Publications by authors named "Catherine Blanchet"

28 Publications

  • Page 1 of 1

Pregnancy in MNGIE: a clinical and metabolic honeymoon.

Ann Clin Transl Neurol 2020 12 7;7(12):2484-2488. Epub 2020 Nov 7.

Département de Neuropédiatrie, CHU Gui de Chauliac, Montpellier, France.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an inherited disease caused by a deficiency in thymidine phosphorylase and characterized by elevated systemic deoxyribonucleotides and gastrointestinal (GI) and neurological manifestations. We report the clinical and biochemical manifestations that were evaluated in a single patient before, during, and after pregnancy, over a period of 7 years. GI symptoms significantly improved, and plasma deoxyribonucleotide concentrations decreased during pregnancy. Within days after delivery, the patient's digestive symptoms recurred, coinciding with a rapid increase in plasma deoxyribonucleotide concentrations. We hypothesize that the clinico-metabolic improvements could be attributed to the enzyme replacement action of the placental thymidine phosphorylase.
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http://dx.doi.org/10.1002/acn3.51202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732247PMC
December 2020

KMT2B-related disorders: expansion of the phenotypic spectrum and long-term efficacy of deep brain stimulation.

Brain 2020 12;143(11):3242-3261

Département de Génétique médicale, Maladies rares et médecine personnalisée, CHU Montpellier, Montpellier, France.

Heterozygous mutations in KMT2B are associated with an early-onset, progressive and often complex dystonia (DYT28). Key characteristics of typical disease include focal motor features at disease presentation, evolving through a caudocranial pattern into generalized dystonia, with prominent oromandibular, laryngeal and cervical involvement. Although KMT2B-related disease is emerging as one of the most common causes of early-onset genetic dystonia, much remains to be understood about the full spectrum of the disease. We describe a cohort of 53 patients with KMT2B mutations, with detailed delineation of their clinical phenotype and molecular genetic features. We report new disease presentations, including atypical patterns of dystonia evolution and a subgroup of patients with a non-dystonic neurodevelopmental phenotype. In addition to the previously reported systemic features, our study has identified co-morbidities, including the risk of status dystonicus, intrauterine growth retardation, and endocrinopathies. Analysis of this study cohort (n = 53) in tandem with published cases (n = 80) revealed that patients with chromosomal deletions and protein truncating variants had a significantly higher burden of systemic disease (with earlier onset of dystonia) than those with missense variants. Eighteen individuals had detailed longitudinal data available after insertion of deep brain stimulation for medically refractory dystonia. Median age at deep brain stimulation was 11.5 years (range: 4.5-37.0 years). Follow-up after deep brain stimulation ranged from 0.25 to 22 years. Significant improvement of motor function and disability (as assessed by the Burke Fahn Marsden's Dystonia Rating Scales, BFMDRS-M and BFMDRS-D) was evident at 6 months, 1 year and last follow-up (motor, P = 0.001, P = 0.004, and P = 0.012; disability, P = 0.009, P = 0.002 and P = 0.012). At 1 year post-deep brain stimulation, >50% of subjects showed BFMDRS-M and BFMDRS-D improvements of >30%. In the long-term deep brain stimulation cohort (deep brain stimulation inserted for >5 years, n = 8), improvement of >30% was maintained in 5/8 and 3/8 subjects for the BFMDRS-M and BFMDRS-D, respectively. The greatest BFMDRS-M improvements were observed for trunk (53.2%) and cervical (50.5%) dystonia, with less clinical impact on laryngeal dystonia. Improvements in gait dystonia decreased from 20.9% at 1 year to 16.2% at last assessment; no patient maintained a fully independent gait. Reduction of BFMDRS-D was maintained for swallowing (52.9%). Five patients developed mild parkinsonism following deep brain stimulation. KMT2B-related disease comprises an expanding continuum from infancy to adulthood, with early evidence of genotype-phenotype correlations. Except for laryngeal dysphonia, deep brain stimulation provides a significant improvement in quality of life and function with sustained clinical benefit depending on symptoms distribution.
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http://dx.doi.org/10.1093/brain/awaa304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719027PMC
December 2020

Hemangiol in infantile haemangioma: A paediatric post-marketing surveillance drug study.

Br J Clin Pharmacol 2021 Apr 16;87(4):1970-1980. Epub 2020 Nov 16.

Department of Paediatric and Congenital Cardiology, M3C Regional Reference Centre, Clinical Investigation Centre, Montpellier University Hospital, Montpellier, France.

Aim: Infantile haemangioma (IH) is the most common benign tumour in children. Since 2014, propranolol has become the first-choice therapy and currently Hemangiol is the only approved drug for complicated haemangioma. This post-marketing study reports the use of Hemangiol for IH in paediatric practice.

