246 research outputs found
New cases of recently described Thauvin-Robinet-Faivre syndrome with a novel homozygous FIBP gene variant
No full textThauvin-Robinet-Faivre syndrome (#617107) is a rare autosomal recessive overgrowth syndrome characterized by intellectual disability, facial dysmorphism, macrocephaly, and variable congenital malformations. It is caused by homozygous or compound heterozygous FIBP gene mutations. The FIBP gene is located on the 11q13.1 region and codes the acidic fibroblast growth factor intracellular binding protein, which is involved in the fibroblast growth factor (FGF) signaling pathway. FGF signaling is required for neurogenesis and neuronal precursor proliferation. The FGF controls cell proliferation, differentiation, and migration in embryonic development and in adult life. Overgrowth syndromes consist of a wide spectrum disorders characterized by prenatal and postnatal excess growth in weight and length, often associated malformations, intellectual disability, and neoplastic predisposition. Embryonic tumors are especially common in these syndromes. Thauvin-Robinet-Faivre syndrome is a recently described overgrowth syndrome with typical facial dysmorphic and clinical features. To date, only four patients have been reported with this disorder. Herein, two new cases of Thauvin-Robinet-Faivre syndrome are reported with overgrowth, intellectual disability, typical dysmorphic signs in one dysplastic kidney, and a novel homozygous FIBP gene variant. Exome sequencing analysis showed that both affected siblings share the same homozygous c. 412-3_415dupCAGTTTG FIBP gene variant. Reporting two new cases with this rare autosomal recessive overgrowth syndrome with a novel FIBP gene variant will support and expand the clinical spectrum of Thauvin-Robinet-Faivre syndrome. Also discussed will be the function of FIBP in tumorigenesis and the possible renal tumor susceptibility in heterozygous carriers will be emphasized
Renal insufficiency, a frequent complication with age in oral-facial-digital syndrome type I.
No full textpeer reviewedSaal S, Faivre L, Aral B, Gigot N, Toutain A, Van Maldergem L, Destree A, Maystadt I, Cosyns J-P, Jouk P-S, Loeys B, Chauveau D, Bieth E, Layet V, Mathieu M, Lespinasse J, Teebi A, Franco B, Gautier E, Binquet C, Masurel-Paulet A, Mousson C, Gouyon J-B, Huet F, Thauvin-Robinet C. Renal insufficiency, a frequent complication with age in oral-facial-digital syndrome type I. The oral-facial-digital syndrome type I (OFD I) is characterized by multiple congenital malformations of the face, oral cavity and digits. A polycystic kidney disease (PKD) is found in about one-third of patients but long-term outcome and complications are not well described in the international literature. Renal findings have been retrospectively collected in a cohort of 34 females all carrying a pathogenic mutation in the OFD1 gene with ages ranging from 1 to 65 years. Twelve patients presented with PKD - 11/16 (69%) if only adults were considered -with a median age at diagnosis of 29 years [IQR (interquartile range) = (23.5-38)]. Among them, 10 also presented with renal impairment and 6 were grafted (median age = 38 years [IQR = (25-48)]. One grafted patient under immunosuppressive treatment died from a tumor originated from a native kidney. The probability to develop renal failure was estimated to be more than 50% after the age of 36 years. Besides, neither genotype-phenotype correlation nor clinical predictive association with renal failure could be evidenced. These data reveal an unsuspected high incidence rate of the renal impairment outcome in OFD I syndrome. A systematic ultrasound (US) and renal function follow-up is therefore highly recommended for all OFD I patients
Expanding the phenotype and genotype in Thauvin‐Robinet‐Faivre syndrome: A new patient with a novel variant and additional clinical findings
No full textThauvin-Robinet-Faivre syndrome (TROFAS; OMIM #617107) is a rare autosomal recessive overgrowth syndrome characterized by generalized overgrowth, dysmorphic facial features, and delayed psychomotor development caused by biallelic pathogenic variants in the FGF-1 intracellular binding protein (FIBP) gene. To date, only four patients from two families have been reported. In this report, we present a 4-year-old male patient with generalized overgrowth and delayed developmental milestones consistent with this syndrome. In addition, he has unique features that were not reported in previous patients, including drooling, recurrent pulmonary infections, chronic pulmonary disease, hyperextensible elbow joints, hypoplastic nipples, unilateral cryptorchidism, and frequent spontaneous erections. We identified a homozygous, likely pathogenic variant, c.415_416insCAGTTTG (p.Asp139AlafsTer3), which causes a frameshift in the FIBP. Additionally, we identified a homozygous missense variant in the Toll-like receptor 5(TLR5) gene and a hemizygous missense variant in the chloride voltage-gated channel 4 (CLCN4) gene, with uncertain significance in either case. In this article, we set out the new observations and also discuss the frequency of the characteristic findings of the syndrome in the patients so far reported
Oral-facial-digital syndrome type i cells exhibit impaired DNA repair; Unanticipated consequences of defective OFD1 outside of the cilia network
