Molecular epidemiology of DFNB1 deafness in France

BACKGROUND: Mutations in the GJB2 gene have been established as a major cause of inherited non syndromic deafness in different populations. A high number of sequence variations have been described in the GJB2 gene and the associated pathogenic effects are not always clearly established. The prevalence of a number of mutations is known to be population specific, and therefore population specific testing should be a prerequisite step when molecular diagnosis is offered. Moreover, population studies are needed to determine the contribution of GJB2 variants to deafness. We present our findings from the molecular diagnostic screening of the GJB2 and GJB6 genes over a three year period, together with a population-based study of GJB2 variants. METHODS AND RESULTS: Molecular studies were performed using denaturing High Performance Liquid Chromatograghy (DHPLC) and sequencing of the GJB2 gene. Over the last 3 years we have studied 159 families presenting sensorineural hearing loss, including 84 with non syndromic, stable, bilateral deafness. Thirty families were genotyped with causative mutations. In parallel, we have performed a molecular epidemiology study on more than 3000 dried blood spots and established the frequency of the GJB2 variants in our population. Finally, we have compared the prevalence of the variants in the hearing impaired population with the general population. CONCLUSION: Although a high heterogeneity of sequence variation was observed in patients and controls, the 35delG mutation remains the most common pathogenic mutation in our population. Genetic counseling is dependent on the knowledge of the pathogenicity of the mutations and remains difficult in a number of cases. By comparing the sequence variations observed in hearing impaired patients with those sequence variants observed in general population, from the same ethnic background, we show that the M34T, V37I and R127H variants can not be responsible for profound or severe deafness

Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy among patients with idiopathic and functional hypothalamic amenorrhea: a systematic review of the literature and a meta-analysis

Objective: To systematically review and appraise the existing evidence in relation to the efficacy and safety of pulsatile gonadotropin-releasing hormone (pGnRH) for the treatment of women with hypothalamic amenorrhea (HA). Design: Systematic review and meta-analysis. Setting: Not applicable. Patient(s): A total of 35 studies (three randomized and 32 observational) encompassing 1,002 women with HA. Intervention(s): None. Main Outcome Measure(s): Primary outcomes: ovulation rate (OvR), pregnancy per ovulatory cycle rate (POR), and live birth per ovulatory cycle rate (LBOR). Secondary outcomes: multiple gestation (MG), ovarian hyperstimulation syndrome (OHSS), and superficial thrombophlebitis (ST) rates. The summary measures were expressed as proportions and 95% confidence intervals (CI). Result(s): Pulsatile GnRH treatment appears to achieve high OvRs. A trend toward high PORs and LBORs among women with HA is demonstrated. SC pGnRH achieves comparable OvR compared with IV pGnRH. The incidence of OHSS is low and of mild severity. Treatment with pGnRH is associated with low but slightly higher MG rates compared with the general population. IV administered pGnRH is rarely associated with ST. Conclusion(s): The high OvRs leading to a high rate of singleton pregnancies and the low likelihood of OHSS render the pGnRH treatment modality both effective and safe for the treatment of women with HA of either primary or secondary origin. © 2017 American Society for Reproductive Medicin

Premature Ovarian Insufficiency: An Adolescent Series

Study Objective To study the presentation and causes of premature ovarian insufficiency (POI) in adolescents. Design Retrospective notes review. Setting Tertiary referral outpatient clinic for pediatric and adolescent gynecology. Participants Adolescents with POI. Interventions Standard POI evaluation. Main Outcome Measures Age and clinical symptoms at presentation, causative factors for POI, if identified. Results We identified 22 girls with POI, with a mean age of 15.6 years. Eight of them presented with delayed puberty, 3 with primary amenorrhea, and the remainder presented with either irregular bleeding (n = 9) or secondary amenorrhea (n = 2). For those who presented with delayed puberty, only 3 were found to have a sex chromosome abnormality. A clear cause for the POI was identified in 3 further cases. Conclusion Although POI in adolescents traditionally is associated with primary amenorrhea and delayed puberty, a proportion of girls will present with irregular bleeding that might be mistaken for expected menstrual disturbances of puberty, thus delaying the diagnosis. We identified a clear cause for POI in 6 cases. Although there were no familial cases of POI, it remains a possibility that genetic reasons might be involved in the pathogenesis. © 2017 North American Society for Pediatric and Adolescent Gynecolog

Genetic Polymorphisms in the UGT1A1 gene and breast cancer risk in Greek women

Uridine diphospho-glucuronosyltransferase 1 (UGT1A1) is involved in estradiol glucuronidation, which may play a central role in the etiology of breast cancer. A common insertion/ deletion polymorphism in the TATAA-box of the promoter region of UGT1A1 results in decreased initiation of transcription, and has been associated with breast cancer risk in different ethnic groups. In the present study, the role of the above genetic variation at the UGT1A1 locus in breast cancer susceptibility was investigated in a homogeneous population. Our case-control study included 136 women with breast cancer and 186 healthy female controls of Greek origin. The polymorphism A(TA) nTAA in the promoter region of UGT1A1 gene was studied using the Fragment Analysis Software of an automated DNA sequencer and three genotypes (homozygous 7/ 7, heterozygous 6/ 7, and normal homozygous 6/ 6) were identified. No significant associations were observed between the 7/ 7 genotype and breast cancer risk, indicating that further studies in Caucasian women are needed to elucidate the role of UGT1A1 polymorphism in breast cancer risk

