Publications by authors named "Eva Pipiras"

25 Publications

  • Page 1 of 1

Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus.

Genet Med 2020 06 26;22(6):1061-1068. Epub 2020 Feb 26.

Institute of Human Genetics, Faculty of Medicine, Technical University München, Munich, Germany.

Purpose: TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum.

Methods: Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR.

Results: We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified.

Conclusion: We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-020-0768-7DOI Listing
June 2020

Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome.

J Med Genet 2020 05 10;57(5):339-346. Epub 2020 Jan 10.

Université de Paris, NeuroDiderot, Inserm UMR1141, Paris, France

Background: The molecular anomalies causing moyamoya disease (MMD) and moyamoya syndromes (MMS) are unknown in most patients.

Objective: This study aimed to identify de novo candidate copy number variants (CNVs) in patients with moyamoya.

Methods: Rare de novo CNVs screening was performed in 13 moyamoya angiopathy trios using whole exome sequencing (WES) reads depth data and whole genome high density SNP array data. WES and SNP array data from an additional cohort of 115 unrelated moyamoya probands were used to search for recurrence of these rare de novo CNVs.

Results: Two de novo CNVs were identified in two unrelated probands by both methods and confirmed by qPCR. One of these CNVs, located on Xq28, was detected in two additional families. This interstitial Xq28 CNV gain is absent from curated gold standard database of control genomic variants and gnomAD databases. The critical region contains five genes, including MAMLD1, a major NOTCH coactivator. Typical MMD was observed in the two families with a duplication, whereas in the triplicated patients of the third family, a novel MMS associating moyamoya and various systemic venous anomalies was evidenced.

Conclusion: The recurrence of this novel Xq28 CNV, its de novo occurrence in one patient and its familial segregation with the affected phenotype in two additional families strongly suggest that it is pathogenic. In addition to genetic counselling application, its association with pulmonary hypertension is of major importance for clinical care. These data also provide new insights into the genomic architecture of this emblematic, non-atherosclerotic, large vessel disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2019-106525DOI Listing
May 2020

New evidence that biallelic loss of function in EEF1B2 gene leads to intellectual disability.

Clin Genet 2020 04 7;97(4):639-643. Epub 2020 Jan 7.

APHP, Département d'Histologie, Embryologie et Cytogénétique, Hôpital Jean Verdier, Bondy, France.

The guanine exchange factor subunit eEF1Bα encoded by the EEF1B2 gene belongs to the eukaryotic elongation translational machinery. Pathogen variants in genes of the translational machinery have been associated with several neurodevelopmental disorders. However, only one family of three siblings with intellectual disability (ID) has been reported so far with a homozygous variant in EEF1B2. Here, we report a second family with a novel homozygous loss of function (LoF) variant p.(Ser128*), carried by two siblings with moderate ID and seizures. Our findings confirm the role of EEF1B2 variants in the pathogenesis of autosomal-recessive ID, expand the variant spectrum and precisely describe the clinical consequences of the LoF of EEF1B2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13688DOI Listing
April 2020

Pontocerebellar hypoplasia with rhombencephalosynapsis and microlissencephaly expands the spectrum of PCH type 1B.

Eur J Med Genet 2020 Apr 23;63(4):103814. Epub 2019 Nov 23.

Normandie Univ, UNIROUEN, INSERM U1245 and Rouen University Hospital, Department of Pathology, F76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France. Electronic address:

Rhombencephalosynapsis is a rare cerebellar malformation developing during embryogenesis defined by vermian agenesis or hypogenesis with fusion of the cerebellar hemispheres. It occurs either alone or in association with other cerebral and/or extracerebral anomalies. Its association with microlissencephaly is exceedingly rare and to date, only a heterozygous de novo missense variant in ADGRL2, a gene encoding Adhesion G-Protein-Coupled Receptor L2, has been identified. We report on two siblings of Roma origin presenting with severe growth retardation, fetal akinesia, microlissencephaly and small cerebellum with vermian agenesis. Neuropathological studies revealed extreme paucity in pontine transverse fibres, rudimentary olivary nuclei and rhombencephalosynapsis with vanishing spinal motoneurons in both fetuses. Comparative fetus-parent exome sequencing revealed in both fetuses a homozygous variant in exon 1 of the EXOSC3 gene encoding a core component of the RNA exosome, c.92G > C; p.(Gly31Ala). EXOSC3 accounts for 40%-75% of patients affected by ponto-cerebellar hypoplasia with spinal muscular atrophy (PCH1B). The c.92G > C variant is a founder mutation in the Roma population and has been reported in severe PCH1B. PCH1B is characterized by a broad phenotypic spectrum, ranging from mild phenotypes with spasticity, mild to moderate intellectual disability, pronounced distal muscular and cerebellar atrophy/hypoplasia, to severe phenotypes with profound global developmental delay, progressive microcephaly and atrophy of the cerebellar hemispheres. In PCH1B, the usual cerebellar lesions affect mainly the hemispheres with relative sparing of vermis that radically differs from rhombencephalosynapsis. This unusual foetal presentation expands the spectrum of PCH1B and highlights the diversity of rhombencephalosynapsis etiologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2019.103814DOI Listing
April 2020