Method And Results: From January 2014 to November 2018, 94 children (median age 4 [0; 21] months; 75% female) treated with Hemangiol for proliferative IH were enrolled in the study. The systematic paediatric cardiology consultation never contraindicated beta-blockers. Two Hemangiol initiation protocols were used: a conventional ambulatory 3-week titration phase protocol (n = 76, 80.9%), and a rapid initiation protocol with a 48-hour dose escalation in conventional hospitalization for severe proliferative or ulcerated IH (n = 18, 19.1%). In both protocols, the haemodynamic tolerance was good. The mean maintenance dose of Hemangiol was 2.7 ± 0.8 mg/kg/day, with a median treatment duration of 7 [1.5; 19] months. Adverse events (AEs) have been found in 25 (26,6%) patients, including 8 (8.5%) patients with serious AEs (uncontrolled bronchial hyperreactivity, n = 5; serious hypoglycaemia, n = 3). Some patients had one or more AEs, a total of 24 nonserious AEs was reported in 19 patients (sleep disturbances, n = 9; respiratory disorders, n = 5; digestive disorders, n = 6). No cardiac adverse event was reported.

Conclusion: This post-marketing surveillance drug study supports the good tolerance of Hemangiol in children with IH. A rapid initiation protocol is of interest when treatment is urgent. The pretherapeutic paediatric cardiology consultation should not be systematic but only indicated for specific patients. CLINICALTRIALS.GOV: NCT04105517.
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http://dx.doi.org/10.1111/bcp.14593DOI Listing
April 2021

A 4.6 Mb Inversion Leading to - and - Fusion Transcripts as a New Pathogenic Mechanism Implicated in Usher Syndrome Type 1.

Front Genet 2020 2;11:623. Epub 2020 Jul 2.

Laboratoire de Génétique Moléculaire, CHU de Montpellier, Université de Montpellier, Montpellier, France.

Usher type 1 syndrome is a rare autosomal recessive disorder involving congenital severe-to-profound hearing loss, development of vision impairment in the first decade, and severe balance difficulties. The gene, one of the five genes implicated in this disease, is involved in 8-20% of cases. In this study, we aimed to identify and characterize the two causal variants in a French patient with typical Usher syndrome clinical features. Massively parallel sequencing-based gene panel and screening for large rearrangements were used, which detected a single multi-exon deletion in the gene. As the second pathogenic event was likely localized in the unscreened regions of the gene, transcripts from cultured nasal cells were analyzed and revealed a loss of junction between exon 13 and exon 14. This aberration could be explained by the identification of two fusion transcripts, - and -, originating from a 4.6 Mb inversion. This complex chromosomal rearrangement could not be detected by our diagnostic approach but was instead characterized by long-read sequencing, which offers the possibility of detecting balanced structural variants (SVs). This finding extends our knowledge of the mutational spectrum of the gene with the first ever identification of a large causal paracentric inversion of chromosome 10 and illustrates the utility of screening balanced SVs in an exhaustive molecular diagnostic approach.
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http://dx.doi.org/10.3389/fgene.2020.00623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343966PMC
July 2020

SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect.

Brain 2020 08;143(8):2380-2387

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA.

The SLC12 gene family consists of SLC12A1-SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16-18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16-18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment.
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http://dx.doi.org/10.1093/brain/awaa176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447514PMC
August 2020

POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4.

Genet Med 2020 03 24;22(3):547-556. Epub 2019 Oct 24.

Service de Génétique Clinique, centre de référence anomalies du développement et syndromes malformatifs, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, Faculté de Médecine, Montpellier, France.

Purpose: Treacher Collins syndrome (TCS) is a rare autosomal dominant mandibulofacial dysostosis, with a prevalence of 0.2-1/10,000. Features include bilateral and symmetrical malar and mandibular hypoplasia and facial abnormalities due to abnormal neural crest cell (NCC) migration and differentiation. To date, three genes have been identified: TCOF1, POLR1C, and POLR1D. Despite a large number of patients with a molecular diagnosis, some remain without a known genetic anomaly.

Methods: We performed exome sequencing for four individuals with TCS but who were negative for pathogenic variants in the known causative genes. The effect of the pathogenic variants was investigated in zebrafish.

Results: We identified three novel pathogenic variants in POLR1B. Knockdown of polr1b in zebrafish induced an abnormal craniofacial phenotype mimicking TCS that was associated with altered ribosomal gene expression, massive p53-associated cellular apoptosis in the neuroepithelium, and reduced number of NCC derivatives.

Conclusion: Pathogenic variants in the RNA polymerase I subunit POLR1B might induce massive p53-dependent apoptosis in a restricted neuroepithelium area, altering NCC migration and causing cranioskeletal malformations. We identify POLR1B as a new causative gene responsible for a novel TCS syndrome (TCS4) and establish a novel experimental model in zebrafish to study POLR1B-related TCS.
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http://dx.doi.org/10.1038/s41436-019-0669-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056642PMC
March 2020

Mutations in PLS1, encoding fimbrin, cause autosomal dominant nonsyndromic hearing loss.

Hum Mutat 2019 12 1;40(12):2286-2295. Epub 2019 Oct 1.

Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.

Nonsyndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e., approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next-generation sequencing to identify causal variants in PLS1 (c.805G>A, p.[E269K]; c.713G>T, p.[L238R], and c.383T>C, p.[F128S]) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin-bundling proteins of the stereocilia. In silico protein modeling suggests that all variants destabilize the structure of the actin-binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1 mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice.
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http://dx.doi.org/10.1002/humu.23891DOI Listing
December 2019

WFS1 in Optic Neuropathies: Mutation Findings in Nonsyndromic Optic Atrophy and Assessment of Clinical Severity.

Ophthalmology 2016 09 7;123(9):1989-98. Epub 2016 Jul 7.

Maladies Sensorielles Génétiques, CHRU, Montpellier, France; INSERM U1051, Institute for Neurosciences of Montpellier, Montpellier, France; Université Montpellier, Montpellier, France. Electronic address:

Purpose: To search for WFS1 mutations in patients with optic atrophy (OA) and assess visual impairment.

Design: Retrospective molecular genetic and clinical study.

Participants: Patients with OA followed at a national referral center specialized in genetic sensory diseases.

Methods: Mutation screening in WFS1 was performed by Sanger sequencing. WFS1-positive patients were evaluated on visual acuity (VA) and retinal nerve fiber layer (RNFL) thickness using time-domain (TD) or spectral-domain (SD) optical coherence tomography (OCT). Statistical analysis was performed.

Main Outcome Measures: Mutation identification, VA values, and RNFL thickness in sectors.

Results: Biallelic WFS1 mutations were found in 3 of 24 unrelated patients (15%) with autosomal recessive nonsyndromic optic atrophy (arNSOA) and in 8 patients with autosomal recessive Wolfram syndrome (arWS) associated with diabetes mellitus and OA. Heterozygous mutations were found in 4 of 20 unrelated patients (20%) with autosomal dominant OA. The 4 WFS1-mutated patients of this latter group with hearing loss were diagnosed with autosomal dominant Wolfram-like syndrome (adWLS). Most patients had VA decrease, with logarithm of the minimum angle of resolution (logMAR) values lower in arWS than in arNSOA (1.530 vs. 0.440; P = 0.026) or adWLS (0.240; P = 0.006) but not differing between arNSOA and adWLS (P = 0.879). All patients had decreased RNFL thickness that was worse in arWS than in arNSOA (SD OCT, 35.50 vs. 53.80 μm; P = 0.018) or adWLS (TD-OCT, 45.84 vs. 59.33 μm; P = 0.049). The greatest difference was found in the inferior bundle. Visual acuity was negatively correlated with RNFL thickness (r = -0.89; P = 0.003 in SD OCT and r = -0.75; P = 0.01 in TD-OCT).

Conclusions: WFS1 is a gene causing arNSOA. Patients with this condition had significantly less visual impairment than those with arWS. Thus systematic screening of WFS1 must be performed in isolated, sporadic, or familial optic atrophies.
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http://dx.doi.org/10.1016/j.ophtha.2016.05.036DOI Listing
September 2016

Whole USH2A Gene Sequencing Identifies Several New Deep Intronic Mutations.

Hum Mutat 2016 Feb 23;37(2):184-93. Epub 2015 Nov 23.

Laboratoire de Génétique de Maladies Rares EA 7402, Université de Montpellier, Montpellier, France.

Deep intronic mutations leading to pseudoexon (PE) insertions are underestimated and most of these splicing alterations have been identified by transcript analysis, for instance, the first deep intronic mutation in USH2A, the gene most frequently involved in Usher syndrome type II (USH2). Unfortunately, analyzing USH2A transcripts is challenging and for 1.8%-19% of USH2 individuals carrying a single USH2A recessive mutation, a second mutation is yet to be identified. We have developed and validated a DNA next-generation sequencing approach to identify deep intronic variants in USH2A and evaluated their consequences on splicing. Three distinct novel deep intronic mutations have been identified. All were predicted to affect splicing and resulted in the insertion of PEs, as shown by minigene assays. We present a new and attractive strategy to identify deep intronic mutations, when RNA analyses are not possible. Moreover, the bioinformatics pipeline developed is independent of the gene size, implying the possible application of this approach to any disease-linked gene. Finally, an antisense morpholino oligonucleotide tested in vitro for its ability to restore splicing caused by the c.9959-4159A>G mutation provided high inhibition rates, which are indicative of its potential for molecular therapy.
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http://dx.doi.org/10.1002/humu.22926DOI Listing
February 2016

Neonatal respiratory distress syndrome revealing a cervical bronchogenic cyst: a case report.

BMC Pediatr 2015 Jun 27;15:72. Epub 2015 Jun 27.

Department of Neonatology and Pediatric Intensive Care Unit, Hôpital Arnaud de Villeneuve, 371 Avenue du Doyen Gaston Giraud, 34295, Montpellier Cedex 5, France.

Background: Bronchogenic cyst is a congenital malformation, rarely located in the cervical region and almost never involved in a neonate with acute respiratory distress in the delivery room.

