Publications by authors named "Laëtitia Lambert"

27 Publications

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Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.

Authors:
Annie Laquerriere Dana Jaber Emanuela Abiusi Jérome Maluenda Dan Mejlachowicz Alexandre Vivanti Klaus Dieterich Radka Stoeva Loic Quevarec Flora Nolent Valerie Biancalana Philippe Latour Damien Sternberg Yline Capri Alain Verloes Bettina Bessieres Laurence Loeuillet Tania Attie-Bitach Jelena Martinovic Sophie Blesson Florence Petit Claire Beneteau Sandra Whalen Florent Marguet Jerome Bouligand Delphine Héron Géraldine Viot Jeanne Amiel Daniel Amram Céline Bellesme Martine Bucourt Laurence Faivre Pierre-Simon Jouk Suonavy Khung Sabine Sigaudy Anne-Lise Delezoide Alice Goldenberg Marie-Line Jacquemont Laetitia Lambert Valérie Layet Stanislas Lyonnet Arnold Munnich Lionel Van Maldergem Juliette Piard Fabien Guimiot Pierre Landrieu Pascaline Letard Fanny Pelluard Laurence Perrin Marie-Hélène Saint-Frison Haluk Topaloglu Laetitia Trestard Catherine Vincent-Delorme Helge Amthor Christine Barnerias Alexandra Benachi Eric Bieth Elise Boucher Valerie Cormier-Daire Andrée Delahaye-Duriez Isabelle Desguerre Bruno Eymard Christine Francannet Sarah Grotto Didier Lacombe Fanny Laffargue Marine Legendre Dominique Martin-Coignard André Mégarbané Sandra Mercier Mathilde Nizon Luc Rigonnot Fabienne Prieur Chloé Quélin Hanitra Ranjatoelina-Randrianaivo Nicoletta Resta Annick Toutain Helene Verhelst Marie Vincent Estelle Colin Catherine Fallet-Bianco Michèle Granier Romulus Grigorescu Julien Saada Marie Gonzales Anne Guiochon-Mantel Jean-Louis Bessereau Marcel Tawk Ivo Gut Cyril Gitiaux Judith Melki

J Med Genet 2021 Apr 5. Epub 2021 Apr 5.

Institut National de la Santé et de la Recherche Médicale (Inserm), UMR-1195, Université Paris Saclay, Le Kremlin-Bicetre, France

Background: Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.

Methods: Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.

Results: We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (, , , , , , , and ). Moreover, we identified pathogenic variants in and expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%).

Conclusion: New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.
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http://dx.doi.org/10.1136/jmedgenet-2020-107595DOI Listing
April 2021

Characterization of Odor-Active Compounds of Ichang Lemon () and Identification of Its Genetic Interspecific Origin by DNA Genotyping.

J Agric Food Chem 2021 Mar 5;69(10):3175-3188. Epub 2021 Mar 5.

UMR AGAP Institut, Université Montpellier, CIRAD, INRAE, Institut Agro, 20230 San Giuliano, France.

Ichang lemon is a citrus fruit whose rind gives off a delicious and much appreciated fragrance and flavor. The volatile components of the fruit peel of Ichang lemon were investigated by GC-MS and GC-O (AEDA method). Simultaneously, its genetic origin was identified by using diagnostic SNP markers specific to ancestral species and multiallelic SSR and InDel markers. Ichang lemon combines three ancestral genomes (, , and ) and may be a pummelo × Yuzu hybrid. Although the major compounds of the Ichang lemon aromatic profile were present in , a few pummelo-specific compounds were also detected, such as indole and nootkatone, in agreement with its maternal lineage. 3-Methyl-3-sulfanylbutyl acetate, reported to occur in passion fruit and brewed coffee, was identified by GC-MS, GC-QTOF-MS, and GC-FTIR for the first time in citrus. This odor-active compound has a sulfurous, tropical fruity, green note.
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http://dx.doi.org/10.1021/acs.jafc.0c07894DOI Listing
March 2021

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

Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy.

Hum Mutat 2020 Dec 10;41(12):2167-2178. Epub 2020 Nov 10.

Centre de Diagnostic Prénatal, Hôpital MFME, Fort de France, Martinique, France.

Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.
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http://dx.doi.org/10.1002/humu.24132DOI Listing
December 2020

Epilepsy with migrating focal seizures: KCNT1 mutation hotspots and phenotype variability.

Neurol Genet 2019 Dec 25;5(6):e363. Epub 2019 Oct 25.

Service de Génétique (G.B., J.-P.B., S.G.-L.), Groupe Hospitalier Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM U1163 (G.B., N.B-.B., R.N.), Université Paris Descartes, PRES Sorbonne Paris Cité, Paris, France; Service de Neurologie Pédiatrique (N.C., N.B-.B., A.K., R.N.), Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; Centre de Référence des Epilepsies Rares (N.C., A.K., R.N.), Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM U1129 (N.N., A.K., R.N.), Paris, France; Service de Neurophysiologie Clinique et Pédiatrie (M.K.), INSERM U1099, Hôpital Universitaire de Rennes, Université de Rennes, France; Service de Neurophysiologie Clinique (M.E., A.K.), Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; Service de Génétique Clinique (V.C.), Hôpital Femme Mère Enfant, Metz-Thionville, France; Pediatric Neurology Research Group (A.M.), Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain; Service de Génétique Clinique (L.L.), Hôpital d'Enfants, CHU de Nancy, Vandoeuvre-Lès-Nancy, France; Service de Pédiatrie (F.D.), CHU de Grenoble, France; Service de Neurologie Pédiatrique (D.D., T.B.V.), Hôpital Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France; Service de Neurologie Pédiatrique (N.V., M.M.), APHM, Hôpital d'Enfants de La Timone, Marseille, France; Service de Neurologie Pédiatrique (M-.A.B., M.M.), Centre Hospitalier Universitaire de Tours, Tours, France; Département de Génétique (C.N., M.M.), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Service de Radiologie Pédiatrique (N.B., M.M.), Hôpital Necker Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; Université Aix-Marseille (M.M.), INSERM, MMG, UMR-S 1251, Faculté de Médecine, Marseille, France; and Unité de Neurologie Pédiatrique (S.A.), Hôpital Rober Debré, Assistance Publique-Hôpitaux de Paris, Paris, France.

Objective: To report new sporadic cases and 1 family with epilepsy of infancy with migrating focal seizures (EIMFSs) due to KCNT1 gain-of-function and to assess therapies' efficacy including quinidine.

Methods: We reviewed the clinical, EEG, and molecular data of 17 new patients with EIMFS and mutations, in collaboration with the network of the French reference center for rare epilepsies.

Results: The mean seizure onset age was 1 month (range: 1 hour to 4 months), and all children had focal motor seizures with autonomic signs and migrating ictal pattern on EEG. Three children also had infantile spasms and hypsarrhythmia. The identified variants clustered as "hot spots" on the C-terminal domain, and all mutations occurred de novo except the p.R398Q mutation inherited from the father with nocturnal frontal lobe epilepsy, present in 2 paternal uncles, one being asymptomatic and the other with single tonic-clonic seizure. In 1 patient with EIMFS, we identified the p.R1106Q mutation associated with Brugada syndrome and saw no abnormality in cardiac rhythm. Quinidine was well tolerated when administered to 2 and 4-year-old patients but did not reduce seizure frequency.

Conclusions: The majority of the mutations appear to cluster in hot spots essential for the channel activity. A same mutation can be linked to a spectrum of conditions ranging from EMFSI to asymptomatic carrier, even in the same family. None of the antiepileptic therapies displayed clinical efficacy, including quinidine in 2 patients.
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http://dx.doi.org/10.1212/NXG.0000000000000363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878841PMC
December 2019

Phenotypic and genetic spectrum of alveolar capillary dysplasia: a retrospective cohort study.

Arch Dis Child Fetal Neonatal Ed 2020 Jul 22;105(4):387-392. Epub 2019 Oct 22.

Clinical Genetics, CHU Nancy, Nancy, France.

Objective: Alveolar capillary dysplasia (ACD) is one of the causes of pulmonary hypertension. Its diagnosis is histological but new pathogenetic data have emerged. The aim of this study was to describe a French cohort of patients with ACD to improve the comprehension and the diagnosis of this pathology which is probably underdiagnosed.

Methods: A retrospective observational study was conducted in French hospitals. Patients born between 2005 and 2017, whose biological samples were sent to the French genetic reference centres, were included. Clinical, histological and genetic data were retrospectively collected.