16p13.11 microduplication in 45 new patients: refined clinical significance and genotype-phenotype correlations.

J Med Genet 2020 05 4;57(5):301-307. Epub 2018 Oct 4.

Neuropediatrics department, Hôpital Raymond Poincaré, Assistance Publique des Hôpitaux de Paris, Garches, France.

Background: The clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype-phenotype correlations to improve genetic counselling and patients' medical care.

Methods: We retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents.

Results: Clinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype-phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, and miR-484 seem to have an essential role in the neurocognitive phenotype.

Conclusion: Our study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2018-105389DOI Listing
May 2020

A framework to identify contributing genes in patients with Phelan-McDermid syndrome.

NPJ Genom Med 2017 23;2:32. Epub 2017 Oct 23.

Genetics Unit, CHU Estaing, Clermont-Ferrand, France.

Phelan-McDermid syndrome (PMS) is characterized by a variety of clinical symptoms with heterogeneous degrees of severity, including intellectual disability (ID), absent or delayed speech, and autism spectrum disorders (ASD). It results from a deletion of the distal part of chromosome 22q13 that in most cases includes the gene. is considered a major gene for PMS, but the factors that modulate the severity of the syndrome remain largely unknown. In this study, we investigated 85 patients with different 22q13 rearrangements (78 deletions and 7 duplications). We first explored the clinical features associated with PMS, and provide evidence for frequent corpus callosum abnormalities in 28% of 35 patients with brain imaging data. We then mapped several candidate genomic regions at the 22q13 region associated with high risk of clinical features, and suggest a second locus at 22q13 associated with absence of speech. Finally, in some cases, we identified additional clinically relevant copy-number variants (CNVs) at loci associated with ASD, such as 16p11.2 and 15q11q13, which could modulate the severity of the syndrome. We also report an inherited deletion transmitted to five affected daughters by a mother without ID nor ASD, suggesting that some individuals could compensate for such mutations. In summary, we shed light on the genotype-phenotype relationship of patients with PMS, a step towards the identification of compensatory mechanisms for a better prognosis and possibly treatments of patients with neurodevelopmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41525-017-0035-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677962PMC
October 2017

Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome.

Am J Med Genet A 2017 Aug 1;173(8):2081-2087. Epub 2017 Jun 1.

Genetics Department, AP-HP, Robert-Debré University Hospital, Paris, France.

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype-phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype-genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4-year-old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.38302DOI Listing
August 2017

A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH.

Eur J Hum Genet 2016 06 28;24(6):844-51. Epub 2015 Oct 28.

Service de Génétique, CHU de Poitiers, Poitiers, France.

Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogénéticiens de Langue Française (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of ∼66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2015.219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867458PMC
June 2016

Clinical and molecular delineation of Tetrasomy 9p syndrome: report of 12 new cases and literature review.

Am J Med Genet A 2015 Jun 2;167(6):1252-61. Epub 2015 Apr 2.

Department of Genetics, APHP-Robert Debré University Hospital, Paris, France.

