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Plaisancie J.,Toulouse University Hospital Center | Bailleul-Forestier I.,University Paul Sabatier | Gaston V.,Toulouse University Hospital Center | Vaysse F.,University Paul Sabatier | And 21 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

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.


Humbert C.,French Institute of Health and Medical Research | Humbert C.,University of Paris Descartes | Silbermann F.,French Institute of Health and Medical Research | Silbermann F.,University of Paris Descartes | And 25 more authors.
American Journal of Human Genetics | Year: 2014

Renal hypodysplasia (RHD) is a heterogeneous condition encompassing a spectrum of kidney development defects including renal agenesis, hypoplasia, and (cystic) dysplasia. Heterozygous mutations of several genes have been identified as genetic causes of RHD with various severity. However, these genes and mutations are not associated with bilateral renal agenesis, except for RET mutations, which could be involved in a few cases. The pathophysiological mechanisms leading to total absence of kidney development thus remain largely elusive. By using a whole-exome sequencing approach in families with several fetuses with bilateral renal agenesis, we identified recessive mutations in the integrin α8-encoding gene ITGA8 in two families. Itga8 homozygous knockout in mice is known to result in absence of kidney development. We provide evidence of a damaging effect of the human ITGA8 mutations. These results demonstrate that mutations of ITGA8 are a genetic cause of bilateral renal agenesis and that, at least in some cases, bilateral renal agenesis is an autosomal-recessive disease. © 2014 The American Society of Human Genetics.


Demurger F.,Service de Genetique Clinique | Ichkou A.,Hopital Necker Enfants Malades | Mougou-Zerelli S.,French Institute of Health and Medical Research | Le Merrer M.,French Institute of Health and Medical Research | And 60 more authors.
European Journal of Human Genetics | Year: 2015

The phenotypic spectrum of GLI3 mutations includes autosomal dominant Greig cephalopolysyndactyly syndrome (GCPS) and Pallister-Hall syndrome (PHS). PHS was first described as a lethal condition associating hypothalamic hamartoma, postaxial or central polydactyly, anal atresia and bifid epiglottis. Typical GCPS combines polysyndactyly of hands and feet and craniofacial features. Genotype-phenotype correlations have been found both for the location and the nature of GLI3 mutations, highlighting the bifunctional nature of GLI3 during development. Here we report on the molecular and clinical study of 76 cases from 55 families with either a GLI3 mutation (49 GCPS and 21 PHS), or a large deletion encompassing the GLI3 gene (6 GCPS cases). Most of mutations are novel and consistent with the previously reported genotype-phenotype correlation. Our results also show a correlation between the location of the mutation and abnormal corpus callosum observed in some patients with GCPS. Fetal PHS observations emphasize on the possible lethality of GLI3 mutations and extend the phenotypic spectrum of malformations such as agnathia and reductional limbs defects. GLI3 expression studied by in situ hybridization during human development confirms its early expression in target tissues. © 2015 Macmillan Publishers Limited.


Bonnet C.,French Institute of Health and Medical Research | Bonnet C.,Institute Pasteur Paris | Grati M.,French Institute of Health and Medical Research | Grati M.,Institute Pasteur Paris | And 40 more authors.
Orphanet Journal of Rare Diseases | Year: 2011

Background: Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool. Methods. We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3). Results: Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel. Conclusions: Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy. © 2011 Bonnet et al; licensee BioMed Central Ltd.


Vanlerberghe C.,Institute Of Genetique Medicale | Petit F.,Service de genetique clinique | Malan V.,Service de cytogenetique et dembryologie | Vincent-Delorme C.,Service de genetique clinique | And 31 more authors.
European Journal of Medical Genetics | Year: 2015

Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients.This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease).Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, '. de novo' microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients.Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies. © 2015.


PubMed | Brest University Hospital Center, Nancy University Hospital Center, Cytogenetics Laboratory, Medecine Legale and 25 more.
Type: Journal Article | Journal: Clinical genetics | Year: 2016

Microarray-based comparative genomic hybridization (aCGH) is commonly used in diagnosing patients with intellectual disability (ID) with or without congenital malformation. Because aCGH interrogates with the whole genome, there is a risk of being confronted with incidental findings (IF). In order to anticipate the ethical issues of IF with the generalization of new genome-wide analysis technologies, we questioned French clinicians and cytogeneticists about the situations they have faced regarding IF from aCGH. Sixty-five IF were reported. Forty corresponded to autosomal dominant diseases with incomplete penetrance, 7 to autosomal dominant diseases with complete penetrance, 14 to X-linked diseases, and 4 were heterozygotes for autosomal recessive diseases with a high prevalence of heterozygotes in the population. Therapeutic/preventive measures or genetic counselling could be argued for all cases except four. These four IF were intentionally not returned to the patients. Clinicians reported difficulties in returning the results in 29% of the cases, mainly when the question of IF had not been anticipated. Indeed, at the time of the investigation, only 48% of the clinicians used consents mentioning the risk of IF. With the emergence of new technologies, there is a need to report such national experiences; they show the importance of pre-test information on IF.


