Publications by authors named "Céline Bonnet"

27 Publications

  • Page 1 of 1

Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia.

J Neurol 2021 Jan 8. Epub 2021 Jan 8.

Service de Génétique Médicale, Hôpitaux de Brabois, CHRU de Nancy, Rue du Morvan, 54500, Vandoeuvre-lès-Nancy, France.

Background: STUB1 has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in STUB1 are now considered a frequent cause of cerebellar ataxia.

Objective: We aimed to improve the clinical, radiological, and molecular delineation of SCAR16 and SCA48.

Methods: Retrospective collection of patients with SCAR16 or SCA48 diagnosed in three French genetic centers (Montpellier, Strasbourg and Nancy).

Results: Here, we report four SCAR16 and nine SCA48 patients from two SCAR16 and five SCA48 unrelated French families. All presented with slowly progressive cerebellar ataxia. Additional findings included cognitive decline, dystonia, parkinsonism and swallowing difficulties. The age at onset was highly variable, ranging from 14 to 76 years. Brain MRI showed marked cerebellar atrophy in all patients. Phenotypic findings associated with STUB1 pathogenic variations cover a broad spectrum, ranging from isolated slowly progressive ataxia to severe encephalopathy, and include extrapyramidal features. We described five new pathogenic variations, two previously reported pathogenic variations, and two rare variants of unknown significance in association with STUB1-related disorders. We also report the first pathogenic variation associated with both dominant and recessive forms of inheritance (SCAR16 and SCA48).

Conclusion: Even though differences are observed between the recessive and dominant forms, it appears that a continuum exists between these two entities. While adding new symptoms associated with STUB1 pathogenic variations, we insist on the difficulty of genetic counselling in STUB1-related pathologies. Finally, we underscore the usefulness of DAT-scan as an additional clue for diagnosis.
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http://dx.doi.org/10.1007/s00415-020-10348-xDOI Listing
January 2021

Evaluation of 3 molecular-based assays for microsatellite instability detection in formalin-fixed tissues of patients with endometrial and colorectal cancers.

Sci Rep 2020 10 2;10(1):16386. Epub 2020 Oct 2.

Service de Biologie Moléculaire des Tumeurs, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne CS 30519, 54519, Vandœuvre-lès-Nancy Cedex, France.

Microsatellite instability (MSI) status is routinely assessed in patients with colorectal and endometrial cancers as it contributes to Lynch syndrome initial screening, tumour prognosis and selecting patients for immunotherapy. Currently, standard reference methods recommended for MSI/dMMR (deficient MisMatch Repair) testing consist of immunohistochemistry and pentaplex PCR-based assays, however, novel molecular-based techniques are emerging. Here, we aimed to evaluate the performance of a custom capture-based NGS method and the Bio-Rad ddPCR and Idylla approaches for the determination of MSI status for theranostic purposes in 30 formalin-fixed paraffin embedded (FFPE) tissue samples from patients with endometrial (n = 15) and colorectal (n = 15) cancers. All samples were previously characterised using IHC and Promega MSI Analysis System and these assays set as golden standard. Overall agreement, sensitivity and specificity of our custom-built NGS panel were 93.30%, 93.75% and 92.86% respectively. Overall agreement, sensitivity and specificity were 100% with the Idylla MSI system. The Bio-Rad ddPCR MSI assay showed a 100% concordance, sensitivity and specificity. The custom capture-based NGS, Bio-Rad ddPCR and Idylla approaches represent viable and complementary options to IHC and Promega MSI Analysis System for the detection of MSI. Bio-Rad ddPCR and Idylla MSI assays accounts for easy and fast screening assays while the NGS approach offers the advantages to simultaneously detect MSI and clinically relevant genomic alterations.
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http://dx.doi.org/10.1038/s41598-020-73421-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532161PMC
October 2020

Evaluation of the Quotient® MosaiQ™ COVID-19 antibody microarray for the detection of IgG and IgM antibodies to SARS-CoV-2 virus in humans.

J Clin Virol 2020 Sep 31;130:104571. Epub 2020 Jul 31.

Unité de Virologie, Institut de Recherche Biomédicales des Armées, Marseille, France.

The MosaiQ® COVID-19 Antibody test fulfills the minimal requirements for serological testing according to the French regulation.
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http://dx.doi.org/10.1016/j.jcv.2020.104571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7392856PMC
September 2020

Toxicity of TiO Nanoparticles: Validation of Alternative Models.

Int J Mol Sci 2020 Jul 9;21(14). Epub 2020 Jul 9.

Institut Jean Lamour, UMR CNRS 7198, Université de Lorraine, CNRS, IJL, F-54000 Nancy, France.