Tetrasomy 9p is a generic term describing the presence of a supernumerary chromosome incorporating two copies of the 9p arm. Two varieties exist: isodicentric chromosome 9p (i(9p)), where the two 9p arms are linked by a single centromeric region, and pseudodicentric 9p (idic(9p)), where one active and one inactive centromere are linked together by a proximal segment of 9q that may incorporate euchromatic material. In living patients, i(9p) and idic(9p) are usually present in a mosaic state. Fifty-four cases, including fetuses, have been reported, of which only two have been molecularly characterized using array-CGH. Tetrasomy 9p leads to a variable phenotype ranging from multiple congenital anomalies with severe intellectual disability and growth delay to subnormal cognitive and physical developments. Hypertelorism, abnormal ears, microretrognathia and bulbous nose are the most common dysmorphic traits. Microcephaly, growth retardation, joint dislocation, scoliosis, cardiac and renal anomalies were reported in several cases. Those physical anomalies are often, but not universally, accompanied by intellectual disability. The most recurrent breakpoints, defined by conventional cytogenetics, are 9p10, 9q12 and 9q13. We report on 12 new patients with tetrasomy 9p (3 i(9p), 8 idic(9p) and one structurally uncharacterized), including the first case of parental germline mosaicism. All rearrangements have been characterized by DNA microarray. Based on our results and a review of the literature, we further delineate the prenatal and postnatal clinical spectrum of this imbalance. Our results show poor genotype-phenotype correlations and underline the need of precise molecular characterization of the supernumerary marker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.36932DOI Listing
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2014-102748DOI Listing
January 2015

Incomplete penetrance and phenotypic variability of 6q16 deletions including SIM1.

Eur J Hum Genet 2015 Aug 5;23(8):1010-8. Epub 2014 Nov 5.

AP-HP, Département de Génétique et Service de Biologie du développement, Hôpital Robert Debré, Université Paris Diderot, Sorbonne Paris Cité, DHU PROTECT, Paris, France.

6q16 deletions have been described in patients with a Prader-Willi-like (PWS-like) phenotype. Recent studies have shown that certain rare single-minded 1 (SIM1) loss-of-function variants were associated with a high intra-familial risk for obesity with or without features of PWS-like syndrome. Although SIM1 seems to have a key role in the phenotype of patients carrying 6q16 deletions, some data support a contribution of other genes, such as GRIK2, to explain associated behavioural problems. We describe 15 new patients in whom de novo 6q16 deletions were characterised by comparative genomic hybridisation or single-nucleotide polymorphism (SNP) array analysis, including the first patient with fetopathological data. This fetus showed dysmorphic facial features, cerebellar and cerebral migration defects with neuronal heterotopias, and fusion of brain nuclei. The size of the deletion in the 14 living patients ranged from 1.73 to 7.84 Mb, and the fetus had the largest deletion (14 Mb). Genotype-phenotype correlations confirmed the major role for SIM1 haploinsufficiency in obesity and the PWS-like phenotype. Nevertheless, only 8 of 13 patients with SIM1 deletion exhibited obesity, in agreement with incomplete penetrance of SIM1 haploinsufficiency. This study in the largest series reported to date confirms that the PWS-like phenotype is strongly linked to 6q16.2q16.3 deletions and varies considerably in its clinical expression. The possible involvement of other genes in the 6q16.2q16.3-deletion phenotype is discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2014.230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795105PMC
August 2015

Cerebral small-vessel disease associated with COL4A1 and COL4A2 gene duplications.

Neurology 2014 Sep 6;83(11):1029-31. Epub 2014 Aug 6.

From CHU Nîmes (D.R., P.L.), Hôpital Caremeau; AP-HP, Service de Génétique Neuro-vasculaire (M.M., E.T.-L.), Hôpital Lariboisière, Paris; UMR-S 1161 Université Paris Diderot (M.M., E.T.-L.), Sorbonne Paris Cité, Génétique des Maladies Vasculaires, Paris; and AP-HP, Hôpital Jean Verdier (E.P., A.D., B.B.), Cytogénétique, Bondy, INSERM, Paris, Université Paris Nord, Sorbonne Paris Cité, Bobigny, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000000769DOI Listing
September 2014

Pre- and postnatal phenotype of 6p25 deletions involving the FOXC1 gene.

Am J Med Genet A 2012 Oct 17;158A(10):2430-8. Epub 2012 Aug 17.

AP-HP, Hôpital Jean Verdier, Service d'Histologie, Embryologie, et Cytogénétique, Bondy, France.

