Didier Lacombe

Publications (132)627.99 Total impact

• Source

  Available from: Dennis Bulman

  Article: The phenotype of floating-harbor syndrome: clinical characterization of 52 individuals with mutations in exon 34 of SRCAP.

  Sarah M Nikkel, Andrew Dauber, Sonja de Munnik, Meghan Connolly, Rebecca L Hood, Oana Caluseriu, Jane Hurst, Usha Kini, Malgorzata J Nowaczyk, Alexandra Afenjar, [......], Dagmar Wierczorek, Jan M Wit, Connie Fung Yee, Chandree L Beaulieu, Sue M White, Dennis E Bulman, Ernie Bongers, Han Brunner, Murray Feingold, Kym M Boycott
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  ABSTRACT: BACKGROUND: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delays in expressive language, and a distinctive facial appearance. Recently, heterozygous truncating mutations in SRCAP were determined to be disease causing. With the availability of a DNA based confirmatory test, we set forth to define the clinical features of this syndrome.Methods and resultsClinical information on fifty-two individuals with SRCAP mutations was collected using standardized questionnaires. Twenty-four males and twenty-eight females were studied with ages ranging from 2 to 52 years. The facial phenotype and expressive language impairments were defining features within the group. Height measurements were typically between minus two and minus four standard deviations, with occipitofrontal circumferences usually within the average range. Thirty-three of the subjects (63%) had at least one major anomaly requiring medical intervention. We did not observe any specific phenotype-genotype correlations. CONCLUSIONS: This large cohort of individuals with molecularly confirmed FHS has allowed us to better delineate the clinical features of this rare but classic genetic syndrome, thereby facilitating the development of management protocols.
  Orphanet Journal of Rare Diseases 04/2013; 8(1):63. · 5.83 Impact Factor
• Article: Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly.

  Karine Poirier, Nicolas Lebrun, Loic Broix, Guoling Tian, Yoann Saillour, Cécile Boscheron, Elena Parrini, Stephanie Valence, Benjamin Saint Pierre, Madison Oger, [......], Patrick Nitschke, Thierry Hieu, Cecile Masson, Diana Zelenika, Annie Andrieux, Fiona Francis, Renzo Guerrini, Nicholas J Cowan, Nadia Bahi-Buisson, Jamel Chelly
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  ABSTRACT: The genetic causes of malformations of cortical development (MCD) remain largely unknown. Here we report the discovery of multiple pathogenic missense mutations in TUBG1, DYNC1H1 and KIF2A, as well as a single germline mosaic mutation in KIF5C, in subjects with MCD. We found a frequent recurrence of mutations in DYNC1H1, implying that this gene is a major locus for unexplained MCD. We further show that the mutations in KIF5C, KIF2A and DYNC1H1 affect ATP hydrolysis, productive protein folding and microtubule binding, respectively. In addition, we show that suppression of mouse Tubg1 expression in vivo interferes with proper neuronal migration, whereas expression of altered γ-tubulin proteins in Saccharomyces cerevisiae disrupts normal microtubule behavior. Our data reinforce the importance of centrosomal and microtubule-related proteins in cortical development and strongly suggest that microtubule-dependent mitotic and postmitotic processes are major contributors to the pathogenesis of MCD.
  Nature Genetics 04/2013; · 35.53 Impact Factor
• Article: Phenotypic Spectrum of Simpson-Golabi-Behmel Syndrome in a Series of 42 Cases With a Mutation in GPC3 and Review of the Literature.