There are many studies concerning titanium dioxide (TiO) nanoparticles (NP) toxicity. Nevertheless, there are few publications comparing and exposure, and even less comparing air-liquid interface exposure (ALI) with other and exposures. The identification and validation of common markers under different exposure conditions are relevant for the development of smart and quick nanotoxicity tests. In this work, cell viability was assessed by WST-1 and LDH assays after the exposure of NR8383 cells to TiO NP sample. To evaluate gene expression profile, NR8383 cells were exposed to TiO NP during 4 h at 3 cm of TiO NP/cm of cells or 19 μg/mL, in two settings-submerged cultures and ALI. For the study, Fischer 344 rats were exposed by inhalation to a nanostructured aerosol at a concentration of 10 mg/m, 6 h/day, 5 days/week for 4 weeks. This was followed immediately by gene expression analysis. The results showed a low cytotoxic potential of TiO NP on NR8383 cells. Despite the absence of toxicity at the doses studied, the different exposures to TiO NP induce 18 common differentially expressed genes (DEG) which are involved in mitosis regulation, cell proliferation and apoptosis and inflammation transport of membrane proteins. Among these genes, we noticed the upregulation of , , and genes which could be suggested as early response biomarkers after exposure to TiO NP. On the other hand, the comparison of the three models helped us to validate the alternative ones, namely submerged and ALI approaches.
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http://dx.doi.org/10.3390/ijms21144855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402355PMC
July 2020

Pathogenic variants in cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD.

J Med Genet 2020 10 9;57(10):717-724. Epub 2020 Mar 9.

Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, Missouri, USA

Background: Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described.

Methods: Clinical and molecular characterisation was performed on 17 patients with variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation.

Results: Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1).

Conclusions: Variants in cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.
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http://dx.doi.org/10.1136/jmedgenet-2019-106470DOI Listing
October 2020

The impact of the French soda tax on prices and purchases. An ex post evaluation.

PLoS One 2019 11;14(10):e0223196. Epub 2019 Oct 11.

Affiliation Department of Statistical Sciences, University of Bologna, Bologna, Italy.

We estimate the price and consumption effects of the 2012 French tax on sweetened non-alcoholic drinks using a difference-in-difference approach. Our identification strategy exploits Italian data as a natural control group. We use French and Italian Consumer Price Indices, purchase prices and quantities from the 2011 and 2012 Kantar and GfK home-scan surveys for two French regions and two neighbouring Italian regions, and expenditure data from the 2011 and 2012 Italian Expenditure Survey. We check for the robustness of our results by applying the difference-in-difference models using only French data and considering water as the benchmark (control) good. We find that the tax is transmitted to the prices of taxed drinks, with full transmission for soft drinks and partial transmission for fruit juices. The evidence on purchase responses is mixed and less robust, indicating at most a very small reduction in soft drink purchases (about half a litre per capita per year), an impact which would be consistent with the low tax rate. We find suggestive evidence of a larger response by the sub-sample of heavy purchasers. Fruit juices and water do not seem to have been affected by the tax.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788734PMC
March 2020

Deletion of chr7p22 and chr15q11: Two Familial Cases of Immune Deficiency: Extending the Phenotype Toward Dysimmunity.

Front Immunol 2019 16;10:1871. Epub 2019 Aug 16.

Clinic Genetics Department, Children Hospital, CHRU Nancy, Nancy, France.

We report here two new familial cases of associated del15q11 and del7p22, with the latter underlining the clinical variability of this deletion. Two siblings patients presented a similar familial imbalanced translocation, originating from a balanced maternal translocation, with deletions of 7p22 and of 15q11 [arr[GRCh37] 7p22.3-p22.2(42976-3736851)x1, 15q11.1-q11.2(20172544-24979427)x1]. We used aCGH array, FISH, and karyotype for studying the phenotype of the two patients. The 7p22 deletion (3.5 Mb) contained 58 genes, including several OMIM genes. Patients 1 and 2 exhibited acquisition delays, morphological particularities, and hypogammaglobulinemia, which was more severe in patient 1. Patient 1 presented also with cerebral vasculitis. We discuss here how the PDGFa, CARD11, LFNG, GPER1, and MAFK genes, included in the deletion 7p22, could be involved in the clinical and biological features of the two patients.
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http://dx.doi.org/10.3389/fimmu.2019.01871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707040PMC
October 2020

Expression of neurotensin receptor 1 in endometrial adenocarcinoma is correlated with histological grade and clinical outcome.

Virchows Arch 2017 Oct 24;471(4):521-530. Epub 2017 Aug 24.