Results: We presented a series of 21 patients. The mean of postmenstrual age at birth was 37.6 weeks. The first symptoms appeared on the median of 2.5 hours. Pulmonary hypertension was diagnosed in 20 patients out of 21. Two cases had prolonged survival (3.3 and 14 months). Histological analysis was done on lung tissue from autopsy (57.1% of cases) or from percutaneous biopsy (28.6%). was found abnormal in 15 patients (71.4%): 8 deletions and 7 point mutations. Two deletions were found by chromosomal microarray.

Conclusion: This study is one of the largest clinically described series in literature. It seems crucial to integrate genetics early into diagnostic support. We propose a diagnostic algorithm for helping medical teams to improve diagnosis of this pathology.
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http://dx.doi.org/10.1136/archdischild-2019-317121DOI Listing
July 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

Variable phenotypic expression of Apert syndrome in monozygotic twins.

Clin Case Rep 2019 Jan 11;7(1):54-57. Epub 2018 Nov 11.

Department of Gynecology and Obstetrics CHRU de Nancy Nancy France.

Apert syndrome in monozygotic twins can lead to different phenotypic expression of the disease in the two fetuses. Apert syndrome can be associated with congenital left diaphragmatic hernia and cleft palate.
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http://dx.doi.org/10.1002/ccr3.1915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333066PMC
January 2019

Annual Injection of Zoledronic Acid Improves Bone Status in Children with Cerebral Palsy and Rett Syndrome.

Calcif Tissue Int 2019 04 15;104(4):355-363. Epub 2018 Dec 15.

Centre de référence des erreurs innées du métabolisme, Hôpital d'Enfants, CHRU Nancy, Nancy, France.

Osteoporosis is a common complication of cerebral palsy and Rett's syndrome. It is responsible for multiple fractures, bone pain, and impaired quality of life. In case of Rett's syndrome, a specific dysfunction of osteoblasts causes bone fragility. We observed the effects of annual zoledronic acid (ZA) infusion in a cohort of children with cerebral palsy and Rett's syndrome. 27 children under 18 years (19 with cerebral palsy and 8 girls with Rett syndrome confirmed by MCEP2 mutation) were treated with an annual injection of 0.1 mg/kg (max 4 mg) of ZA. Calcium and vitamin D were combined in all patients from the first injection of ZA. Dental examination was performed before treatment. Data were analyzed retrospectively. Bone mineral density was measured at diagnosis and yearly thereafter. Bone mass density (BMD) is decreased in patient with cerebral palsy and RS. One year after injection of ZA, we observe an increase of Lumbar spine BMD from - 2.99 to - 2.14 SD (p < 0.0001) and femoral BMD from - 4.26 to - 3.32 SD (p < 0.001) In the subgroup of patient with Rett syndrome, we also observe an increase from - 3.27 to 2.50 SD (p = 0.018) of Lumbar spine BMD. No fractures have been observed in our cohort since the first infusion. Side effects (flu-like syndrome and hypocalcemia) were more common in younger patients and after the first infusion. No serious complications were noticed. This study confirms the efficacy and the safety of an annual injection of ZA to improve bone status in children with cerebral palsy and Rett syndrome. No severe adverse effects were observed.
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http://dx.doi.org/10.1007/s00223-018-0505-2DOI Listing
April 2019

Mutation update for the GPC3 gene involved in Simpson-Golabi-Behmel syndrome and review of the literature.

Hum Mutat 2018 06 24;39(6):790-805. Epub 2018 Apr 24.

Service de Génétique, CHU de Tours, Hôpital Bretonneau, Tours, France.

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked multiple congenital anomalies and overgrowth syndrome caused by a defect in the glypican-3 gene (GPC3). Until now, GPC3 mutations have been reported in isolated cases or small series and the global genotypic spectrum of these mutations has never been delineated. In this study, we review the 57 previously described GPC3 mutations and significantly expand this mutational spectrum with the description of 29 novel mutations. Compiling our data and those of the literature, we provide an overview of 86 distinct GPC3 mutations identified in 120 unrelated families, ranging from single nucleotide variations to complex genomic rearrangements and dispersed throughout the entire coding region of GPC3. The vast majority of them are deletions or truncating mutations (frameshift, nonsense mutations) predicted to result in a loss-of-function. Missense mutations are rare and the two which were functionally characterized, impaired GPC3 function by preventing GPC3 cleavage and cell surface addressing respectively. This report by describing for the first time the wide mutational spectrum of GPC3 could help clinicians and geneticists in interpreting GPC3 variants identified incidentally by high-throughput sequencing technologies and also reinforces the need for functional validation of non-truncating mutations (missense, in frame mutations, duplications).
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http://dx.doi.org/10.1002/humu.23428DOI Listing
June 2018

Further delineation of the duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features.