PubMed | Guys and St Thomas Hospital, University Institute of La Paz, Hospital Charles Nicolle, Brest University Hospital Center and 35 more.
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2016

Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. 2016 Wiley Periodicals, Inc.


Tatton-Brown K.,Institute of Cancer Research | Murray A.,Institute of Cancer Research | Hanks S.,Institute of Cancer Research | Douglas J.,Institute of Cancer Research | And 29 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve. © 2013 Wiley Periodicals, Inc.


Huber C.,French Institute of Health and Medical Research | Faqeih E.A.,Childrens Hospital | Bartholdi D.,University of Zürich | Bole-Feysot C.,Plateforme de Genomique | And 12 more authors.
American Journal of Human Genetics | Year: 2013

Opsismodysplasia (OPS) is a severe autosomal-recessive chondrodysplasia characterized by pre- and postnatal micromelia with extremely short hands and feet. The main radiological features are severe platyspondyly, squared metacarpals, delayed skeletal ossification, and metaphyseal cupping. In order to identify mutations causing OPS, a total of 16 cases (7 terminated pregnancies and 9 postnatal cases) from 10 unrelated families were included in this study. We performed exome sequencing in three cases from three unrelated families and only one gene was found to harbor mutations in all three cases: inositol polyphosphate phosphatase-like 1 (INPPL1). Screening INPPL1 in the remaining cases identified a total of 12 distinct INPPL1 mutations in the 10 families, present at the homozygote state in 7 consanguinous families and at the compound heterozygote state in the 3 remaining families. Most mutations (6/12) resulted in premature stop codons, 2/12 were splice site, and 4/12 were missense mutations located in the catalytic domain, 5-phosphatase. INPPL1 belongs to the inositol-1,4,5-trisphosphate 5-phosphatase family, a family of signal-modulating enzymes that govern a plethora of cellular functions by regulating the levels of specific phosphoinositides. Our finding of INPPL1 mutations in OPS, a severe spondylodysplastic dysplasia with major growth plate disorganization, supports a key and specific role of this enzyme in endochondral ossification. © 2013 The American Society of Human Genetics.


PubMed | Unite de Genetique Medicale, Laboratoire Of Cytogenetique and University of Strasbourg
Type: Journal Article | Journal: Molecular human reproduction | Year: 2015

The purpose of this study was to analyze DPY19L2 sequence variants to investigate the mechanism leading to the entire DPY19L2 deletion in a large cohort of infertile globozoospermic patients.An improved analysis of the DPY19L2 deletion breakpoints (BPs) allowed us to identify two BPs located in a small 1 kb region and to more precisely localize the BPs reported previously.Three genes [spermatogenesis associated 16 (SPATA16), protein interacting with PRKCA (PICK1) and DPY19L2] were previously correlated with globozoospermia, but a homozygous deletion of the entire DPY19L2 was identified as the most frequent alteration causing this phenotype. In addition, several point mutations in this gene were reported. In previous work, we have identified nine BPs for the DPY19L2 deletion clustered in two hotspot regions, while others reported a total of five BPs.We screened for the DPY19L2 deletion and for mutations in the DPY19L2, SPATA16 and PICK1 genes in a cohort of 21 Tunisian globozoospermic patients. In order to characterize the DPY19L2 deletion BPs, we sequenced a 2 kb fragment on low copy repeat (LCR) 1 and LCR2 in Tunisian fertile controls to distinguish between single-nucleotide polymorphisms (SNPs) and LCR-specific markers.Molecular analyses performed on 18 genetically independent individuals showed that 11 (61.1%) were homozygous for the DPY19L2 deletion, 2 (11.1%) were homozygous for the non-synonymous mutation (p.R298C) in exon 8, 1 patient (5.6%) was homozygous for a new splice-site mutation at the junction exon-intron 16 [c.1579_1580+4delAGGTAAinsTCAT] and no DPY19L2, SPATA16 or PICK1 mutations were identified for 4 patients (22.2%). By defining 15 specific LCR markers, we characterized 2 BPs for the DPY19L2 deletion in 11 patients showing the homozygous deletion. Using 20 non-LCR-specific SNPs, we identified 8 distinct haplotypes.A limitation of this study is the small number of patients owing to the rarity of this form of male infertility.Our data showed that some nucleotides, described by others as LCR-specific markers and used to limit their BPs, were in fact SNPs demonstrating the difficulty in precisely determining the localization of BPs.Not applicable.This work was supported by the French Centre National de la Recherche Scientifique (CNRS), Institut National de la Sant et de la Recherche Mdicale (INSERM), the Ministre de lEducation Nationale et de lEnseignement Suprieur et de la Recherche, the University of Strasbourg, the University Hospital of Strasbourg, the Agence Nationale pour la Recherche, the Agence de la BioMdecine and lAgence Universitaire de la Francophonie (AUF). There are no conflicts of interest to declare.

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