  Edouard Cottereau, Isabelle Mortemousque, Marie-Pierre Moizard, Lydie Bürglen, Didier Lacombe, Brigitte Gilbert-Dussardier, Sabine Sigaudy, Odile Boute, Albert David, Laurence Faivre, [......], Pierre Sarda, Marjolaine Willems, Adeline Jacquinet, Ilham Ratbi, Jenneke VAN DEN Ende, Marylin Lackmy-Port Lis, Alice Goldenberg, Dominique Bonneau, Sylvie Rossignol, Annick Toutain
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  ABSTRACT: Simpson-Golabi-Behmel syndrome (SGBS) is a rare X-linked multiple congenital abnormality/intellectual disability syndrome characterized by pre- and post-natal overgrowth, distinctive craniofacial features, macrocephaly, variable congenital malformations, organomegaly, increased risk of tumor and mild/moderate intellectual deficiency. In 1996, Glypican 3 (GPC3) was identified as the major gene causing SGBS but the mutation detection rate was only 28-70%, suggesting either genetic heterogeneity or that some patients could have alternative diagnoses. This was particularly suggested by some reports of atypical cases with more severe prognoses. In the family reported by Golabi and Rosen, a duplication of GPC4 was recently identified, suggesting that GPC4 could be the second gene for SGBS but no point mutations within GPC4 have yet been reported. In the genetics laboratory in Tours Hospital, GPC3 molecular testing over more than a decade has detected pathogenic mutations in only 8.7% of individuals with SGBS. In addition, GPC4 mutations have not been identified thus raising the question of frequent misdiagnosis. In order to better delineate the phenotypic spectrum of SGBS caused by GPC3 mutations, and to try to define specific clinical criteria for GPC3 molecular testing, we reviewed the clinical features of all male cases with a GPC3 mutation identified in the two molecular laboratories providing this test in France (Tours and Paris). We present here the results of the analysis of 42 patients belonging to 31 families and including five fetuses and three deceased neonates. © 2013 Wiley Periodicals, Inc.
  American Journal of Medical Genetics Part C Seminars in Medical Genetics 04/2013; · 4.06 Impact Factor
• Article: Clinical and Molecular Spectrum of Renal Malformations in Kabuki Syndrome.

  Jean-Benoît Courcet, Laurence Faivre, Caroline Michot, Antoine Burguet, Stéphanie Perez-Martin, Eudeline Alix, Jeanne Amiel, Clarisse Baumann, Marie-Pierre Cordier, Valérie Cormier-Daire, [......], Catherine Vincent-Delorme, Christiane Mousson, Sandrine Vinault, Christine Binquet, Frédéric Huet, Pierre Sarda, Rémi Salomon, Stanislas Lyonnet, Damien Sanlaville, David Geneviève
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  ABSTRACT: OBJECTIVE: To determine the frequency and types of renal malformations, and to evaluate renal function in a cohort of patients with Kabuki syndrome (KS). STUDY DESIGN: Renal ultrasound scans and plasma creatinine measurements were collected from a French cohort of 94 patients with genotyped KS. Renal function was evaluated based on the estimated glomerular filtration rate. A genotype-phenotype study was conducted for renal and urinary tract malformations. RESULTS: Renal malformations were present in 22% of cases, and urinary tract anomalies were present in 15%. Renal malformations were observed in 28% of the MLL2 mutation-positive group and in 0% of the MLL2 mutation-negative group (P = .015). No correlation was found between the presence or absence of renal or urinary tract malformations and the location or type of MLL2 mutation. Renal function was normal except for 1 patient with a MLL2 mutation diagnosed in the first days of life and severe renal disease due to unilateral renal agenesia and controlateral severe hypoplasia that progressed to the terminal stage at age 2 years. CONCLUSION: Our study emphasizes the need for ultrasound and renal function screening in children diagnosed with KS.
  The Journal of pediatrics 03/2013; · 4.02 Impact Factor
• Article: Detailed clinical, genetic and neuroimaging characterization of OFD VI syndrome.

  Véronique Darmency-Stamboul, Lydie Burglen, Estelle Lopez, Nathalie Mejean, John Dean, Brunella Franco, Diana Rodriguez, Didier Lacombe, Isabelle Desguerres, Valérie Cormier-Daire, [......], Marie Gonzales, Matthew Pastore, Melissa L Loscalzo, Frédéric Huet, Nadège Gigot, Bernard Aral, Patrick Callier, Laurence Faivre, Tania Attié-Bitach, Christel Thauvin-Robinet
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  ABSTRACT: Oral-facial-digital syndrome type VI (OFD VI) is characterized by the association of malformations of the face, oral cavity and extremities, distinguished from the 12 other OFD syndromes by cerebellar and metacarpal abnormalities. Cerebellar malformations in OFD VI have been described as a molar tooth sign (MTS), thus, including OFD VI among the «Joubert syndrome related disorders» (JSRD). OFD VI diagnostic criteria have recently been suggested: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of hands or feet; 3) hypothalamic hamartoma. In order to further delineate this rare entity, we present the neurological and radiological data of 6 additional OFD VI patients. All patients presented oral malformations, facial dysmorphism and distal abnormalities including frequent polydactyly (66%), as well as neurological symptoms with moderate to severe mental retardation. Contrary to historically reported patients, mesoaxial polydactyly did not appear to be a predominant clinical feature in OFD VI. Sequencing analyses of the 14 genes implicated in JSRD up to 2011 revealed only an OFD1 frameshift mutation in one female OFD VI patient, strengthening the link between these two oral-facial-digital syndromes and JSRD.
  European journal of medical genetics 03/2013; · 1.57 Impact Factor
• Article: Prenatal diagnosis using array-CGH: a French experience.