INSERM U954, Université de Lorraine, Vandœuvre-lès-Nancy, France.

The promalignant effects of neurotensin (NTS) are sustained in many solid tumors, including hormone-dependent cancers. As the endometrium is also subjected to hormonal regulation, we evaluated the contribution of NTS to endometrial carcinogenesis. Neurotensin receptor 1 (NTSR1) expression and NTSR1 promoter methylation (HM450) were analyzed in 385 cases of endometrial carcinoma from The Cancer Genome Atlas (TCGA). Additionally, from a series of 100 endometrial carcinomas, and 66 benign endometrium samples, NTS and NTSR1 labeling was evaluated by immunohistochemistry. Using TCGA series, NTSR1 messenger RNA (mRNA) level was negatively correlated with overall survival (OS) and progression-free survival (PFS) (p = 0.0012 and p = 0.0116, respectively), and positively correlated with the grade (p = 0.0008). When including only endometrioid carcinomas, NTSR1 mRNA level continued to be negatively correlated with OS (log-rank: p < 0.0001) and PFS (log-rank: p = 0.002). A higher NTSR1 mRNA level was significantly associated with a loss of NTSR1 promoter methylation. Immunohistochemical expression of NTS and NTSR1 was significantly increased in adenocarcinoma (n = 100), as compared to benign endometrium (p < 0.001). NTSR1 expression was positively correlated with grade (p = 0.004). High immunohistochemical expression of cytoplasmic NTSR1 was significantly correlated with a shorter OS and PFS (p < 0.001 and p = 0.001, respectively). This correlation remained significant when excluding non-endometrioid subtypes (p = 0.04 and p = 0.02, respectively). In multivariate analysis, the expression of NTSR1 was an independent prognostic factor (p = 0.004). NTSR1 overexpression is a poor prognostic factor in endometrial cancer, highlighting the contribution of NTS in endometrial cancer progression and its uses as a prognostic marker, and as a potential therapeutic target.
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http://dx.doi.org/10.1007/s00428-017-2215-yDOI Listing
October 2017

Refinement of genotype-phenotype correlation in 18 patients carrying a 1q24q25 deletion.

Am J Med Genet A 2015 May 25;167A(5):1008-17. Epub 2015 Feb 25.

Hospices Civils de Lyon, Service de Génétique, Laboratoire de Cytogénétique Constitutionnelle, Bron, France.

Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial dysmorphism. In this study, we describe the largest series reported to date, including 18 patients (4M/14F) aged from 2 days to 67 years and comprising two familial cases. The patients presented with a characteristic phenotype including mild to moderate intellectual disability (100%), intrauterine (92%) and postnatal (94%) growth retardation, microcephaly (77%), short hands and feet (83%), brachydactyly (70%), fifth finger clinodactyly (78%) and facial dysmorphism with a bulbous nose (72%), abnormal ears (67%) and micrognathia (56%). Other findings were abnormal palate (50%), single transverse palmar crease (53%), renal (38%), cardiac (38%), and genital (23%) malformations. The deletions were characterized by chromosome microarray. They were of different sizes (490 kb to 20.95 Mb) localized within chromosome bands 1q23.3-q31.2 (chr1:160797550-192912120, hg19). The 490 kb deletion is the smallest deletion reported to date associated with this phenotype. We delineated three regions that may contribute to the phenotype: a proximal one (chr1:164,501,003-167,022,133), associated with cardiac and renal anomalies, a distal one (chr1:178,514,910-181,269,712) and an intermediate 490 kb region (chr1:171970575-172460683, hg19), deleted in the most of the patients, and containing DNM3, MIR3120 and MIR214 that may play an important role in the phenotype. However, this genetic region seems complex with multiple regions giving rise to the same phenotype.
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http://dx.doi.org/10.1002/ajmg.a.36856DOI Listing
May 2015

A new case of de novo 19p13.2p13.12 deletion in a girl with overgrowth and severe developmental delay.

Mol Cytogenet 2014 5;7:40. Epub 2014 Jun 5.

Département de Génétique Médicale, Institut National d'Hygiène, Rabat, Morocco ; Centre de génomique humaine, Faculté de médecine et de pharmacie, Université Mohammed V, Rabat, Morocco.

Background: We report clinical and molecular cytogenetic characterization of a 2 year-old girl with 19p13.2p13.12 microdeletion and compare her clinical features with those of three other patients reported before.

Result: Array comparative genomic hybridization (aCGH) revealed in the present patient a de novo microdeletion of 1.45 Mb within 19p13.2p13.12. The deletion includes seven OMIM genes: MAN2B1, RNASEH2A, KLF1, GCDH, NFIX, CACNA1A and CC2D1A.