Authors:
Marguerite Miguet Laurence Faivre Jeanne Amiel Mathilde Nizon Renaud Touraine Fabienne Prieur Laurent Pasquier Mathilde Lefebvre Julien Thevenon Christèle Dubourg Sophie Julia Catherine Sarret Ganaëlle Remerand Christine Francannet Fanny Laffargue Odile Boespflug-Tanguy Albert David Bertrand Isidor Jacqueline Vigneron Bruno Leheup Laetitia Lambert Christophe Philippe Mylène Béri-Dexheimer Jean-Marie Cuisset Joris Andrieux Ghislaine Plessis Annick Toutain Laurent Guibaud Valérie Cormier-Daire Marlene Rio Jean-Paul Bonnefont Bernard Echenne Hubert Journel Lydie Burglen Sandrine Chantot-Bastaraud Thierry Bienvenu Clarisse Baumann Laurence Perrin Séverine Drunat Pierre-Simon Jouk Klaus Dieterich Françoise Devillard Didier Lacombe Nicole Philip Sabine Sigaudy Anne Moncla Chantal Missirian Catherine Badens Nathalie Perreton Christel Thauvin-Robinet Réseau AChro-Puce Jean-Michel Pedespan Caroline Rooryck Cyril Goizet Catherine Vincent-Delorme Bénédicte Duban-Bedu Nadia Bahi-Buisson Alexandra Afenjar Kim Maincent Delphine Héron Jean-Luc Alessandri Dominique Martin-Coignard Gaëtan Lesca Massimiliano Rossi Martine Raynaud Patrick Callier Anne-Laure Mosca-Boidron Nathalie Marle Charles Coutton Véronique Satre Cédric Le Caignec Valérie Malan Serge Romana Boris Keren Anne-Claude Tabet Valérie Kremer Sophie Scheidecker Adeline Vigouroux Marilyn Lackmy-Port-Lis Damien Sanlaville Marianne Till Maryline Carneiro Brigitte Gilbert-Dussardier Marjolaine Willems Hilde Van Esch Vincent Des Portes Salima El Chehadeh

J Med Genet 2018 Jun 4;55(6):359-371. Epub 2018 Apr 4.

Service de génétique médicale, Institut de Génétique Médicale d'Alsace (IGMA), Centre de Référence Maladies Rares "Anomalies du développement et syndromes malformatifs", Centre de Référence Maladies Rares "Des déficiences intellectuelles de causes rares", Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.

The Xq28 duplication involving the gene ( duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.
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http://dx.doi.org/10.1136/jmedgenet-2017-104956DOI Listing
June 2018

Diagnostic strategy in segmentation defect of the vertebrae: a retrospective study of 73 patients.

J Med Genet 2018 Jun 19;55(6):422-429. Epub 2018 Feb 19.

Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Est, FHU-TRANSLAD, CHU Dijon, Dijon, France.

Background: Segmentation defects of the vertebrae (SDV) are non-specific features found in various syndromes. The molecular bases of SDV are not fully elucidated due to the wide range of phenotypes and classification issues. The genes involved are in the Notch signalling pathway, which is a key system in somitogenesis. Here we report on mutations identified in a diagnosis cohort of SDV. We focused on spondylocostal dysostosis (SCD) and the phenotype of these patients in order to establish a diagnostic strategy when confronted with SDV.

Patients And Methods: We used DNA samples from a cohort of 73 patients and performed targeted sequencing of the five known SCD-causing genes (, , , and ) in the first 48 patients and whole-exome sequencing (WES) in 28 relevant patients.