  Caroline Rooryck, Jérôme Toutain, Dorothée Cailley, Julie Bouron, Jacques Horovitz, Didier Lacombe, Benoit Arveiler, Robert Saura
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  ABSTRACT: Array-CGH or Chromosomal Microarray Analysis (CMA) is increasingly used in prenatal diagnosis throughout the world. However, routine practices are very different among centers and countries, regarding CMA indications, design and resolution of microarrays, notification and interpretation of Copy Number Alterations (CNA). We present our data and experience from our Fetal Medecine Center on 224 prospective prenatal diagnoses. Our approach is practical, and aims to propose a strategy to offer Chromosomal Microarray Analysis (CMA) to selected fetuses and to help to interpret CNA. We hope that this publication could encourage development of CMA in centers that have not started yet this activity in prenatal routine, and could contribute to edict guidelines in this field.
  European journal of medical genetics 02/2013; · 1.57 Impact Factor
• Article: Mutations in WNT10A are frequently involved in oligodontia associated with minor signs of ectodermal dysplasia.

  Julie Plaisancié, Isabelle Bailleul-Forestier, Véronique Gaston, Fréderic Vaysse, Didier Lacombe, Muriel Holder-Espinasse, Marc Abramowicz, Christine Coubes, Ghislaine Plessis, Laurence Faivre, [......], Hélène Dollfus, Sabine Sigaudy, Encarna Guillén-Navarro, Alain Verloes, Philippe Jonveaux, Dominique Martin-Coignard, Estelle Colin, Eric Bieth, Patrick Calvas, Nicolas Chassaing
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  ABSTRACT: Ectodermal dysplasias (ED) are a clinically and genetically heterogeneous group of hereditary disorders that have in common abnormal development of ectodermal derivatives. Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of eccrine sweat glands, hair, and teeth. The X-linked form of the disease, caused by mutations in the EDA gene, represents the majority of patients with the hypohidrotic form. Autosomal dominant and autosomal recessive forms are occasionally seen, and result from mutations in at least three genes (WNT10A, EDAR, or more rarely EDARADD). We have screened for mutations in EDAR (commonly involved in the hypohidrotic form) and WNT10A (involved in a wide spectrum of ED and in isolated hypodontia) in a cohort of 36 patients referred for EDA molecular screening, which failed to identify any mutation. We identified eight EDAR mutations in five patients (two with homozygous mutations, one with compound heterozygous mutations, and two with heterozygous mutation), four of which were novel variants. We identified 28 WNT10A mutations in 16 patients (5 with homozygous mutations, 7 with compound heterozygous mutations, and 4 with heterozygous mutations), seven of which were novel variants. Our study allows a more precise definition of the phenotypic spectrum associated with EDAR and WNT10A mutations and underlines the importance of the implication of WNT10A among patients with ED. © 2013 Wiley Periodicals, Inc.
  American Journal of Medical Genetics Part A 02/2013; · 2.39 Impact Factor
• Article: Germiline Mosaicism in Rubinstein-Taybi Syndrome.