Discussion: The present case and three other patients with partially overlapping 19p13 microdeletion share the following features: psychomotor and language delay, intellectual disability, seizures, hypotonia, skeletal anomalies and facial dysmorphism. The smallest region of overlapping between all four reported patients is around 300 kb and spans only two genes: NFIX and CACNA1A. Their haploinsufficincy could be the base for the phenotype -genotype correlation.
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http://dx.doi.org/10.1186/1755-8166-7-40DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068972PMC
June 2014

[An adult patient with 49, XXXXY syndrome: further clinical and biological delineation].

Ann Biol Clin (Paris) 2014 May-Jun;72(3):371-7

Laboratoire de génétique, Inserm U-954, Université de Lorraine, Centre Hospitalier de Nancy, Vandoeuvre les Nancy, France.

49, XXXXY syndrome is a rare sex chromosome aneuploidy occurring in 1:80 000-1:100 000 male births. Data on this aneuploidy in adulthood are limited, with most of the literature data based on paediatric patients. We report a new male patient whose 49, XXXXY diagnosis was formally made at the age of 54 years. So far, no medical follow-up was performed specifically for his condition. This man presented with facial features (epicanthus, hypertelorism, up-slanting palpebral fissures), microorchidism and features of chronic hypoandrogenism with muscular weakness, sparse body hair, dry skin with abnormal healing of skin wounds. Endocrine evaluation confirmed a hypergonadotropic hypogonadism. He had moderate intellectual deficiency with more affected verbal skills. A recent deep vein thrombosis was diagnosed in his left leg. Unusually, in addition to moderate deafness, he developed progressively a severe vision impairment leading to blindness. There have been very few reports of adult individuals with 49, XXXXY syndrome and this kind of report may contribute to improved management of prospective medical healthcare associated with this condition in older individuals.
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http://dx.doi.org/10.1684/abc.2014.0954DOI Listing
May 2016

How to Set up an Effective Food Tax? Comment on "Food Taxes: A New Holy Grail?".

Authors:
Céline Bonnet

Int J Health Policy Manag 2013 Sep 17;1(3):233-4. Epub 2013 Sep 17.

Toulouse School of Economics, University of Toulouse 1 Capitole, Toulouse, France.

Whereas public information campaigns have failed to reverse the rising trend in obesity, economists support food taxes as they suggest they can force individuals to change their eating behavior and make the agro-food industry think more about healthy food products. Excise taxes based on the unhealthy nutrient content would be more effective since they impact more on unhealthy food products than VAT (value-added-tax) taxes. Taxes based only on junk food products would avoid perverse effects on healthy nutrient. However, as eating behavior of consumers is complex, a modeling analysis would allow to assess unexpected effects on other unhealthy nutrients or products.
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http://dx.doi.org/10.15171/ijhpm.2013.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3937888PMC
September 2013

De novo complex X chromosome rearrangement unmasking maternally inherited CSF2RA deletion in a girl with pulmonary alveolar proteinosis.

Am J Med Genet A 2013 Oct 5;161A(10):2594-9. Epub 2013 Aug 5.

Laboratoire de Génétique Médicale, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France; Service de Médecine Infantile 3 et Génétique Clinique, Centre Hospitalier Universitaire de Nancy, Vandoeuvre-les-Nancy, France.

We report on a 3-year-old girl with a de novo complex X chromosome rearrangement associated with congenital pulmonary alveolar proteinosis (PAP) and short stature. Array comparative genome hybridization and FISH analyses contributed to characterize the complex rearrangement consisting of a 7.37 Mb terminal deletion of Xp22.33p22.2, a 17.3 Mb interstitial inverted duplication of Xp22.2p21.3, and a 10.14 Mb duplication of Xq27.3q28. PCR analysis of microsatellite markers supported a paternal origin of the X chromosome rearrangement. A pre-meiotic two-step mechanism may explain the occurrence of this complex X rearrangement: an inverted duplication deletion event on Xp, and duplication of the Xq27.3qter region through a telomere capture event stabilizing the broken chromosome Xp end. The girl has also inherited from her healthy mother an X chromosome with a colony stimulating factor 2 receptor, alpha (CSF2RA) gene deletion. Consistent with the recessive mode of inheritance, the de novo paternal Xp22.33p22.2 deletion combined to the maternally inherited CSF2RA gene deletion led to homozygous deletion of CSF2RA and PAP diagnosis in the girl. The Xp deletion encompasses the pseudoautosomal region 1 (PAR1) which contains genes that escape X inactivation. Short stature homeobox (SHOX) haploinsufficiency explains growth retardation. Absence of other symptoms in relation to the X deletion/amplification is most probably due to skewed X inactivation. Finally, inherited deletions may unmask rare pathogenic genomic rearrangement and contribute to clinical phenotypes by a recessive mode of gene action.
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http://dx.doi.org/10.1002/ajmg.a.36097DOI Listing
October 2013

Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth.