FOXC1 deletion, duplication, and mutations are associated with Axenfeld-Rieger anomaly, and Dandy-Walker malformation spectrum. We describe the clinical history, physical findings, and available brain imaging studies in three fetuses, two children, and one adult with 6p25 deletions encompassing FOXC1. Various combinations of ocular and cerebellar malformations were found. In all three fetuses, necropsy including detailed microscopic assessments of the eyes and brains showed ocular anterior segment dysgenesis suggestive of Axenfeld-Rieger anomaly. Five 6p25 deletions were terminal, including two derived from inherited reciprocal translocations; the remaining 6p25 deletion was interstitial. The size and breakpoints of these deletions were characterized using comparative genomic hybridization arrays. All six deletions included FOXC1. Our data confirm that FOXC1 haploinsufficiency plays a major role in the phenotype of patients with 6p25 deletions. Histopathological features of Axenfeld-Rieger anomaly were clearly identifiable before the beginning of the third-trimester of gestation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.35548DOI Listing
October 2012

Haploinsufficiency of SOX5 at 12p12.1 is associated with developmental delays with prominent language delay, behavior problems, and mild dysmorphic features.

Hum Mutat 2012 Apr;33(4):728-40

Signature Genomic Laboratories, PerkinElmer, Inc., Spokane, Washington 99207, USA.

SOX5 encodes a transcription factor involved in the regulation of chondrogenesis and the development of the nervous system. Despite its important developmental roles, SOX5 disruption has yet to be associated with human disease. We report one individual with a reciprocal translocation breakpoint within SOX5, eight individuals with intragenic SOX5 deletions (four are apparently de novo and one inherited from an affected parent), and seven individuals with larger 12p12 deletions encompassing SOX5. Common features in these subjects include prominent speech delay, intellectual disability, behavior abnormalities, and dysmorphic features. The phenotypic impact of the deletions may depend on the location of the deletion and, consequently, which of the three major SOX5 protein isoforms are affected. One intragenic deletion, involving only untranslated exons, was present in a more mildly affected subject, was inherited from a healthy parent and grandparent, and is similar to a deletion found in a control cohort. Therefore, some intragenic SOX5 deletions may have minimal phenotypic effect. Based on the location of the deletions in the subjects compared to the controls, the de novo nature of most of these deletions, and the phenotypic similarities among cases, SOX5 appears to be a dosage-sensitive, developmentally important gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.22037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618980PMC
April 2012

Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies.

Eur J Hum Genet 2012 May 11;20(5):527-33. Epub 2012 Jan 11.

AP-HP, Hôpital Jean Verdier, Service d'Histologie, Embryologie, et Cytogénétique, Bondy, France.

In 65 patients, who had unexplained ocular developmental anomalies (ODAs) with at least one other birth defect and/or intellectual disability, we performed oligonucleotide comparative genome hybridisation-based microarray analysis (array-CGH; 105A or 180K, Agilent Technologies). In four patients, array-CGH identified clinically relevant deletions encompassing a gene known to be involved in ocular development (FOXC1 or OTX2). In four other patients, we found three pathogenic deletions not classically associated with abnormal ocular morphogenesis, namely, del(17)(p13.3p13.3), del(10)(p14p15.3), and del(16)(p11.2p11.2). We also detected copy number variations of uncertain pathogenicity in two other patients. Rearranged segments ranged in size from 0.04 to 5.68 Mb. These results show that array-CGH provides a high diagnostic yield (15%) in patients with syndromal ODAs and can identify previously unknown chromosomal regions associated with these conditions. In addition to their importance for diagnosis and genetic counselling, these data may help identify genes involved in ocular development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ejhg.2011.233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3330214PMC
May 2012

Congenital macular dystrophy, corpus callosum agenesis, hippocampi hypoplasia--a novel neuro-ophthalmic syndrome: case report.

Ophthalmic Genet 2012 Mar 11;33(1):39-43. Epub 2011 Aug 11.

Génétique Médicale, Hôpital Jean Verdier AP-HP, C.H.U. Paris Nord, Bondy, France.

Introduction: Macular dystrophy is a cause of childhood and adult visual handicap and has been associated with multiple gene defects. Syndromic macular dystrophy is rare and a novel congenital form of syndromic macular dystrophy is presented. The authors report on a consanguineous family in which the 5-year-old female proband presented with nystagmus and low vision due to congenital macular dystrophy visible on fundus examination associated with complete corpus callosum agenesis, hippocampi hypoplasia and recurrent illnesses.

Materials And Methods: Patients signed informed consent forms to participate in the research. Proband was screened for 18 recessive macular dystrophy genes and ABCA4 and had a G banded karyotype on peripheral blood lymphocytes. Patients were evaluated using ocular biomicrosopy, fluorescein retinal angiograms, electroretinograms, visual evoked potentials, retinal optical coherence tomography, brain MRI and multifocal electroretinograms.