Case Presentation: A female newborn with respiratory distress syndrome caused by a large left cervical mass. Intubation was difficult due to tracheal deviation. Magnetic resonance imaging confirmed a left cervical cyst displacing the trachea and esophagus laterally. Surgical excision was performed via a cervical approach on the 5th day, and pathological examination revealed a bronchogenic cyst. The patient's course was complicated by left vocal cord paralysis and necrotic lesions in the glottic and subglottic regions; she required a tracheostomy on the 13th day. Inflammatory stenosis in the subglottic region required balloon dilation once, 20 days later. Proximal esophageal stenosis induced transient upper airway obstruction with salivary stasis. Decannulation was performed at 2 months and the patient was discharged 10 days later.

Conclusion: A bronchogenic cyst can exceptionally obstruct the airways in the neonatal period. Surgical excision is necessary, but postoperative complications may occur if the cyst is in close contact with the trachea and esophagus, including necrotic and stenotic lesions of the upper aerodigestive tract. In those situations, tracheostomy may be necessary for mechanical ventilation weaning and the initiation of oral feeding.
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http://dx.doi.org/10.1186/s12887-015-0363-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491209PMC
June 2015

Treacher Collins syndrome: a clinical and molecular study based on a large series of patients.

Genet Med 2016 Jan 19;18(1):49-56. Epub 2015 Mar 19.

Service de Génétique Médicale, CHU Strasbourg, Strasbourg, France.

Purpose: Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C.

Methods: We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene.

Results: We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encompassing TCOF1 and CAMK2A in particular. Congenital cardiac defects occurred more frequently among patients with TCOF1 mutation (7/92, 8%) than reported in the literature.

Conclusion: Even though TCOF1 and POLR1D were associated with extreme clinical variability, we found no phenotype-genotype correlation. In cases with a typical phenotype of TCS, 6/146 (4%) remained with an unidentified molecular defect.
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http://dx.doi.org/10.1038/gim.2015.29DOI Listing
January 2016

Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction.

J Neurol Sci 2015 Feb 13;349(1-2):154-60. Epub 2015 Jan 13.

INSERM, U-1051, Institut des Neurosciences, Montpellier, France; CHU Montpellier, Centre of Reference for Genetic Sensory Diseases, Montpellier, France.

Objective: OPA1 mutations are responsible for more than half of autosomal dominant optic atrophy (ADOA), a blinding disease affecting the retinal ganglion neurons. In most patients the clinical presentation is restricted to the optic nerve degeneration, albeit in 20% of them, additional neuro-sensorial symptoms might be associated to the loss of vision, as frequently encountered in mitochondrial diseases. This study describes clinical and neuroradiological features of OPA1 patients.

Methods: Twenty two patients from 17 families with decreased visual acuity related to optic atrophy and carrying an OPA1 mutation were enrolled. Patients underwent neuro-ophthalmological examinations. Brain magnetic resonance imaging (T1, T2 and flair sequences) was performed on a 1.5-Tesla MR Unit. Twenty patients underwent 2-D proton spectroscopic imaging.

Results: Brain imaging disclosed abnormalities in 12 patients. Cerebellar atrophy mainly involving the vermis was observed in almost a quarter of the patients; other abnormalities included unspecific white matter hypersignal, hemispheric cortical atrophy, and lactate peak. Neurological examination disclosed one patient with a transient right hand motor deficit and ENT examination revealed hearing impairment in 6 patients. Patients with abnormal MRI were characterized by: (i) an older age (ii) more severe visual impairment with chronic visual acuity deterioration, and (iii) more frequent associated deafness.

Conclusions: Our results demonstrate that brain imaging abnormalities are common in OPA1 patients, even in those with normal neurological examination. Lactate peak, cerebellar and cortical atrophies are consistent with the mitochondrial dysfunction related to OPA1 mutations and might result from widespread neuronal degeneration.
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http://dx.doi.org/10.1016/j.jns.2015.01.008DOI Listing
February 2015

Refining the audiological assessment in children using narrow-band CE-Chirp-evoked auditory steady state responses.

Int J Audiol 2015 Feb 18;54(2):106-13. Epub 2014 Jul 18.

* ENT Department and University Montpellier 1, University Hospital Gui de Chauliac , Montpellier , France.

Objective: To demonstrate the feasibility and reliability of simultaneous binaural recording of auditory steady-state responses (ASSR) in young children using narrow-band CE-Chirps as stimuli.

Design: Prospective cohort study comparing ASSR thresholds to four frequency stimuli (0.5, 1, 2, and 4 kHz), with click-evoked auditory brainstem responses (ABR) and behavioral response audiometry.

Study Sample: Thirty-two young children (mean age 7.4 ± 5.2 months) referred for auditory assessment were evaluated.

Results: The mean duration for ABR recordings was 13.3 ± 7.2 min versus 22.9 ± 15.8 min for ASSR (p < 0.01). ASSR (means of 2 and 4 kHz thresholds) were highly correlated with ABR thresholds (R2 = 0.935, p < 0.001), though significantly different (3 ± 10.7 dB, p = 0.02). ASSR (means of 0.5, 1, 2, and 4 kHz thresholds) were highly correlated with mean behavioral response audiometry thresholds (R2 = 0.968, p < 0.001). ASSRs were highly and significantly correlated with behavioral response audiometry at 0.5, 1, 2, and 4 kHz (R2 = 0.845, 0.907, 0.929, and 0.859 respectively, p < 0.001). 87.5% and 90.7% ASSR thresholds were within a ± 10 dB range around their corresponding ABR and mean behavioral response audiometry thresholds.