  Mariam Tajir, Patricia Fergelot, Guenaelle Lancelot, Siham Chafai Elalaoui, Benoit Arveiler, Didier Lacombe, Abdelaziz Sefiani
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  ABSTRACT: Rubinstein-Taybi syndrome is an autosomal dominant disorder with multiple congenital anomalies and genetic heterogeneity. Clinical manifestations include mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and characteristic facial features. Mutations in the gene encoding the transcriptional coactivator CREB-binding protein (CREBBP; OMIM 600140) on chromosome 16p13, account for about 50% to 70% of patients. Most of CREBBP mutations are de novo and the rate of recurrence in a family is low. Families with several affected children are extremely rare. We report here a Moroccan family with two children with RSTS and apparently unaffected parents. The molecular studies showed a heterozygous mutation c.4361T>A (p.Leu1454His) in exon 26 of the CREBBP gene in the two affected sibs. Neither the parents, nor the healthy brother, carry this mutation in hematologic cells. The mutation was also absent in buccal epithelial cells of both parents. We discuss the hypothesis of germinal mosaicism. This concept is very important because it complicates genetic counseling of this family who has a risk of recurrence of the mutation in subsequent pregnancies.
  Gene 01/2013; · 2.34 Impact Factor
• Article: Reduced Placental Telomere Length during Pregnancies Complicated by Intrauterine Growth Restriction.

  Jérôme Toutain, Martina Prochazkova-Carlotti, David Cappellen, Ana Jarne, Edith Chevret, Jacky Ferrer, Yamina Idrissi, Fanny Pelluard, Dominique Carles, Brigitte Maugey-Laulon, Didier Lacombe, Jacques Horovitz, Jean-Philippe Merlio, Robert Saura
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  ABSTRACT: Recent studies have shown that telomere length was significantly reduced in placentas collected at delivery from pregnancies complicated by intrauterine growth restriction secondary to placental insufficiency. Placental telomere length measurement during ongoing pregnancies complicated by intrauterine growth restriction has never been reported. This was the main objective of our study. In our center, late chorionic villus samplings were performed between 18 and 37 weeks of amenorrhea in 24 subjects with severe intrauterine growth restriction (cases) and in 28 subjects with other indications for prenatal diagnosis (controls). Placental insufficiency was assessed by histo-pathological examination. Relative measurement of telomere length was carried out prospectively by quantitative Fluorescent In Situ Hybridization using fluorescent Peptide Nucleic Acid probes on interphase nuclei obtained from long-term cultured villi and with an automated epifluorescent microscope. A quantitative Polymerase Chain Reaction technique was performed to confirm the quantitative Fluorescent In Situ Hybridization results. The number of copies of gene loci encoding the RNA template (hTERC) and the catalytic subunit (hTERT) of the enzyme complex telomerase were also estimated in these placentas by Fluorescent In Situ Hybridization. Mean fluorescence intensity of telomere probes estimated by quantitative Fluorescent In Situ Hybridization was significantly less for cases compared to controls (p<0.001). This result indicated that mean telomere length was significantly reduced in placentas during pregnancies complicated by intrauterine growth restriction. Reduced telomere length was confirmed by the quantitative Polymerase Chain Reaction technique. No copy number variation of the hTERC and hTERT loci was noticed for cases, or for controls. This study clearly demonstrates a reduction of placental telomere length in ongoing pregnancies (from 18 to 37 weeks of amenorrhea) complicated by severe intrauterine growth restriction secondary to placental insufficiency.
  PLoS ONE 01/2013; 8(1):e54013. · 4.09 Impact Factor
• Source

  Available from: Sylvie Hanu Manouvrier

  Dataset: Hyperprolinemia-Del22

  Gaelle Opolczynski, Didier Lacombe, Valérie Layet, Cyril Coizet, Georges-Marie M Brévière, Yves Alembik, Gabriella Di Rosa, Valérie Drouin-Garraud, Giuseppina Pustorino, Marie Lemarchand, [......], Thierry Frebourg, Dominique Campion, Anne Philippe, Marie Christine Nolen, Delphine Heron, Pierre Sarda, Ann Swillen, Carole Fantini, Solenn Legallic, Jacqueline Bou
• Article: EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia.

