy repeat region disrupting the CPEB1gene, which represents a strong candidate gene for POI as it is known to be implicated in oocyte meiosis. No mutation was identified by sequencing CPEB1gene. Therefore, heterozygous deletion of CPEB1gene leading to haploinsufficiency could be responsible for POI in humans.Conclusion:Microdeletions of CPEB1were identified in 1.3% of patients with POI, whereas no mutation was identified. This microdeletion is rare but recurrent as it is mediated by nonallelic homologous recombination due to the existence of low-copy repeats in the region. This result demonstrates the importance of DNA microarray analysis in etiological evaluation and counseling of patients with POI.

Familial Mediterranean fever (FMF) is an autosomal recessively inherited disease affecting patients of the Mediterranean basin. FMF is characterized by recurrent episodes of fever accompanied with topical signs of inflammation. Some patients can develop a renal amyloidosis associated (AA) amyloidosis. The administration of colchicine is an effective preventive treatment of both the attacks and amyloidosis. The FMF gene (MEFV) was cloned and missense mutations were found to be responsible for the disease. We investigated a large series of 303 unselected and unrelated patients of various ethnic backgrounds with a clinical suspicion of FMF to confirm or invalidate the diagnosis of FMF and to determine the spectrum of MEFV mutations. Molecular analysis focused on all the most frequent mutations identified so far, and an exhaustive analysis of exon 10, containing the mutational hot-spot, was performed through DNA sequencing. Sixty-two percent of Sephardic, North African Arabs, Armenian and Turkish patients were either homozygous or compound heterozygous for MEFV mutations. In other populations surrounding the Mediterranean Sea such as Greek, Italian, Portuguese, Kurdish and Lebanese populations, mutations were also found. In general, patients without Mediterranean origin had no mutations in the MEFV gene. Two new missense mutations were identified in exon 10 of the MEFV gene: the S675N in an Italian patient and the M680L in a French patient without any known at-risk ethnic ancestry. Am. J. Med. Genet. 92:241–246, 2000. © 2000 Wiley-Liss, Inc.

The diagnosis of familial Mediterranean fever (FMF) has until recently been based on clinical signs alone. Discovery of the MEFV gene has enabled a molecular approach to diagnosis, which is already well established for diagnosing typical clinical forms of FMF. We evaluated the utility of this molecular approach in a large series of patients with various clinical presentations and ethnic origins. We looked for mutations in the MEFV gene in 303 unselected consecutive patients with a variable (from high to low) clinical suspicion of FMF. Two mutations were found in 133 patients (44%). In 22 patients (7%), the clinical diagnosis of FMF was unlikely according to the Tel Hashomer clinical criteria. Our results suggest that the spectrum of FMF‐associated signs is broader than previously believed. Wider indications for genotyping should lead to more frequent diagnosis of FMF.

Abstract BackgroundHuntington's disease is a neurodegenerative disorder due to an excessive number of CAG repeats in the IT15 gene on chromosome 4. The first symptoms are typically choreic movements or psychiatric disorders, whereas global cognitive decline generally becomes obvious later. This study was aimed at detecting early subtle cognitive deficits in asymptomatic gene carriers. MethodsAs part of the testing procedure for predictive diagnosis of Huntington's disease, 91 asymptomatic at risk candidates had a neuropsychological examination, evaluating global efficiency, attention, memory (Wechsler memory scale and California verbal learning test), and executive functions. ResultsThe groups of carriers (n=42) and non-carriers (n=49) differed only on a few memory variables. When we considered the group of gene carriers as a whole, significant correlations emerged between the number of CAG repeats and (a ) performance on several tests of executive functions, and (b ) performance on the hard pairs associates of the Wechsler memory scale. Further analysis of performance on this memory subtest led to the division of the group of carriers into two subgroups, without any overlap. The performance of subjects without cognitive deficits (n=32) was similar to that of non-carriers on all tests. The subjects with cognitive deficits (n=10) differed from both carriers without cognitive deficits and non-carriers over a wide array of variables measuring executive functions and memory. Moreover, qualitative aspects of the performance of carriers with cognitive deficits in the California verbal learning test closely resembled those of patients diagnosed as having Huntington's disease. ConclusionThis suggests that these subjects already have Huntington's disease, despite a total lack of motor and psychiatric signs. An ongoing follow up study is testing the prediction that they will develop the full range of symptoms of the disease earlier than carriers without cognitive deficits.

The authors report a large series of patients with Huntington disease (HD)–like phenotype without CAG repeat expansions in the IT15gene that were screened for the newly identified CAG/CTG expansion in the gene encoding junctophilin-3. Normal alleles in controls had from 8 to 28 repeats. A single patient of North African origin with typical HD carried an allele with 50 uninterrupted repeats, representing approximately 2 of the non-IT15HD patients tested. Therefore, further genetic heterogeneity is expected in HD.

Le syndrome d’hyperstimulation ovarienne spontanée (SHSOs) est une pathologie rare et sévère survenant généralement en début de grossesse, en dehors de tout traitement de stimulation. Il se définit par la présence de gros ovaires multikystiques pouvant être associés à une extravasation vasculaire. Parmi les étiologies décrites dans la littérature, quelques mutations hétérozygotes activatrices du gène du récepteur de la FSH (FSHR) ont été décrites.

L’insuffisance ovarienne primaire (IOP) est une cause majeure d’anovulation et d’infertilité chez la femme. Cette insuffisance est le résultat d’une déplétion du stock des follicules ou d’un blocage de leur maturation. De ce fait, la stérilité est le plus souvent définitive. Une origine génétique de cette maladie est parfois retrouvée avec des mutations du chromosome X ou des autosomes, mais dans plus de 80 % des cas l’IOP est idiopathique. L’enjeu est donc d’identifier de nouveaux gènes candidats. Dans cette étude nous validons la prévalence des mutations du gène NOBOX faisant de ce facteur un des gènes clés de l’IOP. Par ailleurs, le séquençage de 2egénération multiplex par puces PGM™ ION TORRENT nous a permis de mettre en évidence dans 20 % de la cohorte étudiée des mutations de 10 gènes, dont 4 nouveaux candidats. De façon intéressante, la présence d’au moins deux gènes mutés chez 7 patientes induit une apparition plus précoce de la maladie. Cette étude contribue à une meilleure compréhension de l’origine génétique de l’IOP et met pour la première fois en lumière le phénomène d’oligogénicité chez des patientes en IOP.