Results: The older brother presented with subclinical findings of bilateral absence of foveal macular peak on multifocal electroretinograms and minimal corpus callosum hypoplasia. The younger sister was recently discovered to have a similar macular dystrophy. The father showed subclinical unilateral decreased foveal macular peak and the mother showed a granular-appearing fundus. No mutations were identified in the RP and macular dystrophy genes screened.

Discussion: A review of the literature confirms that this is the first report of a congenital and possibly developmental macular dystrophy, with neurologic syndromic features and possible autosomal recessive inheritance but varying penetrance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3109/13816810.2011.596892DOI Listing
March 2012

Molecular characterization of a de novo 6q24.2q25.3 duplication interrupting UTRN in a patient with arthrogryposis.

Am J Med Genet A 2010 Jul;152A(7):1781-8

AP-HP, Cytogenetics Unit, Department of Genetics, Robert Debré Hospital, Paris, France.

Chromosome 6q duplications have been documented repeatedly, allowing the delineation of a "6q duplication syndrome," characterized by hypertelorism, downslanting palpebral fissures, tented upper lip, short neck, severe mental and growth retardation, and joint contractures. Most reported cases result from malsegregation of a reciprocal translocation leading to a terminal 6q duplication and partial monosomy of another chromosome. Only 11 cases of de novo pure duplication have been reported so far. The breakpoints do not appear to be recurrent, but in most cases they have not been characterized molecularly, precluding genotype-phenotype correlation. We report on an 8-year-old girl with a phenotype consistent with mild 6q duplication syndrome, including characteristic physical findings, mild mental retardation, and joint contractures. She carries a 13 Mb de novo 6q24.2q25.3 duplication, diagnosed by high-resolution karyotype and confirmed by array-CGH. Molecular characterization of the duplicated segment with quantitative PCR showed that the proximal breakpoint is localized within the UTRN gene, encoding utrophin, the autosomal homologue of dystrophin. We discuss the possible implication of UTRN in arthrogryposis associated with duplications spanning the 6q23q26 region.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.33433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2962443PMC
July 2010

Identification of gene copy number variations in patients with mental retardation using array-CGH: Novel syndromes in a large French series.

Eur J Med Genet 2010 Mar-Apr;53(2):66-75. Epub 2009 Oct 28.

Laboratoire de Cytogénétique et Biologie Cellulaire, CHU Pontchaillou, Rennes, France.

Array-CGH has revealed a large number of copy number variations (CNVs) in patients with multiple congenital anomalies and/or mental retardation (MCA/MR). According to criteria recently listed, pathogenicity was clearly suspected for some CNVs but benign CNVs, considered as polymorphisms, have complicated the interpretation of the results. In this study, genomic DNAs from 132 French patients with unexplained mental retardation were analysed by genome wide high-resolution Agilent 44K oligonucleotide arrays. The results were in accordance with those observed in previous studies: the detection rate of pathogenic CNVs was 14.4%. A non-random involvement of several chromosomal regions was observed. Some of the microimbalances recurrently involved regions (1q21.1, 2q23.1, 2q32q33, 7p13, 17p13.3, 17p11.2, 17q21.31) corresponding to known or novel syndromes. For all the pathogenic CNVs, further cases are needed to allow more accurate genotype-phenotype correlations underscoring the importance of databases to group patients with similar molecular data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2009.10.002DOI Listing
July 2010

First cryptic balanced reciprocal translocation mosaicism and familial transmission.

Am J Med Genet A 2008 Nov;146A(22):2971-4

Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.32547DOI Listing
November 2008

Brief report: visual-spatial deficit in a 16-year-old girl with maternally derived duplication of proximal 15q.

J Autism Dev Disord 2007 Sep 28;37(8):1585-91. Epub 2006 Sep 28.

Département de Psychiatrie de l'Enfant et de l'Adolescent, Université Pierre et Marie Curie, Groupe Hospitalier Pitié-Salpétrière, AP-HP, 47 bd de l'Hôpital, 75013 Paris, France.