  Christopher T Gordon, Florence Petit, Myriam Oufadem, Charles Decaestecker, Anne-Sophie Jourdain, Joris Andrieux, Valérie Malan, Jean-Luc Alessandri, Geneviève Baujat, Clarisse Baumann, [......], Ingrid Simonic, Arnold Munnich, Michel Vekemans, Nicole Porchet, Loïc de Pontual, Sabine Sarnacki, Tania Attie-Bitach, Stanislas Lyonnet, Muriel Holder-Espinasse, Jeanne Amiel
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  ABSTRACT: : Oesophageal atresia (OA) and mandibulofacial dysostosis (MFD) are two congenital malformations for which the molecular bases of syndromic forms are being identified at a rapid rate. In particular, the EFTUD2 gene encoding a protein of the spliceosome complex has been found mutated in patients with MFD and microcephaly (MIM610536). Until now, no syndrome featuring both MFD and OA has been clearly delineated. : We report on 10 cases presenting with MFD, eight of whom had OA, either due to de novo 17q21.31 deletions encompassing EFTUD2 and neighbouring genes or de novo heterozygous EFTUD2 loss-of-function mutations. No EFTUD2 deletions or mutations were found in a series of patients with isolated OA or isolated oculoauriculovertebral spectrum (OAVS). : These data exclude a contiguous gene syndrome for the association of MFD and OA, broaden the spectrum of clinical features ascribed to EFTUD2 haploinsufficiency, define a novel syndromic OA entity, and emphasise the necessity of mRNA maturation through the spliceosome complex for global growth and within specific regions of the embryo during development. Importantly, the majority of patients reported here with EFTUD2 lesions were previously diagnosed with Feingold or CHARGE syndromes or presented with OAVS plus OA, highlighting the variability of expression and the wide range of differential diagnoses.
  Journal of Medical Genetics 12/2012; 49(12):737-46. · 6.36 Impact Factor
• Article: The 2q37-deletion syndrome: an update of the clinical spectrum including overweight, brachydactyly and behavioural features in 14 new patients.

  Camille Leroy, Emilie Landais, Sylvain Briault, Albert David, Olivier Tassy, Nicolas Gruchy, Bruno Delobel, Marie-José Grégoire, Bruno Leheup, Laurence Taine, [......], Nathalie Leporrier, Jacques Motte, Caroline Fiquet, Olivier Brichet, Monique Mozelle-Nivoix, Pascal Sabouraud, Nathalie Golovkine, Nathalie Bednarek, Dominique Gaillard, Martine Doco-Fenzy
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  ABSTRACT: The 2q37 locus is one of the most commonly deleted subtelomeric regions. Such a deletion has been identified in >100 patients by telomeric fluorescence in situ hybridization (FISH) analysis and, less frequently, by array-based comparative genomic hybridization (array-CGH). A recognizable '2q37-deletion syndrome' or Albright's hereditary osteodystrophy-like syndrome has been previously described. To better map the deletion and further refine this deletional syndrome, we formed a collaboration with the Association of French Language Cytogeneticists to collect 14 new intellectually deficient patients with a distal or interstitial 2q37 deletion characterized by FISH and array-CGH. Patients exhibited facial dysmorphism (13/14) and brachydactyly (10/14), associated with behavioural problems, autism or autism spectrum disorders of varying severity and overweight or obesity. The deletions in these 14 new patients measured from 2.6 to 8.8 Mb. Although the major role of HDAC4 has been demonstrated, the phenotypic involvement of several other genes in the deleted regions is unknown. We further refined the genotype-phenotype correlation for the 2q37 deletion. To do this, we examined the smallest overlapping deleted region for candidate genes for skeletal malformations (facial dysmorphism and brachydactyly), overweight, behavioural problems and seizures, using clinical data, a review of the literature, and the Manteia database. Among the candidate genes identified, we focus on the roles of PRLH, PER2, TWIST2, CAPN10, KIF1A, FARP2, D2HGDH and PDCD1.European Journal of Human Genetics advance online publication, 17 October 2012; doi:10.1038/ejhg.2012.230.
  European journal of human genetics: EJHG 10/2012; · 3.56 Impact Factor
• Article: A homozygous balanced reciprocal translocation suggests LINC00237 as a candidate gene for MOMO (macrosomia, obesity, macrocephaly, and ocular abnormalities) syndrome.