Conclusions: Narrow-band CE-Chirps allow a fast and reliable assessment of auditory thresholds in children, especially in the low-frequency range, by comparison with other stimuli.
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http://dx.doi.org/10.3109/14992027.2014.935496DOI Listing
February 2015

Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.

Hum Mutat 2014 Oct 15;35(10):1179-86. Epub 2014 Jul 15.

CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, F-34000, France.

Alterations of USH2A, encoding usherin, are responsible for more than 70% of cases of Usher syndrome type II (USH2), a recessive disorder that combines moderate to severe hearing loss and retinal degeneration. The longest USH2A transcript encodes usherin isoform b, a 5,202-amino-acid transmembrane protein with an exceptionally large extracellular domain consisting notably of a Laminin N-terminal domain and numerous Laminin EGF-like (LE) and Fibronectin type III (FN3) repeats. Mutations of USH2A are scattered throughout the gene and mostly private. Annotating these variants is therefore of major importance to correctly assign pathogenicity. We have extensively genotyped a novel cohort of 152 Usher patients and identified 158 different mutations, of which 93 are newly described. Pooling this new data with the existing pathogenic variants already incorporated in USHbases reveals several previously unappreciated features of the mutational spectrum. We show that parts of the protein are more likely to tolerate single amino acid variations, whereas others constitute pathogenic missense hotspots. We have found, in repeated LE and FN3 domains, a nonequal distribution of the missense mutations that highlights some crucial positions in usherin with possible consequences for the assessment of the pathogenicity of the numerous missense variants identified in USH2A.
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http://dx.doi.org/10.1002/humu.22608DOI Listing
October 2014

Large deletions encompassing the TCOF1 and CAMK2A genes are responsible for Treacher Collins syndrome with intellectual disability.

Eur J Hum Genet 2014 Jan 22;22(1):52-6. Epub 2013 May 22.

Département de Génétique Médicale, CHRU Montpellier, Faculté de Médecine de Montpellier-Mimes, Université Montpellier 1, Montpellier, France.

Mandibulofacial dysostosis is part of a clinically and genetically heterogeneous group of disorders of craniofacial development, which lead to malar and mandibular hypoplasia. Treacher Collins syndrome is the major cause of mandibulofacial dysostosis and is due to mutations in the TCOF1 gene. Usually patients with Treacher Collins syndrome do not present with intellectual disability. Recently, the EFTUD2 gene was identified in patients with mandibulofacial dysostosis associated with microcephaly, intellectual disability and esophageal atresia. We report on two patients presenting with mandibulofacial dysostosis characteristic of Treacher Collins syndrome, but associated with unexpected intellectual disability, due to a large deletion encompassing several genes including the TCOF1 gene. We discuss the involvement of the other deleted genes such as CAMK2A or SLC6A7 in the cognitive development delay of the patients reported, and we propose the systematic investigation for 5q32 deletion when intellectual disability is associated with Treacher Collins syndrome.
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http://dx.doi.org/10.1038/ejhg.2013.98DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865420PMC
January 2014

Relative frequencies of inherited retinal dystrophies and optic neuropathies in Southern France: assessment of 21-year data management.

Ophthalmic Epidemiol 2013 ;20(1):13-25

CHRU Montpellier, Genetics of Sensory Diseases, Montpellier, France.

Purpose: Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are rare diseases defined by specific clinical and molecular features. The relative prevalence of these conditions was determined in Southern France.

Methods: Patients recruited from a specialized outpatient clinic over a 21-year period underwent extensive clinical investigations and 107 genes were screened by polymerase chain reaction/sequencing.

Results: There were 1957 IRD cases (1481 families) distributed in 70% of pigmentary retinopathy cases (56% non-syndromic, 14% syndromic), 20% maculopathies and 7% stationary conditions. Patients with retinitis pigmentosa were the most frequent (47%) followed by Usher syndrome (10.8%). Among non-syndromic pigmentary retinopathy patients, 84% had rod-cone dystrophy, 8% cone-rod dystrophy and 5% Leber congenital amaurosis. Macular dystrophies were encountered in 398 cases (30% had Stargardt disease and 11% had Best disease). There were 184 ION cases (127 families) distributed in 51% with dominant optic neuropathies, 33% with recessive/sporadic forms and 16% with Leber hereditary optic neuropathy. Positive molecular results were obtained in 417/609 families with IRDs (68.5%) and in 27/58 with IONs (46.5%). The sequencing of 5 genes (ABCA4, USH2A, MYO7A, RPGR and PRPH2) provided a positive molecular result in 48% of 417 families with IRDs. Except for autosomal retinitis pigmentosa, in which less than half the families had positive molecular results, about 75% of families with other forms of retinal conditions had a positive molecular diagnosis.