Hum Mol Genet 2013 Aug 24;22(16):3306-14. Epub 2013 Apr 24.

Centre de Génétique Humaine, Université de Franche-Comté, 25000 Besançon, France.

Existence of a discrete new X-linked intellectual disability (XLID) syndrome due to KIAA2022 deficiency was questioned by disruption of KIAA2022 by an X-chromosome pericentric inversion in a XLID family we reported in 2004. Three additional families with likely pathogenic KIAA2022 mutations were discovered within the frame of systematic parallel sequencing of familial cases of XLID or in the context of routine array-CGH evaluation of sporadic intellectual deficiency (ID) cases. The c.186delC and c.3597dupA KIAA2022 truncating mutations were identified by X-chromosome exome sequencing, while array CGH discovered a 70 kb microduplication encompassing KIAA2022 exon 1 in the third family. This duplication decreased KIAA2022 mRNA level in patients' lymphocytes by 60%. Detailed clinical examination of all patients, including the two initially reported, indicated moderate-to-severe ID with autistic features, strabismus in all patients, with no specific dysmorphic features other than a round face in infancy and no structural brain abnormalities on magnetic resonance imaging (MRI). Interestingly, the patient with decreased KIAA2022 expression had only mild ID with severe language delay and repetitive behaviors falling in the range of an autism spectrum disorder (ASD). Since little is known about KIAA2022 function, we conducted morphometric studies in cultured rat hippocampal neurons. We found that siRNA-mediated KIAA2022 knockdown resulted in marked impairment in neurite outgrowth including both the dendrites and the axons, suggesting a major role for KIAA2022 in neuron development and brain function.
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http://dx.doi.org/10.1093/hmg/ddt187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723314PMC
August 2013

Extended spectrum of MBD5 mutations in neurodevelopmental disorders.

Eur J Hum Genet 2013 Dec 20;21(12):1457-61. Epub 2013 Feb 20.

Laboratoire de Génétique, EA 4368, Université de Lorraine, Centre Hospitalier Universitaire de Nancy, Vandoeuvre les Nancy, France.

Intellectual disability (ID) is a clinical sign reflecting diverse neurodevelopmental disorders that are genetically and phenotypically heterogeneous. Just recently, partial or complete deletion of methyl-CpG-binding domain 5 (MBD5) gene has been implicated as causative in the phenotype associated with 2q23.1 microdeletion syndrome. In the course of systematic whole-genome screening of individuals with unexplained ID by array-based comparative genomic hybridization, we identified de novo intragenic deletions of MBD5 in three patients leading, as previously documented, to haploinsufficiency of MBD5. In addition, we described a patient with an unreported de novo MBD5 intragenic duplication. Reverse transcriptase-PCR and sequencing analyses showed the presence of numerous aberrant transcripts leading to premature termination codon. To further elucidate the involvement of MBD5 in ID, we sequenced ten coding, five non-coding exons and an evolutionary conserved region in intron 2, in a selected cohort of 78 subjects with a phenotype reminiscent of 2q23.1 microdeletion syndrome. Besides variants most often inherited from an healthy parent, we identified for the first time a de novo nonsense mutation associated with a much more damaging phenotype. Taken together, these results extend the mutation spectrum in MBD5 gene and contribute to refine the associated phenotype of neurodevelopmental disorder.
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http://dx.doi.org/10.1038/ejhg.2013.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831065PMC
December 2013

Intragenic CAMTA1 rearrangements cause non-progressive congenital ataxia with or without intellectual disability.

J Med Genet 2012 Jun;49(6):400-8

Centre de Génétique et Centre de Référence, Anomalies du Développement et Syndromes Malformatifs, Hôpital d'Enfants, CHU Dijon, Dijon, France.

Background: Non-progressive congenital ataxias (NPCA) with or without intellectual disability (ID) are clinically and genetically heterogeneous conditions. As a consequence, the identification of the genes responsible for these phenotypes remained limited.

Objective: Identification of a new gene responsible for NPCA and ID. Methods Following the discovery of three familial or sporadic cases with an intragenic calmodulin-binding transcription activator 1 (CAMTA1) rearrangement identified by an array-CGH and recruited from a national collaboration, the authors defined the clinical and molecular characteristics of such rearrangements, and searched for patients with point mutations by direct sequencing.