  Phi Yen Vu, Jérôme Toutain, David Cappellen, Marie-Ange Delrue, Hussein Daoud, Azza Abd El Moneim, Pascal Barat, Orianne Montaubin, Françoise Bonnet, Zong Qi Dai, Christophe Philippe, Cong Toai Tran, Caroline Rooryck, Benoît Arveiler, Robert Saura, Sylvain Briault, Didier Lacombe, Laurence Taine
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  ABSTRACT: Macrosomia, obesity, macrocephaly, and ocular abnormalities syndrome (MOMO syndrome) has been reported in only four patients to date. In these sporadic cases, no chromosomal or molecular abnormality has been identified thus far. Here, we report on the clinical, cytogenetic, and molecular findings in a child of healthy consanguineous parents suffering from MOMO syndrome. Conventional karyotyping revealed an inherited homozygous balanced reciprocal translocation (16;20)(q21;p11.2). Uniparental disomy testing showed bi-parental inheritance for both derivative chromosomes 16 and 20. The patient's oligonucleotide array-comparative genomic hybridization profile revealed no abnormality. From the homozygous balanced reciprocal translocation (16;20)(q21;p11.2), a positional cloning strategy, designed to narrow 16q21 and 20p11.2 breakpoints, revealed the disruption of a novel gene located at 20p11.23. This gene is now named LINC00237, according to the HUGO (Human Genome Organization) nomenclature. The gene apparently leads to the production of a non-coding RNA. We established that LINC00237 was expressed in lymphocytes of control individuals while normal transcripts were absent in lymphocytes of our MOMO patient. LINC00237 was not ubiquitously expressed in control tissues, but it was notably highly expressed in the brain. Our results suggested autosomal recessive inheritance of MOMO syndrome. LINC00237 could play a role in the pathogenesis of this syndrome and could provide new insights into hyperphagia-related obesity and intellectual disability. © 2012 Wiley Periodicals, Inc.
  American Journal of Medical Genetics Part A 10/2012; 158A(11):2849-56. · 2.39 Impact Factor
• Article: Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström syndromes.

  Claire Redin, Stéphanie Le Gras, Oussema Mhamdi, Véronique Geoffroy, Corinne Stoetzel, Marie-Claire Vincent, Pietro Chiurazzi, Didier Lacombe, Ines Ouertani, Florence Petit, Marianne Till, Alain Verloes, Bernard Jost, Habiba Bouhamed Chaabouni, Helene Dollfus, Jean-Louis Mandel, Jean Muller
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  ABSTRACT: Bardet-Biedl syndrome (BBS) is a pleiotropic recessive disorder that belongs to the rapidly growing family of ciliopathies. It shares phenotypic traits with other ciliopathies, such as Alström syndrome (ALMS), nephronophthisis (NPHP) or Joubert syndrome. BBS mutations have been detected in 16 different genes (BBS1-BBS16) without clear genotype-to-phenotype correlation. This extensive genetic heterogeneity is a major concern for molecular diagnosis and genetic counselling. While various strategies have been recently proposed to optimise mutation detection, they either fail to detect mutations in a majority of patients or are time consuming and costly. We tested a targeted exon-capture strategy coupled with multiplexing and high-throughput sequencing on 52 patients: 14 with known mutations as proof-of-principle and 38 with no previously detected mutation. Thirty genes were targeted in total including the 16 BBS genes, the 12 known NPHP genes, the single ALMS gene ALMS1 and the proposed modifier CCDC28B. This strategy allowed the reliable detection of causative mutations (including homozygous/heterozygous exon deletions) in 68% of BBS patients without previous molecular diagnosis and in all proof-of-principle samples. Three probands carried homozygous truncating mutations in ALMS1 confirming the major phenotypic overlap between both disorders. The efficiency of detecting mutations in patients was positively correlated with their compliance with the classical BBS phenotype (mutations were identified in 81% of 'classical' BBS patients) suggesting that only a few true BBS genes remain to be identified. We illustrate some interpretation problems encountered due to the multiplicity of identified variants. This strategy is highly efficient and cost effective for diseases with high genetic heterogeneity, and guarantees a quality of coverage in coding sequences of target genes suited for diagnosis purposes.
  Journal of Medical Genetics 07/2012; 49(8):502-12. · 6.36 Impact Factor
• Article: Molecular characterization of 1q44 microdeletion in 11 patients reveals three candidate genes for intellectual disability and seizures.