Conclusions: Although gene discovery considerably improved molecular diagnosis in many subgroups of IRDs and IONs, retinitis pigmentosa, accounting for almost half of IRDs, remains only partly molecularly defined.
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http://dx.doi.org/10.3109/09286586.2012.737890DOI Listing
May 2013

Variability in nitrogen content of submerged aquatic vegetation: utility as an indicator of N dynamics within and among lakes.

Water Sci Technol 2012 ;65(7):1151-7

Département de Sciences biologiques, Université de Montréal, Montréal, QC, Canada.

Submerged aquatic vegetation (SAV) may serve as an integrative proxy of spatial and temporal nitrogen (N) availability in aquatic ecosystems as plants are physiologically capable of storing variable amounts of N. However, it is important to understand whether plant species behave similarly or differently within and among systems. We sampled different SAV species along a nutrient gradient at multiple sites within several lakes to determine variability in C:N ratios and % N content among species, among plants of the same species at a single site, among sites and among lakes. Species respond differently suggesting that not all plant types can be used universally as nutrient proxies. The greatest variability in % N and C:N ratios for Valliseneria americana was observed among lakes whereas for Elodea canadensis it was among sites within a lake and among plants within a site. This suggests that V. americana could be a particularly useful indicator of N availability at larger spatial scales (regional and within a large fluvial lake) but that E. canadensis was not a particularly useful proxy.
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http://dx.doi.org/10.2166/wst.2012.065DOI Listing
June 2012

Non-USH2A mutations in USH2 patients.

Hum Mutat 2012 Mar 6;33(3):504-10. Epub 2012 Jan 6.

CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France.

We have systematically analyzed the two known minor genes involved in Usher syndrome type 2, DFNB31 and GPR98, for mutations in a cohort of 31 patients not linked to USH2A. PDZD7, an Usher syndrome type 2 (USH2) related gene, was analyzed when indicated. We found that mutations in GPR98 contribute significantly to USH2. We report 17 mutations in 10 individuals, doubling the number of GPR98 mutations reported to date. In contrast to mutations in usherin, the mutational spectrum of GPR98 predominantly results in a truncated protein product. This is true even when the mutation affects splicing, and we have incorporated a splicing reporter minigene assay to show this, where appropriate. Only two mutations were found which we believe to be genuine missense changes. Discrepancy in the mutational spectrum between GPR98 and USH2A is discussed. Only two patients were found with mutations in DFNB31, showing that mutations of this gene contribute to only a very small extent to USH2. Close examination of the clinical details, where available, for patients in whom no mutation was found in USH2A, GPR98, or DFNB31, showed that most of them had atypical features. In effect, these three genes account for the vast majority of USH2 patients and their analysis provide a robust pathway for routine molecular diagnosis.
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http://dx.doi.org/10.1002/humu.22004DOI Listing
March 2012

Usher syndrome type 2 caused by activation of an USH2A pseudoexon: implications for diagnosis and therapy.

Hum Mutat 2012 Jan 16;33(1):104-8. Epub 2011 Nov 16.

CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France.

USH2A sequencing in three affected members of a large family, referred for the recessive USH2 syndrome, identified a single pathogenic alteration in one of them and a different mutation in the two affected nieces. As the patients carried a common USH2A haplotype, they likely shared a mutation not found by standard sequencing techniques. Analysis of RNA from nasal cells in one affected individual identified an additional pseudoexon (PE) resulting from a deep intronic mutation. This was confirmed by minigene assay. This is the first example in Usher syndrome (USH) with a mutation causing activation of a PE. The finding of this alteration in eight other individuals of mixed European origin emphasizes the importance of including RNA analysis in a comprehensive diagnostic service. Finally, this mutation, which would not have been found by whole-exome sequencing, could offer, for the first time in USH, the possibility of therapeutic correction by antisense oligonucleotides (AONs).
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http://dx.doi.org/10.1002/humu.21634DOI Listing
January 2012

Cataract as a phenotypic marker for a mutation in WFS1, the Wolfram syndrome gene.

Eur J Ophthalmol 2012 Mar-Apr;22(2):254-8

CHRU Montpellier, Centre de Référence Genetic Sensory Diseases, Montpellier, France.

Purpose: Wolfram syndrome (WS) or diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD) (OMIM 222300) is an inherited neurodegenerative disease characterized by diabetes mellitus and optic atrophy as the 2 major criteria, followed later in life by deafness, diabetes insipidus, and various signs of neurologic impairment. The presence of a cataract has been variably mentioned in WS.

Method: Two members of a family had thorough ophthalmic examination and their DNA was screened for mutations in mitochondrial DNA, WFS1, OPA1, and OPA3 genes.

Results: We report a patient who first had surgery for bilateral cataract at age 5 and who subsequently presented typical signs of WS, i.e., diabetes mellitus, optic atrophy with reduced visual acuity at 20/400 on both eyes at age 22, and mild deafness. The patient was found to be a compound heterozygote for 2 truncating mutations in WFS1, the major WS gene. She carried the previously reported c.1231_1233 delCT and a novel c.2431_2465dup35 mutation. She also was heterozygote for a novel OPA1 sequence variant, c.929A>G in exon 9, whose pathogenicity remains uncertain. The patient's mother was a heterozygous carrier of the c.2431_2465dup35 mutation. She did not have diabetes mellitus or optic atrophy but had bilateral polar cataract. She did not carry the OPA1 sequence variant.