Results: Intragenic copy number variations of CAMTA1 were all located in the CG-1 domain of the gene. It segregated with autosomal dominant ID with non-progressive congenital cerebellar ataxia (NPCA) in two unrelated families, and was de novo deletion located in the same domain in a child presenting with NPCA. In the patients with ID, the deletion led to a frameshift, producing a truncated protein, while this was not the case for the patient with isolated childhood ataxia. Brain MRI of the patients revealed a pattern of progressive atrophy of cerebellum medium lobes and superior vermis, parietal lobes and hippocampi. DNA sequencing of the CG-1 domain in 197 patients with sporadic or familial non-syndromic intellectual deficiency, extended to full DNA sequencing in 50 patients with ID and 47 additional patients with childhood ataxia, identified no pathogenic mutation.

Conclusion: The authors have evidence that loss-of-function of CAMTA1, a brain-specific calcium responsive transcription factor, is responsible for NPCA with or without ID. Accession numbers CAMTA1 reference sequence used was ENST00000303635. Protein sequence was ENSP00000306522.
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http://dx.doi.org/10.1136/jmedgenet-2012-100856DOI Listing
June 2012

Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures.

Am J Med Genet A 2012 Jul 7;158A(7):1633-40. Epub 2012 Jun 7.

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

Patients with a submicroscopic deletion at 1q43q44 present with intellectual disability (ID), microcephaly, craniofacial anomalies, seizures, limb anomalies, and corpus callosum abnormalities. However, the precise relationship between most of deleted genes and the clinical features in these patients still remains unclear. We studied 11 unrelated patients with 1q44 microdeletion. We showed that the deletions occurred de novo in all patients for whom both parents' DNA was available (10/11). All patients presented with moderate to severe ID, seizures and non-specific craniofacial anomalies. By oligoarray-based comparative genomic hybridization (aCGH) covering the 1q44 region at a high resolution, we obtained a critical deleted region containing two coding genes-HNRNPU and FAM36A-and one non-coding gene-NCRNA00201. All three genes were expressed in different normal human tissues, including in human brain, with highest expression levels in the cerebellum. Mutational screening of the HNRNPU and FAM36A genes in 191 patients with unexplained isolated ID did not reveal any deleterious mutations while the NCRNA00201 non-coding gene was not analyzed. Nine of the 11 patients did not present with microcephaly or corpus callosum abnormalities and carried a small deletion containing HNRNPU, FAM36A, and NCRNA00201 but not AKT3 and ZNF238, two centromeric genes. These results suggest that HNRNPU, FAM36A, and NCRNA00201 are not major genes for microcephaly and corpus callosum abnormalities but are good candidates for ID and seizures.
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http://dx.doi.org/10.1002/ajmg.a.35423DOI Listing
July 2012

Exploring the potential role of disease-causing mutation in a gene desert: duplication of noncoding elements 5' of GRIA3 is associated with GRIA3 silencing and X-linked intellectual disability.

Hum Mutat 2012 Feb 28;33(2):355-8. Epub 2011 Nov 28.

Laboratoire de Génétique, EA 4368, Nancy Université, Centre Hospitalier Universitaire de Nancy, France.

GRIA3 encodes glutamate receptor ionotropic AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) subunit 3 and has been previously involved in X-linked intellectual disability (ID). We report on a male proband with ID and epilepsy associated with a duplication mapping within a gene desert, 874-kb upstream of the GRIA3 gene. This 970-kb duplication is maternally inherited. The proband's mother has a skewed X chromosome-inactivation pattern in agreement with her normal cognitive function. Quantitative polymerase chain reaction analysis indicates absence of GRIA3 mRNA in the proband lymphocytes relative to a wild-type control. Centromeric to the duplicated region, comparative genomic analysis showed a 2268-bp evolutionarily conserved region that could be a critical transcription factor binding-site for GRIA3 expression. The repositioning of distant-acting sequences, rather a missense/nonsense mutation, is considered to be causative for GRIA3-linked ID. This study illustrates the importance of high-resolution array-Comparative Genomic Hybridization analysis in exploring the potential role of disease-causing mutation in functional noncoding sequences.
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http://dx.doi.org/10.1002/humu.21649DOI Listing
February 2012

Microtriplication of 11q24.1: a highly recognisable phenotype with short stature, distinctive facial features, keratoconus, overweight, and intellectual disability.

J Med Genet 2011 Sep 26;48(9):635-9. Epub 2011 May 26.

Laboratoire de Ge´ne´tique, EA4368, Nancy-Universite´, CHUNancy, France.