Results: Ten diagnoses, including four biallelic variants in , two biallelic variants in and , and one in and , were made with the gene panel, and two diagnoses, including biallelic variants in and one variant in were made by WES. The diagnostic yield of the gene panel was 10/73 (13.7%) in the global cohort but 8/10 (80%) in the subgroup meeting the SCD criteria; the diagnostic yield of WES was 2/28 (8%).

Conclusion: After negative array CGH, targeted sequencing of the five known SCD genes should only be performed in patients who meet the diagnostic criteria of SCD. The low proportion of candidate genes identified by WES in our cohort suggests the need to consider more complex genetic architectures in cases of SDV.
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http://dx.doi.org/10.1136/jmedgenet-2017-104939DOI Listing
June 2018

Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses.

Eur J Med Genet 2017 Nov 12;60(11):595-604. Epub 2017 Aug 12.

Equipe Génétique des Anomalies du Développement, INSERM UMR1231, Université de Bourgogne-Franche Comté, Dijon, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d'Enfants, CHU Dijon et Université de Bourgogne, Dijon, France. Electronic address:

Background And Objective: Whole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results.

Methods: WES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation.

Results: The diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials.

Conclusions: This pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families.
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http://dx.doi.org/10.1016/j.ejmg.2017.08.011DOI Listing
November 2017

and screen in the Sotos-like syndrome French cohort.

J Med Genet 2016 Nov 17;53(11):743-751. Epub 2016 Jun 17.

Département de Génétique, Centre de référence des anomalies du développement et syndromes malformatifs, Hôpital Trousseau, AP-HP, Paris, France.

Background: Heterozygous mutations were identified in 60%-90% of patients with Sotos syndrome. Recently, mutations of the and genes were identified in patients exhibiting only some Sotos syndrome features. Both and genes encode epigenetic 'writer' proteins that catalyse methylation of histone 3 lysine 36 (H3K36me). The gene encodes an epigenetic 'reader' protein of the H3K36me chromatin mark.

Methods: We aimed at confirming the implication of and mutations in an overgrowth phenotype, through a comprehensive targeted-next generation sequencing (NGS) screening in 210 well-phenotyped index cases with a Sotos-like phenotype and no mutation, from a French cohort.

Results: Six unreported heterozygous likely pathogenic variants in were identified in seven patients: two nonsense variants and four de novo missense variants. One de novo unreported heterozygous frameshift variant was identified in in one patient. All the four DNMT3A missense variants affected DNMT3A functional domains, suggesting a potential deleterious impact. -mutated index cases shared similar clinical features including overgrowth phenotype characterised by postnatal tall stature (≥+2SD), macrocephaly (≥+2SD), overweight or obesity at older age, intellectual deficiency and minor facial features. The phenotype associated with mutations remains to be described more precisely. The p.Arg882Cys missense de novo constitutional DNMT3A variant found in two patients is the most frequent somatic mutation in acute leukaemia.

Conclusions: Our results illustrate the power of targeted NGS to identify rare disease-causing variants. These observations provided evidence for a unifying mechanism (disruption of apposition and reading of the epigenetic chromatin mark H3K36me) that causes an overgrowth syndrome phenotype. Further studies are needed in order to assess the role of and in intellectual deficiency without overgrowth.
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http://dx.doi.org/10.1136/jmedgenet-2015-103638DOI Listing
November 2016

Large national series of patients with Xq28 duplication involving MECP2: Delineation of brain MRI abnormalities in 30 affected patients.

Am J Med Genet A 2016 Jan 30;170A(1):116-29. Epub 2015 Sep 30.

Service de Radiologie, Hôpital Femme Mère Enfant, Bron, France.