Association of repeat polymorphisms in the estrogen receptors alpha, beta (ESR1, ESR2) and androgen receptor (AR) genes with the occurrence of breast cancer

Genetic variation in genes involved in estrogen biosynthesis, metabolism and signal transduction have been suggested to play a role in breast cancer. To determine the possible contribution of genetic variation in the ESR1 (ER-α), ESR2 (ER-β) and AR genes in breast cancer risk the -1174(TA)7-27, c. 1092+3607(CA)10-26 and c. 172(CAG)6-40 repeat variants were studied in a case-control study of 79 women with sporadic breast cancer and 155 controls. No significant difference was observed in the frequency distribution of -1174(TA)7-27 in the ESR1 gene between patients and controls, while a significant difference was observed for repeat polymorphisms c. 1092+3607(CA)10-26 in the ESR2 gene and c. 172(CAG)6-40 in the AR gene (p≤0.0001). A significantly decreased odds ratio (OR) for breast cancer risk was observed in individuals having the LL and the SL genotypes for both the ESR2 (OR=0.010, 95% CI 0.003-0.036, p<0.001; OR=0.013, 95% CI 0.004-0.040, p<0.0001, respectively) and the AR gene (OR=0.040, 95% CI 0.011-0.138, p<0.0001; OR=0.189, 95% CI 0.10-0.359, p<0.0001, respectively), compared to SS genotype. The protective effect of these genotypes remained evident even after adjustment for various risk factors (BMI, age, age at menarche and menopause, family history). In conclusion, an association for breast cancer risk between short (SS) alleles for the repeat variants of the ESR2 and AR genes was found in women of Greek descent. © 2007 Elsevier Ltd. All rights reserved

De novo interstitial duplication of the 15q11.2-q14 PWS/AS region of maternal origin: Clinical description, array CGH analysis, and review of the literature

The 15q11-q13 PWS/AS critical region involves genes that are characterized by genomic imprinting. Multiple repeat elements within the region mediate rearrangements, including interstitial duplications, interstitial triplications, and supernumerary isodicentric marker chromosomes, as well as the deletions that cause Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Recently, duplications of maternal origin concerning the same critical region have been implicated in autism spectrum disorders (ASD). We present a 6-month-old girl carrying a de novo duplication of maternal origin of the 15q11.2-q14 PWS/AS region (17.73Mb in size) [46,XX,dup(15)(q11.2-q14)] detected with a high-resolution microarray-based comparative genomic hybridization (array-CGH). The patient is characterized by severe hypotonia, obesity, microstomia, long eyelashes, hirsutism, microretrognathia, short nose, severe psychomotor retardation, and multiple episodes of drug-resistant epileptic seizures, while her brain magnetic resonance imaging (MRI) documented partial corpus callosum dysplasia. In our patient the duplicated region is quite large extending beyond the Prader-Willi-Angelman critical region (PWACR), containing a number of genes that have been shown to be involved in ASD, exhibiting a severe phenotype, beyond the typical PWS/AS clinical manifestations. Reporting of similar well-characterized clinical cases with clearly delineated breakpoints of the duplicated region will clarify the contribution of specific genes to the phenotype. © 2010 Wiley-Liss, Inc

Mutation screening in the Greek population and evaluation of NLGN3 and NLGN4X genes causal factors for autism

Molecular and neurobiological evidence for the involvement of neuroligins (particularly NLGN3 and NLGN4X genes) in autistic disorder is accumulating. However, previous mutation screening studies on these two genes have yielded controversial results. The present study explores, for the first time, the contribution of NLGN3 and NLGN4X genetic variants in Greek patients with autistic disorder. We analyzed the full exonic sequence of NLGN3 and NLGN4X genes in 40 patients strictly fulfilling the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. criteria for autistic disorder. We identified nine nucleotide changes in NLGN4X - one probable causative mutation (p.K378R) previously reported by our research group, one novel variant (c.-206G>C), one nonvalidated single nucleotide polymorphism (SNP, rs111953947), and six known human SNPs reported in the SNP database - and one known human SNP in NLGN3 also reported in the SNP database. The variants identified are expected to be benign. However, they should be investigated in the context of variants in interacting cellular pathways to assess their contribution to the etiology of autism. © 2013 Wolters Kluwer Health | Lippincott Williams and Wilkins

Recurrent copy number variations as risk factors for autism spectrum disorders: Analysis of the clinical implications

Chromosomal microarray analysis (CMA) is currently considered a first-tier diagnostic assay for the investigation of autism spectrum disorders (ASD), developmental delay and intellectual disability of unknown etiology. High-resolution arrays were utilized for the identification of copy number variations (CNVs) in 195 ASD patients of Greek origin (126 males, 69 females). CMA resulted in the detection of 65 CNVs, excluding the known polymorphic copy number polymorphisms also found in the Database of Genomic Variants, for 51/195 patients (26.1%). Parental DNA testing in 20/51 patients revealed that 17 CNVs were de novo, 6 paternal and 3 of maternal origin. The majority of the 65 CNVs were deletions (66.1%), of which 5 on the X-chromosome while the duplications, of which 7 on the X-chromosome, were rarer (22/65, 33.8%). Fifty-one CNVs from a total of 65, reported for our cohort of ASD patients, were of diagnostic significance and well described in the literature while 14 CNVs (8 losses, 6 gains) were characterized as variants of unknown significance and need further investigation. Among the 51 patients, 39 carried one CNV, 10 carried two CNVs and 2 carried three CNVs. The use of CMA, its clinical validity and utility was assessed. © 2016 John Wiley & Sons A/S