Conclusions: Cataract could be a marker for the WFS1 heterozygosity in this family, namely the c.2431_2465dup35 mutation.
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http://dx.doi.org/10.5301/EJO.2011.8370DOI Listing
August 2012

Four-year follow-up of diagnostic service in USH1 patients.

Invest Ophthalmol Vis Sci 2011 Jun 8;52(7):4063-71. Epub 2011 Jun 8.

Laboratoire de Génétique Moléculaire, Montpellier, France.

Purpose: The purpose of this study was to establish the mutation spectrum of an Usher type I cohort of 61 patients from France and to describe a diagnostic strategy, including a strategy for estimating the pathogenicity of sequence changes.

Methods: To optimize the identification of Usher (USH)-causative mutations, taking into account the genetic heterogeneity, preliminary haplotyping at the five USH1 loci was performed to prioritize the gene to be sequenced, as previously described. Coding exons and flanking intronic sequences were sequenced and, where necessary, semiquantitative PCR and multiplex ligation-dependent probe amplification (MLPA) were performed to detect large genomic rearrangements.

Results: Four years ' experience confirms that the chosen approach provides an efficient diagnostic service. Sixty-one patients showed an abnormal genotype in one of the five USH1 genes. Genetic heterogeneity was confirmed, and, although MYO7A remains the major gene, involvement of other genes is considerable. Distribution of missense, splicing, premature termination codons (PTCs; due to point substitution and small deletions/ or insertions), and large genomic alterations was determined among the USH genes and clearly highlights the need to pay special attention to the diagnostic approach and interpretation, depending on the mutated gene.

Conclusions: Over the 4 years of a diagnostic service offering USH1 patient testing, pathogenic genotypes were identified in most cases (>90%). The complexity and heterogeneity of mutations reinforces the need for a comprehensive approach. Because 32% of the mutations are newly described, the results show that a screening strategy based on known mutations would have solved less than 55% of the cases.
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http://dx.doi.org/10.1167/iovs.10-6869DOI Listing
June 2011

Dominant TNF-α+ Mycobacterium tuberculosis-specific CD4+ T cell responses discriminate between latent infection and active disease.

Nat Med 2011 Mar 20;17(3):372-6. Epub 2011 Feb 20.

Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.

Rapid diagnosis of active Mycobacterium tuberculosis (Mtb) infection remains a clinical and laboratory challenge. We have analyzed the cytokine profile (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2)) of Mtb-specific T cells by polychromatic flow cytometry. We studied Mtb-specific CD4+ T cell responses in subjects with latent Mtb infection and active tuberculosis disease. The results showed substantial increase in the proportion of single-positive TNF-α Mtb-specific CD4+ T cells in subjects with active disease, and this parameter was the strongest predictor of diagnosis of active disease versus latent infection. We validated the use of this parameter in a cohort of 101 subjects with tuberculosis diagnosis unknown to the investigator. The sensitivity and specificity of the flow cytometry-based assay were 67% and 92%, respectively, the positive predictive value was 80% and the negative predictive value was 92.4%. Therefore, the proportion of single-positive TNF-α Mtb-specific CD4+ T cells is a new tool for the rapid diagnosis of active tuberculosis disease.
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http://dx.doi.org/10.1038/nm.2299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6570988PMC
March 2011

Management of infantile subglottic hemangioma: acebutolol or propranolol?

Int J Pediatr Otorhinolaryngol 2010 Aug 16;74(8):959-61. Epub 2010 Jun 16.

ENT Department, CHU Montpellier, France.

The successful management of subglottic hemangioma with propranolol has been reported. We report three cases of subglottic hemangioma treated with the cardioselective beta-blocker acebutolol, 8 mg/kg/day. Treatment was efficient in two cases while an open procedure was necessary in the third child. In our experience, acebutolol could be easily administered in oral form twice-a-day only with a dose that was adaptable according to the growth of the child and showed no side effects. We also report a case of rebound growth after beta-mimetic drug use and the efficiency of propranolol treatment in such a recurrence. Considering the lack of side effects and the advantages in terms of administration, we suggest acebutolol as a first-line treatment of subglottic hemangiomas for which intervention is required.
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http://dx.doi.org/10.1016/j.ijporl.2010.05.013DOI Listing
August 2010

Nasal epithelial cells are a reliable source to study splicing variants in Usher syndrome.

Hum Mutat 2010 Jun;31(6):734-41

CHU Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France.