Xq28 duplications encompassing MECP2 have been described in male patients with a severe neurodevelopmental disorder associated with hypotonia and spasticity, severe learning disability, stereotyped movements, and recurrent pulmonary infections. We report on standardized brain magnetic resonance imaging (MRI) data of 30 affected patients carrying an Xq28 duplication involving MECP2 of various sizes (228 kb to 11.7 Mb). The aim of this study was to seek recurrent malformations and attempt to determine whether variations in imaging features could be explained by differences in the size of the duplications. We showed that 93% of patients had brain MRI abnormalities such as corpus callosum abnormalities (n = 20), reduced volume of the white matter (WM) (n = 12), ventricular dilatation (n = 9), abnormal increased hyperintensities on T2-weighted images involving posterior periventricular WM (n = 6), and vermis hypoplasia (n = 5). The occipitofrontal circumference varied considerably between >+2SD in five patients and <-2SD in four patients. Among the nine patients with dilatation of the lateral ventricles, six had a duplication involving L1CAM. The only patient harboring bilateral posterior subependymal nodular heterotopia also carried an FLNA gene duplication. We could not demonstrate a correlation between periventricular WM hyperintensities/delayed myelination and duplication of the IKBKG gene. We thus conclude that patients with an Xq28 duplication involving MECP2 share some similar but non-specific brain abnormalities. These imaging features, therefore, could not constitute a diagnostic clue. The genotype-phenotype correlation failed to demonstrate a relationship between the presence of nodular heterotopia, ventricular dilatation, WM abnormalities, and the presence of FLNA, L1CAM, or IKBKG, respectively, in the duplicated segment.
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http://dx.doi.org/10.1002/ajmg.a.37384DOI Listing
January 2016

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.

UF de Génétique Moléculaire, Service de Biochimie et Biologie Moléculaire, Hôpital Lariboisière, Paris, 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

WWOX and severe autosomal recessive epileptic encephalopathy: first case in the prenatal period.

J Hum Genet 2015 May 26;60(5):267-71. Epub 2015 Feb 26.

Laboratoire de Génétique Médicale, Centre Hospitalier Universitaire de Nancy, INSERM U954, Université de Lorraine, Rue du Morvan, Vandoeuvre-les-Nancy, France.

WWOX has been recently implicated in autosomal recessive spinocerebellar ataxia type 12 (SCAR12) and severe early-onset epileptic encephalopathy (EOEE). By array comparative genomic hybridization, we identified a 0.6 Mb homozygous deletion in 16q23.1 in a fetus presenting with brain anomalies. His older sister who died at the age of 22 months from an EOEE was also homozygous for the copy number variations in 16q23.1. This deletion includes the first six exons of WWOX and results in a null genotype in homozygous patients. This family gives additional support for the implication of WWOX in severe EOEEs. We report for the first time prenatal ultrasound findings in a fetus with a WWOX-null genotype. Our study expands the range of brain abnormalities in WWOX-related EOEEs. This additional family confirms the genotype-phenotype correlation with WWOX-null alleles associated with the most severe form of WWOX-related epileptic encephalopathy with premature death.
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http://dx.doi.org/10.1038/jhg.2015.17DOI Listing
May 2015

WWOX-related encephalopathies: delineation of the phenotypical spectrum and emerging genotype-phenotype correlation.

J Med Genet 2015 Jan 19;52(1):61-70. Epub 2014 Nov 19.

Laboratoire de Génétique Médicale, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France. Université de Lorraine, Inserm U954 Nutrition-Genetics-Environmental Risk Exposure, Medical Faculty, Vandoeuvre-les-Nancy, France.

Background: Homozygous mutations in WWOX were reported in eight individuals of two families with autosomal recessive spinocerebellar ataxia type 12 and in two siblings with infantile epileptic encephalopathy (IEE), including one who deceased prior to DNA sampling.

Methods: By combining array comparative genomic hybridisation, targeted Sanger sequencing and next generation sequencing, we identified five further patients from four families with IEE due to biallelic alterations of WWOX.

Results: We identified eight deleterious WWOX alleles consisting in four deletions, a four base-pair frameshifting deletion, one missense and two nonsense mutations. Genotype-phenotype correlation emerges from the seven reported families. The phenotype in four patients carrying two predicted null alleles was characterised by (1) little if any psychomotor acquisitions, poor spontaneous motility and absent eye contact from birth, (2) pharmacoresistant epilepsy starting in the 1st weeks of life, (3) possible retinal degeneration, acquired microcephaly and premature death. This contrasted with the less severe autosomal recessive spinocerebellar ataxia type 12 phenotype due to hypomorphic alleles. In line with this correlation, the phenotype in two siblings carrying a null allele and a missense mutation was intermediate.