Duplications of chromosome 15 may be one of the most common single genetic causes of autism spectrum disorders (ASD), aside from fragile X. Most of the cases are associated with maternally derived interstitial duplication involving 15q11-13. This case report describes a female proband with a maternally derived interstitial duplication of proximal 15q. She did not exhibit any symptoms of ASD apart from some developmental delay. By adolescence, she showed mild dysmorphism, a discrepant profile on the Wechsler Intelligence Scale for Children (Verbal IQ = 87; Performance IQ = 65) and a major deficit in visual-spatial abilities affecting fine motor skills, mathematical reasoning, visual memory and some global reading tasks. This is one of the first reports of a child with a maternal duplication who exhibits a visual-spatial deficit without ASD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10803-006-0228-5DOI Listing
September 2007

Retrospective diagnosis of Pallister-Killian syndrome by CGH array.

Fetal Diagn Ther 2006 12;21(6):485-8. Epub 2006 Sep 12.

Service d'Histologie Embryologie Cytogénétique BDR, Hôpital Jean Verdier, Bondy, AP-HP, UFR-USMBH, Paris XIII, France.

Objective And Methods: We report a girl presenting with a polymalformation syndrome. Despite a normal karyotype on peripheral lymphocytes and the unavailability of cultured fibroblasts, a tetrasomy 12p was identified on pulmonary DNA extracted from a postmortem biopsy, by use of comparative genomic hybridization (CGH) and confirmed by CGH array. The clinical picture of our patient was consistent, but not specific of the diagnosis of Pallister-Killian syndrome. She presented with the association of antenatal polyhydramnios, craniofacial dysmorphic features, skeletal abnormalities, and a congenital cardiopathy.

Conclusion: We discuss the usefulness of CGH and CGH array in prenatal and constitutional cytogenetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000095658DOI Listing
January 2007

Clinical findings and cytogenetic analysis of small supernumerary ring chromosomes 7: report of two new cases.

Ann Genet 2004 Jul-Sep;47(3):241-9

Service d'Histologie, Biologie de la Reproduction et Cytogénétique (UPMC-EA 1533), Hôpital Tenon (AP-HP), 75020 Paris, France.

Two new patients, mosaic for a small supernumerary ring chromosome 7 are described. There are only seven published reported concerning supernumerary ring chromosome 7 and we reviewed the previously reported cases in an attempt to establish genotype-phenotype correlations, which are particularly important for genetic counselling and clinical genetics. Our first case was a 20 months old girl who was referred for a mild motor developmental delay, an asymmetric facial appearance, a plagiocephaly and a short nose with anteverted nostrils. Our second case was a 9 years old boy who was referred for a IQ at the lower end of the normal range (? 80), obesity, hyperactivity and some dysmorphic features including hypertelorism and down slanting palpebral fissures. In both cases, chromosome analysis after G and R banding and FISH showed a small ring chromosome 7 in respectively 76% and 50% of consecutively scored metaphases. Both ring chromosomes were labelled by FISH using the Williams Syndrome locus probe (Elastin Gene D7S486). Comparison between these two cases and previously published cases allowed to delineate frequent clinical findings. A mild mental retardation was found in the majority of patients. which is an important data for genetic counselling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.anngen.2004.02.003DOI Listing
October 2004

CGH and direct diagnosis of mosaic structural chromosomal abnormalities: description of a mosaic ring chromosome 17 and review of the literature.

Eur J Hum Genet 2003 Jun;11(6):452-6

Service d'Histologie-Embryologie Cytogénétique Biologie de la Reproduction, Hôpital Jean Verdier (AP-HP), Avenue du 14 Juillet-93143, Bondy Cedex, France.

We report the characterisation of a de novo supernumerary chromosome marker in a mosaic state (50%) by comparative genomic hybridisation (CGH) in an 8-year-old child with hypotonia, dysmorphia and mild-to-moderate mental retardation. We describe the combined use of CGH and fluorescence in situ hybridisation (FISH) to identify the origin of the additional chromosomal material. Visual analysis of 10 CGH-metaphase spreads revealed a gain of green fluorescent signal on pericentromeric region of chromosome 17. The CGH finding was confirmed by FISH analysis using a whole chromosome 17 paint, a chromosome 17 centromeric probe and the probe coding for the Smith-Magenis locus in 17p11.2. These results show that performing both CGH and FISH in combination with classical karyotyping will certainly allow the identification of imbalanced chromosome rearrangements and, by the way, allow the identification of genes involved in mental retardation and/or malformative pathology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/sj.ejhg.5200984DOI Listing
June 2003