  Gaelle Thierry, Claire Bénéteau, Olivier Pichon, Elisabeth Flori, Bertrand Isidor, Françoise Popelard, Marie-Ange Delrue, Laetitia Duboscq-Bidot, Ann-Charlotte Thuresson, Bregje W M van Bon, [......], Bassim Tou, Marie-Pierre Quéré, Cecilia Soussi-Zander, Annick Toutain, Didier Lacombe, Benoit Arveiler, Bert B A de Vries, Philippe Jonveaux, Albert David, Cédric Le Caignec
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  ABSTRACT: 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.
  American Journal of Medical Genetics Part A 06/2012; 158A(7):1633-40. · 2.39 Impact Factor
• Article: Oral manifestations of patients with Kenny-Caffey Syndrome.

  Youssra Moussaid, Didier Griffiths, Béatrice Richard, Anne Dieux, Martine Lemerrer, Juliane Léger, Didier Lacombe, Isabelle Bailleul-Forestier
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  ABSTRACT: Kenny-Caffey syndrome (KCS) is a rare osteosclerotic bone dysplasia characterized by hypocalcemia, short stature, ophthalmological features, and teeth anomalies. The TBCE gene coding for a tubulin-specific chaperone E, is located at chromosome 1q42-q43, and is responsible for the recessive form. After reviewing the literature, we found around 60 cases, however with limited dental data. In this article 5 new individuals with KCS, are described focusing on oral findings. All cases had short roots and showed dental anomalies as hypo/oligodontia, microdontia. Dental anomalies are a constant feature in KCS, further study is required to better delineate the syndrome.
  European journal of medical genetics 03/2012; 55(8-9):441-5. · 1.57 Impact Factor
• Source

  Available from: Sylvie Joriot

  Article: Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient.

  Lydie Burglen, Sandra Chantot-Bastaraud, Catherine Garel, Mathieu Milh, Renaud Touraine, Ginevra Zanni, Florence Petit, Alexandra Afenjar, Cyril Goizet, Sabina Barresi, [......], Christine Ioos, Leila Lazaro, Sylvie Joriot, Isabelle Desguerre, Didier Lacombe, Vincent des Portes, Enrico Bertini, Jean-Pierre Siffroi, Thierry Billette de Villemeur, Diana Rodriguez
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  ABSTRACT: Pontocerebellar hypoplasia (PCH) is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to TSEN54 mutations being the most frequent. PCH is most often autosomal recessive though de novo anomalies in the X-linked gene CASK have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH). Fourteen patients (12 females and two males; aged 16 months-14 years) presenting with PCH at neuroimaging and with clinical characteristics unsuggestive of PCH1 or PCH2 were included. The CASK gene screening was performed using Array-CGH and sequencing. Clinical and neuroradiological features were collected. We observed a high frequency of patients with a CASK mutation (13/14). Ten patients (8 girls and 2 boys) had intragenic mutations and three female patients had a Xp11.4 submicroscopic deletion including the CASK gene. All were de novo mutations. Phenotype was variable in severity but highly similar among the 11 girls and was characterized by psychomotor retardation, severe intellectual disability, progressive microcephaly, dystonia, mild dysmorphism, and scoliosis. Other signs were frequently associated, such as growth retardation, ophthalmologic anomalies (glaucoma, megalocornea and optic atrophy), deafness and epilepsy. As expected in an X-linked disease manifesting mainly in females, the boy hemizygous for a splice mutation had a very severe phenotype with nearly no development and refractory epilepsy. We described a mild phenotype in a boy with a mosaic truncating mutation. We found some degree of correlation between severity of the vermis hypoplasia and clinical phenotype. This study describes a new series of PCH female patients with CASK inactivating mutations and confirms that these patients have a recognizable although variable phenotype consisting of a specific form of pontocerebellar hypoplasia. In addition, we report the second male patient to present with a severe MICPCH phenotype and a de novo CASK mutation and describe for the first time a mildly affected male patient harboring a mosaic mutation. In our reference centre, CASK related PCH is the second most frequent cause of PCH. The identification of a de novo mutation in these patients enables accurate and reassuring genetic counselling.
  Orphanet Journal of Rare Diseases 03/2012; 7:18. · 5.83 Impact Factor
• Article: Adaptative Capacity of Mitochondrial Biogenesis and of Mitochondrial Dynamics in Response to Pathogenic Respiratory Chain Dysfunction.