Conclusions: Our results obtained by a combination of different molecular techniques undoubtedly incriminate WWOX as a gene for recessive IEE and illustrate the usefulness of high throughput data mining for the identification of genes for rare autosomal recessive disorders. The structure of the WWOX locus encompassing the FRA16D fragile site might explain why constitutive deletions are recurrently reported in genetic databases, suggesting that WWOX-related encephalopathies, although likely rare, may not be exceptional.
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http://dx.doi.org/10.1136/jmedgenet-2014-102748DOI Listing
January 2015

[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

Late onset epileptic spasms is frequent in MECP2 gene duplication: electroclinical features and long-term follow-up of 8 epilepsy patients.

Eur J Paediatr Neurol 2014 Jul 26;18(4):475-81. Epub 2014 Mar 26.

APHP, Hôpital Robert Debré, Service de Neurologie Pédiatrique, 75019 Paris, France; Inserm, U676, 75019 Paris, France; Univ Paris Diderot, Sorbonne Paris Cité, INSERM UMR676, 75019 Paris, France. Electronic address:

Unlabelled: Mutation of the X-linked methyl CpG binding protein 2 (MECP2) has been first identified as the cause of Rett syndrome. More recently, MECP2 gene duplication syndrome has been identified in males. The MECP2 duplication syndrome is characterized by severe mental retardation, infantile hypotonia, progressive spasticity and recurrent infections. Epileptic seizures are inconstant but poorly described. The aim of the study is to describe the electroclinical features of epilepsy in MECP2 duplication patients in order to refine the epilepsy phenotype and its evolution.

Methods: We conducted a retrospective study in four child neurology departments in France. Eight boys with a MECP2 gene duplication and epilepsy were retrospectively studied. We evaluated both clinical and electroencephalographic data before seizure onset, at seizure onset and during the follow-up.

Results: The patients started seizures at the median age of 6 years (range: 2.5-17 years). Half exhibits late onset epileptic spasms while the other exhibit either focal epilepsy or unclassified generalized epilepsy. Before seizure onset, EEGs were abnormal in all patients showing a slowing of the background or a normal background with fast activities, while EEG performed in epileptic patients, showed a slowing of the background in 6/8 and localized slow or sharp waves in 7/8. Most patients (6/8) have evolved to drug resistant epilepsy.

Conclusion: Although late onset epileptic spasms are common in patients with MECP2 duplication, no specific electroclinical phenotype emerges, probably due to genetic heterogeneity of the syndrome. Further studies are needed to individualize specific epileptic subtype in larger cohort of patients.
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http://dx.doi.org/10.1016/j.ejpn.2014.03.005DOI Listing
July 2014

Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.

Hum Mutat 2014 Mar 13;35(3):356-67. Epub 2014 Jan 13.

Department of Medicine and Health Science, University of Molise, Campobasso, Italy.

Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy." In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies.
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http://dx.doi.org/10.1002/humu.22500DOI Listing
March 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

Autoimmune limbic encephalopathy and anti-Hu antibodies in children without cancer.

Neurology 2013 Jun 8;80(24):2226-32. Epub 2013 May 8.

French Reference Center on Paraneoplastic Neurological Syndrome, Hospices Civils de Lyon, Hôpital Neurologique, Neurologie B, Bron, France.

Objective: The aim of this study was to describe the clinical presentation of children and adolescents with anti-Hu antibodies (Hu-Abs).

Methods: This was a retrospective study of children and adolescents with Hu-Abs collected by the French Paraneoplastic Neurological Syndrome (PNS) Reference Center between January 1, 2000 and December 31, 2011.

Results: The center identified 251 patients with Hu-Abs. Only 8 patients were younger than 18 years. All of the 243 adult patients had PNS. In contrast, of the 8 children, only 2 (25%, Fisher exact test p = 0.0003) had neuroblastoma and opsoclonus-myoclonus. The other 6 children (5 female and 1 male) presented with limbic encephalitis (progressive personality changes, memory loss, and seizure) and were free of cancer (mean follow-up time: 50 months; range: 34-72 months). Brain MRI scans were abnormal in 4 of the 6 patients, with left, right, or bitemporal T2/fluid-attenuated inversion recovery hyperintensity. Protein levels and cell counts in the CSF were normal in all patients, but numerous oligoclonal bands were observed in 4 patients. All 6 patients received antiepileptic drugs and immunotherapy, but management of epilepsy was difficult in all of them. Five of the children developed cognitive impairments.