Background: Partial tetrasomy is mainly described as a cytogenetically visible rearrangement due to a supernumerary chromosome (i(12p), i(18p), inv dup(15)). Except for chromosome 15q11q13, intrachromosomal triplications are rare and so far not associated with a recognisable phenotype.

Methods And Results: This report describes two unrelated patients with a de novo non-recurrent submicroscopic interstitial triplication 11q24.1 detected with array comparative genomic hybridisation and confirmed by fluorescence in situ hybridisation, molecular combing, and quantitative PCR. Microsatellite analysis suggested that a common mechanism of rearrangement might have been involved. These patients share remarkably similar clinical features including distinctive facial dysmorphisms, short stature with small extremities, keratoconus, overweight, and intellectual disability. The overlapping region of 1.8 Mb contains 11 RefSeq genes and three microRNA related genes. Interestingly, the overexpression of ASAM, a gene encoding an adipocyte specific adhesion molecule, may contribute to patients' obesity. Upregulation of BILD, known to mediate apoptosis in a caspase dependent manner, could deserve further investigation into the pathological mechanism of keratoconus.

Conclusion: Isolated duplications of distal 11q region have been previously reported and associated with intellectual disability but without a consistent set of clinical features. These findings support the proposal that microtriplication 11q24.1 is a well recognisable clinical entity.
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http://dx.doi.org/10.1136/jmedgenet-2011-100008DOI Listing
September 2011

Does the EU sugar policy reform increase added sugar consumption? An empirical evidence on the soft drink market.

Health Econ 2011 Sep 14;20(9):1012-24. Epub 2011 Feb 14.

Toulouse School of Economics (INRA, GREMAQ), Toulouse, France.

Whereas National Health authorities recommend a decrease in the consumption of 'added' sugar, a reform on the sugar market will lead to a 36% decrease of the sugar price in the EU. Using French data on soft drinks purchases, this paper investigates the anticipated impact of this reform on the consumption of sugar-sweetened beverages. The reform of the EU sugar policy leads to a decrease in regular soft drink prices by 3% and varies across brands. To assess substitution within this food category, we use a random-coefficients logit model that takes into account a large number of differentiated products and heterogeneity in consumers' behavior. Results suggest that price changes would lead to an increase in market shares of regular products by 7.5% and to substitutions between brands to the benefit of products with the highest sugar content. On the whole, it would raise consumption of regular soft drinks by more than 1 litre per person per year and consumption of added sugar by 124 g per person per year, this increase being larger in households composed of overweight and obese individuals.
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http://dx.doi.org/10.1002/hec.1721DOI Listing
September 2011

Clinical and molecular characterization of a large family with an interstitial 15q11q13 duplication.

Am J Med Genet A 2010 Aug;152A(8):1933-41

Service de Médecine Infantile III et Génétique Clinique, Centre de référence Anomalies du développement et Syndromes malformatifs, Centre Hospitalier Universitaire de Nancy, Nancy-Université Henri Poincaré, Vandoeuvre les Nancy, France.

The clinical significance of an interstitial duplication of chromosome 15q11q13 is still not well documented. This abnormality has been associated with autistic spectrum disorders (ASD) and varying degrees of mental retardation. The clinical variability appears to be influenced by the parental origin of the duplication. We present here the clinical evaluation and psychological assessment of the largest reported family with 12 carriers on three generations. Patients exhibit mental retardation, motor and visuo-motor skills impairments and adaptive functioning deficit without formal diagnosis of autism. There appeared to be evidence in the family of reduced penetrance in duplication of paternal origin. This familial 15q11q13 duplication was precisely investigated by cytogenetic and molecular techniques including fluorescence in situ hybridization (FISH), PCR analysis of microsatellite markers, array-comparative genomic hybridization analysis (Array-CGH) and semi-quantitative methylation-sensitive PCR. Results showed an inherited 15q11q13 duplication of maternal origin in 10 patients and of paternal origin in the remaining two. The size of the duplicated area was around 6 Mb with breakpoints in accordance with those previously reported. This report extends the clinical spectrum of the 15q11q13 duplication, and we recommend the investigation of 15q11q13 duplication not only in subjects with autistic spectrum disorder but also in patients with low normal intelligence and dyspraxia.
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http://dx.doi.org/10.1002/ajmg.a.33521DOI Listing
August 2010

Clinical phenotype of germline RUNX1 haploinsufficiency: from point mutations to large genomic deletions.

Eur J Hum Genet 2008 Aug 14;16(8):1014-8. Epub 2008 May 14.

Laboratoire de Génétique, Centre Hospitalier Universitaire de Nancy Brabois, Nancy Université, EA4002, France.