  Giovanni Benard, Thomas Trian, Nadège Bellance, Patrick Berger, Julie Lavie, Caroline Espil-Taris, Christophe Rocher, Sandrine Eimer-Bouillot, Cyril Goizet, Karine Nouette-Gaulain, Thierry Letellier, Didier Lacombe, Rodrigue Rossignol
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  ABSTRACT: Abstract Aims: Cellular energy homeostasy relies on mitochondrial plasticity, the molecular determinants of which are multiple. Yet, the relative contribution of and possible cooperation between mitochondrial biogenesis and morphogenesis to cellular energy homeostasy remains elusive. Here we analyzed the adaptative capacity of mitochondrial content and dynamics in muscle biopsies of patients with a complex IV defect, and in skin fibroblasts challenged with complex IV inhibition. Results: We observed a biphasic variation of the mitochondrial content upon complex IV inhibition in muscle biopsies and in skin fibroblasts. Adjustment of mitochondrial content for respiratory maintenance was blocked by using a dominant negative form of CREB (CREB-M1) and by L-NAME, a blocker of NO production. Accordingly, cells treated with KCN 6 μM showed higher levels of phospho-CREB, PGC1α mRNA, eNOS mRNA, and mtTFA mRNA. We also observed the increased expression of the fission protein DRP1 during fibroblasts adaptation, as well as mitochondrial ultrastructural defects indicative of increased fission in patients muscle micrographs. Accordingly, the expression of a dominant negative form of DRP1 (K38A mutant) reduced the biogenic response in fibroblasts challenged with 6 μM KCN. Innovation: Our findings indicate that mitochondrial biogenesis and mitochondrial fission cooperate to promote cellular adaptation to respiratory chain inhibition. Conclusions: Our data show for the first time that DRP1 intervenes during the initiation of the mitochondrial adaptative response to respiratory chain defects. The evidenced pathway of mitochondrial adaptation to respiratory chain deficiency provides a safety mechanism against mitochondrial dysfunction. Antioxid. Redox Signal. 00, 000-000.
  Antioxidants & Redox Signaling 02/2012; · 8.20 Impact Factor
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  Available from: Caio Robledo D C Quaio

  Article: Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome.

  Rebecca L Hood, Matthew A Lines, Sarah M Nikkel, Jeremy Schwartzentruber, Chandree Beaulieu, Małgorzata J M Nowaczyk, Judith Allanson, Chong Ae Kim, Dagmar Wieczorek, Jukka S Moilanen, [......], George McGillivray, Ruobing Zou, D Ross McLeod, Albert E Chudley, Bernard N Chodirker, Janet Marcadier, Jacek Majewski, Dennis E Bulman, Susan M White, Kym M Boycott
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  ABSTRACT: Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.
  The American Journal of Human Genetics 02/2012; 90(2):308-13. · 10.60 Impact Factor
• Article: Atypical male and female presentations of FLNA-related periventricular nodular heterotopia.

  Patricia Fergelot, Isabelle Coupry, Caroline Rooryck, Julie Deforges, Elise Maurat, Guilhem Solé, Odile Boute, Anne Dieux-Coeslier, Albert David, Cécile Marchal, Jean-Benoit Thambo, Didier Lacombe, Benoit Arveiler, Cyril Goizet
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  ABSTRACT: Periventricular nodular heterotopia, the most common form of cortical malformation in adulthood, is characterized by nodules of neurons ectopically placed along the lateral ventricles. Classically, ectopic nodules are bilateral and symmetric defining bilateral periventricular nodular heterotopia (BPNH). BPNH can lead to epilepsy and intellectual disability of variable severity. The X-linked dominant form of BPNH, related to mutations in FLNA encoding filamin A, is the major cause of BPNH, causing prenatal and neonatal lethality in males that explain the excess of affected women. However, few living males have been described with this condition. In addition, mutations in FLNA have been also exceptionally associated with unilateral nodular heterotopia. We describe here three new patients, all carrying a novel missense mutation in FLNA. Two of the patients were adult males with BPNH; both had normal cognitive development and one did not manifest any seizure until he died at age 57. The last patient was a female adult with epilepsy and focal nodules essentially located along the right ventricle. We compare the clinical and imaging data of our patients with those of previously described similar cases. The type and location of FLNA mutations leading to such atypical presentations are discussed.
  European journal of medical genetics 02/2012; 55(5):313-8. · 1.57 Impact Factor