We have shown that nasal ciliated epithelium, which can be easily biopsied under local anesthetic, provides a good source of RNA transcripts from eight of the nine known genes that cause Usher syndrome, namely, MYO7A, USH1C, CDH23, PCDH15, USH1G for Usher type 1, and USH2A, GPR98, WHRN for Usher type 2. Furthermore, the known or predicted effect on mRNA splicing of eight variants was faithfully reproduced in the biopsied sample as measured by nested RT-PCR. These included changes at the canonical acceptor site, changes within the noncanonical acceptor site and both synonymous and nonsynonymous amino acid changes. This shows that mRNA analysis by this method will help in assessing the pathogenic effect of variants, which is a major problem in the molecular diagnosis of Usher syndrome.
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http://dx.doi.org/10.1002/humu.21255DOI Listing
June 2010

Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene.

Eur J Hum Genet 2009 Apr 5;17(4):517-24. Epub 2008 Nov 5.

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.

Hereditary hearing loss (HL) is a very heterogeneous trait, with 46 gene identifications for non-syndromic HL. Mutations in GJB2 cause up to half of all cases of severe-to-profound congenital autosomal recessive non-syndromic HL, with 35delG being the most frequent mutation in Caucasians. Although a genotype-phenotype correlation has been established for most GJB2 genotypes, the HL of 35delG homozygous patients is mild to profound. We hypothesise that this phenotypic variability is at least partly caused by the influence of modifier genes. By performing a whole-genome association (WGA) study on 35delG homozygotes, we sought to identify modifier genes. The association study was performed by comparing the genotypes of mild/moderate cases and profound cases. The first analysis included a pooling-based WGA study of a first set of 255 samples by using both the Illumina 550K and Affymetrix 500K chips. This analysis resulted in a ranking of all analysed single-nucleotide polymorphisms (SNPs) according to their P-values. The top 250 most significantly associated SNPs were genotyped individually in the same sample set. All 192 SNPs that still had significant P-values were genotyped in a second independent set of 297 samples for replication. The significant P-values were replicated in nine SNPs, with combined P-values between 3 x 10(-3) and 1 x 10(-4). This study suggests that the phenotypic variability in 35delG homozygous patients cannot be explained by the effect of one major modifier gene. Significantly associated SNPs may reflect a small modifying effect on the phenotype. Increasing the power of the study will be of greatest importance to confirm these results.
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http://dx.doi.org/10.1038/ejhg.2008.201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2883287PMC
April 2009

Pure-tone threshold description of an elderly French screened population.

Otol Neurotol 2008 Jun;29(4):432-40

Centre Hospitalier Universitaire, Hôpital Gui de Chauliac, France.

Objectives: To describe the distribution of pure-tone hearing thresholds of a Caucasian population living in the south of France aged 70 years and older. To establish age- and sex-adjusted normative hearing thresholds based on results of subjects free of noise and ototoxic drug exposure and to compare them with hearing thresholds of exposed (E) subjects.

Design: Cross-sectional analysis of a longitudinal epidemiologic cohort study.

Setting: Montpellier suburb, south of France.

Participants: A total of 778 subjects 70 years old and older were examined. Noise exposure, ototoxic medication use, and medical history were collected. Hearing thresholds were obtained via pure-tone audiometry. After excluding patients with ear-related disease, 659 subjects were further analyzed (270 men and 389 women). Noise or ototoxic medication exposure was found in 364 subjects (E subjects), whereas 295 had no exposure (nonexposed [NE] subjects).

Methods: Median pure-tone thresholds, lower deviation, and upper deviation were calculated for the NE subjects with a statistical method similar to the ISO 7029 norm and were compared with thresholds of E subjects.

Results: Hearing thresholds, especially in high frequencies, increased with age more for women than for men. Median thresholds of E subjects were significantly higher than those for the NE sample in men.

Conclusion: Age- and sex-adjusted hearing thresholds could well be useful in the study of the impact of environmental and genetic factors on hearing loss in the elderly. The next step would be to quantify the impact of noise, ototoxic drug exposure, and genetics using these age- and sex-adjusted thresholds.
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http://dx.doi.org/10.1097/MAO.0b013e3181719746DOI Listing
June 2008

Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients.

Hum Mutat 2007 Aug;28(8):781-9

Centre Hospitalier Universitaire (CHU) Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France.

The usherin gene (USH2A) has been screened for mutations causing Usher syndrome type II (USH2). Two protein isoforms have been identified: a short isoform of 1,546 amino acids and a more recently recognized isoform extending to 5,202 amino acids. We have screened the full length by genomic sequencing. We confirm that many mutations occur in the exons contributing solely to the longer form. USH2 is an autosomal recessive disorder and, in contrast to previous studies, both mutations were identified in 23 patients and a single mutation in 2 out of 33 patients. A total of 34 distinct mutated alleles were identified, including one complex allele with three variants and another with two. A total of 27 of these are novel, confirming that most mutations in usherin are private. Many of the mutations will lead to prematurely truncated protein but as there are a substantial number of missense variants, we have used in silico analysis to assess their pathogenicity. Evidence that they are disease-causing has been produced by protein alignments and three-dimensional (3D) structural predictions when possible. We have identified a previously unrecognized cysteine rich structural domain, containing 12 dicysteine repeats, and show that three missense mutations result in the loss of one of a pair of the defining cysteine-cysteine pairs.
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http://dx.doi.org/10.1002/humu.20513DOI Listing
August 2007