Germline RUNX1 mutations result in a rare autosomal dominant condition characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies (familial platelet disorder with propensity to acute myeloid leukaemia, FPD/AML). Only 13 pedigrees have previously been described so far. We report on two novel germline RUNX1 mutations: (1) an out-of-frame 8 bp heterozygous deletion (c.442_449del) in an FPD/AML pedigree and (2) a de novo 3.5 Mb deletion in the 21q22.11.21q22.12 region encompassing the RUNX1 gene in a mentally retarded female patient with short stature and thrombocytopenia. Interestingly, a similar de novo submicroscopic deletion has been recently reported in the literature in a mentally retarded patient. Mental retardation is one of the most common disorders and primary causes of thrombocytopenia are rare. When occurring together, these features should prompt to test for 21q22 deletion for comprehensive genetic counselling and clinical management.
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http://dx.doi.org/10.1038/ejhg.2008.89DOI Listing
August 2008

Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome.

Hum Mutat 2007 Nov;28(11):1098-107

Department of Genetics, Rouen University Hospital, University of Rouen, Rouen, France.

Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features, learning difficulties, and macrocephaly with frequent pre- and postnatal overgrowth with advanced bone age. Here, we report on our experience in the molecular diagnostic of Sotos syndrome on 116 patients. Using direct sequencing and a quantitative multiplex PCR of short fluorescent fragments (QMPSF)-based assay allowing accurate detection of both total and partial NSD1 deletions, we identified NSD1 abnormalities in 104 patients corresponding to 102 Sotos families (90%). NSD1 point mutations were detected in 80% of the index cases, large deletions removing the NSD1 gene entirely in 14%, and intragenic NSD1 rearrangements in 6%. Among the 69 detected distinct point mutations, 48 were novel. The QMPSF assay detected an exonic duplication and a mosaic partial deletion. QMPSF mapping of the 15 large deletions revealed the heterogeneity of the deletions, which vary in size from 1 to 4.5 Mb. Clinical features of NSD1-positive Sotos patients revealed that the phenotype in patients with nontruncating mutations was less severe that in patients with truncating mutations. This study confirms the heterogeneity of NSD1 alterations in Sotos syndrome and therefore the need to complete sequencing analysis by screening for partial deletions and duplications to ensure an accurate molecular diagnosis of this syndrome.
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http://dx.doi.org/10.1002/humu.20568DOI Listing
November 2007

NDRG1-linked Charcot-Marie-Tooth disease (CMT4D) with central nervous system involvement.

Neuromuscul Disord 2007 Feb 4;17(2):163-8. Epub 2006 Dec 4.

Département de Neurologie, Hôpital Civil de Strasbourg, 1 Place de l'Hôpital, BP426, 67091 Strasbourg, France.

Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal recessive demyelinating polyneuropathy, associated with deafness exclusively found in Gypsies and resulting from a homozygous R148X mutation in the N-myc downstream-regulated gene 1 (NDRG1). We report the detailed phenotypic study of a family without Gypsy ancestry, who presented with severe demyelinating polyneuropathy, deafness, subcortical white matter abnormalities on brain magnetic resonance imaging studies, and the R148X mutation in NDRG1. For the first time, central nervous system white matter lesions are demonstrated in CMT4D. This report extends the clinical knowledge of CMT4D and indicates that the role of the R148X mutation in NDRG1 in the central nervous system should be further studied.
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http://dx.doi.org/10.1016/j.nmd.2006.10.002DOI Listing
February 2007

Characterization of mosaic supernumerary ring chromosomes by array-CGH: segmental aneusomy for proximal 4q in a child with tall stature and obesity.

Am J Med Genet A 2006 Feb;140(3):233-7

Laboratoire de Génétique EA 3441, Centre Hospitalier Universitaire de Nancy, Vandoeuvre les Nancy, France.

We report on a 6-year-old girl with developmental delay, tall stature, and obesity. G-banded chromosome analysis revealed mosaicism for one to three small de novo rings in 82% of peripheral lymphocytes. Fluorescence in situ hybridization (FISH) studies and metaphase comparative genomic hybridization (CGH) demonstrated that the rings were derived from 4q10-4q13. A higher resolution investigation was initiated using array-CGH analysis and revealed a gain of 11 adjacent clones spanning a 16 Mb region at 4q11-q13.2 and including the insulin-like growth factor binding protein 7 (IGFBP7) gene. This finding suggests that postnatal overgrowth observed in our patient might be related to a dosage effect of the IGFBP7 gene.
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http://dx.doi.org/10.1002/ajmg.a.31075DOI Listing
February 2006