Conclusion: In children, as in adults, Hu-Abs can be a marker of PNS. However, in contrast to adults, Hu-Abs in children are also associated with an aggressive form of autoimmune nonparaneoplastic limbic encephalitis. Future studies should be conducted to determine the incidence of this syndrome and whether earlier diagnosis and T-cell-directed immunotherapies may improve its prognosis.
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http://dx.doi.org/10.1212/WNL.0b013e318296e9c3DOI Listing
June 2013

The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy.

J Med Genet 2012 Dec 25;49(12):731-6. Epub 2012 Oct 25.

Equipe émergente GAD EA 4271 (Génétique des Anomalies du développement), IFR Santé STIC, Université de Bourgogne, Dijon, France.

Background: DYRK1A plays different functions during development, with an important role in controlling brain growth through neuronal proliferation and neurogenesis. It is expressed in a gene dosage dependent manner since dyrk1a haploinsufficiency induces a reduced brain size in mice, and DYRK1A overexpression is the candidate gene for intellectual disability (ID) and microcephaly in Down syndrome. We have identified a 69 kb deletion including the 5' region of the DYRK1A gene in a patient with growth retardation, primary microcephaly, facial dysmorphism, seizures, ataxic gait, absent speech and ID. Because four patients previously reported with intragenic DYRK1A rearrangements or 21q22 microdeletions including only DYRK1A presented with overlapping phenotypes, we hypothesised that DYRK1A mutations could be responsible for syndromic ID with severe microcephaly and epilepsy.

Methods: The DYRK1A gene was studied by direct sequencing and quantitative PCR in a cohort of 105 patients with ID and at least two symptoms from the Angelman syndrome spectrum (microcephaly < -2.5 SD, ataxic gait, seizures and speech delay).

Results: We identified a de novo frameshift mutation (c.290_291delCT; p.Ser97Cysfs*98) in a patient with growth retardation, primary severe microcephaly, delayed language, ID, and seizures.

Conclusion: The identification of a truncating mutation in a patient with ID, severe microcephaly, epilepsy, and growth retardation, combined with its dual function in regulating the neural proliferation/neuronal differentiation, adds DYRK1A to the list of genes responsible for such a phenotype. ID, microcephaly, epilepsy, and language delay are the more specific features associated with DYRK1A abnormalities. DYRK1A studies should be discussed in patients presenting such a phenotype.
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http://dx.doi.org/10.1136/jmedgenet-2012-101251DOI Listing
December 2012

14q12 and severe Rett-like phenotypes: new clinical insights and physical mapping of FOXG1-regulatory elements.

Eur J Hum Genet 2012 Dec 27;20(12):1216-23. Epub 2012 Jun 27.

EA 4368, Déficiences mentales et anomalies de structure du génome, Faculté de Médecine, Université de Lorraine, Vandoeuvre-les-Nancy, France.

The Forkhead box G1 (FOXG1) gene has been implicated in severe Rett-like phenotypes. It encodes the Forkhead box protein G1, a winged-helix transcriptional repressor critical for forebrain development. Recently, the core FOXG1 syndrome was defined as postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and dysgenesis of the corpus callosum. We present seven additional patients with a severe Rett-like neurodevelopment disorder associated with de novo FOXG1 point mutations (two cases) or 14q12 deletions (five cases). We expand the mutational spectrum in patients with FOXG1-related encephalopathies and precise the core FOXG1 syndrome phenotype. Dysgenesis of the corpus callosum and dyskinesia are not always present in FOXG1-mutated patients. We believe that the FOXG1 gene should be considered in severely mentally retarded patients (no speech-language) with severe acquired microcephaly (-4 to-6 SD) and few clinical features suggestive of Rett syndrome. Interestingly enough, three 14q12 deletions that do not include the FOXG1 gene are associated with phenotypes very reminiscent to that of FOXG1-mutation-positive patients. We physically mapped a putative long-range FOXG1-regulatory element in a 0.43 Mb DNA segment encompassing the PRKD1 locus. In fibroblast cells, a cis-acting regulatory sequence located more than 0.6 Mb away from FOXG1 acts as a silencer at the transcriptional level. These data are important for clinicians and for molecular biologists involved in the management of patients with severe encephalopathies compatible with a FOXG1-related phenotype.
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http://dx.doi.org/10.1038/ejhg.2012.127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499785PMC
December 2012