No full textDefects in OFD1 underlie the clinically complex ciliopathy, Oral-Facial-Digital syndrome Type I (OFD Type I). Our understanding of the molecular, cellular and clinical consequences of impaired OFD1 originates from its characterised roles at the centrosome/basal body/cilia network. Nonetheless, the first described OFD1 interactors were components of the TIP60 histone acetyltransferase complex. We find that OFD1 can also localise to chromatin and its reduced expression is associated with mis-localization of TIP60 in patient-derived cell lines. TIP60 plays important roles in controlling DNA repair. OFD Type I cells exhibit reduced histone acetylation and altered chromatin dynamics in response to DNA double strand breaks (DSBs). Furthermore, reduced OFD1 impaired DSB repair via homologous recombination repair (HRR). OFD1 loss also adversely impacted upon the DSB-induced G2-M checkpoint, inducing a hypersensitive and prolonged arrest. Our findings show that OFD Type I patient cells have pronounced defects in the DSB-induced histone modification, chromatin remodelling and DSB-repair via HRR; effectively phenocopying loss of TIP60. These data extend our knowledge of the molecular and cellular consequences of impaired OFD1, demonstrating that loss of OFD1 can negatively impact upon important nuclear events; chromatin plasticity and DNA repair
Lung disease associated with periventricular nodular heterotopia and an FLNA mutation
No full textX-linked periventricular nodular heterotopia (PH) is a neuronal migration disorder caused by mutations in the gene encoding filamin A (FLNA). High phenotypic diversity, ranging from PH to otopalatodigital syndrome and frontometaphyseal dysplasia has been described in association with FLNA mutations. Extra-neurological features including cardiovascular abnormalities, coagulopathy, skeletal dysplasia and joint hypermobility have sometimes been described in patients with PH. Respiratory manifestations have not been associated with FLNA disorders with the exception of tracheal stenosis and pulmonary hypoplasia associated with frontometaphyseal dysplasia and Melnick-Needles syndrome. Here, we report on a male patient aged 6 years presenting with a mosaic nonsense mutation c.994delG within the FLNA gene, PH and severe congenital lung disease comprising bilateral atelectasis, lung cysts, tracheobronchomalacia, pulmonary arterial hypertension and long-term oxygen dependence; histology of resected lung showed panpulmonary emphysema with marked reduction of bronchial cartilage. Rare male patients with PH and FLNA mutations have already been reported, usually with early lethality. These observations suggest the possibility of a link between FLNA mutations and congenital lung disease. A prospective study of patients with PH and FLNA mutations would be helpful in order to test this hypothesis.Alice Masurel-Paulet, Eric Haan, Elizabeth M. Thompson, Cyril Goizet, Christel Thauvin-Robinet, Andrew Tai, Declan Kennedy, Greg Smith, Teck Yee Khong, Guilhem Solé, Elodie Guerineau, Isabelle Coupry, Frédéric Huet, Stephen Robertson, Laurence Faivr
CNS involvement in OFD1 syndrome: a clinical, molecular, and neuroimaging studyOral-Facial-Digital Type I
No full textOral-facial-digital type 1 syndrome (OFD1; OMIM 311200) belongs to the expanding group of disorders ascribed to ciliary dysfunction. With the aim of contributing to the understanding of the role of primary cilia in the central nervous system (CNS), we performed a thorough characterization of CNS involvement observed in this disorder
Multi-omic explorations of transcriptional anomalies in rare developmental diseases
No full textL’expression des gènes passe par le processus de transcription dans le noyau des cellules eucaryotes qui produit les ARNs, intermédiaires indispensables pour former des protéines. La synthèse et le devenir des ARNs sont soumis à un contrôle complexe assuré par de nombreux acteurs incluant entre autres les séquences d'ADN non codantes régulatrices qui assurent une régulation spatio-temporelle fine de l’expression génique et les ribonucléoprotéines hétérogènes nucléaires (hnRNP) capables de lier les molécules d’ARN et de réguler leur maturation, leur stabilité et leur localisation.L'approche standard actuelle pour l'exploration moléculaire des patients atteints d'anomalies du développement (AD) et/ou de déficience intellectuelle (DI), déploie la combinaison de l’analyse chromosomique par puces à ADN, le test de l’X fragile, le séquençage d'exome, et plus récemment le séquençage du génome pour établir un diagnostic moléculaire. L’ensemble de ces approches comporte un rendement diagnostique inférieur à 50% pour les AD/DI. Cependant, les analyses peuvent parfois mettre en évidence la présence de variations de signification incertaine dans des gènes candidats, non encore impliqués en pathologie humaine. Des tests fonctionnels sont alors nécessaires afin d’établir une correcte corrélation génotype-phénotype. De cette manière, des variations pathogènes ont été identifiées au sein de deux gènes candidats codant des hnRNPs intervenant dans le métabolisme des ARNs : PTBP1 et PTBP2. Le but de cette première étude est de décrire le mécanisme cellulaire physiopathologique lié aux défauts transcriptionnels à l'origine de l’atteinte neurodéveloppementale syndromique (pour PTBP1) ou non syndromique (pour PTBP2) par des approches moléculaires fonctionnelles in vitro et in vivo dont le séquençage d'ARNs immunoprécipités (RIP-seq) dans une cohorte d’individus atteints.Dans certains cas, l’analyse génomique met en évidence la présence de variations de structure complexes, pouvant interrompre la séquence d’un gène sensible au dosage, modifier l’activité d’un enhancer ou encore exercer des effets de position sur l'expression génique en altérant les interactions enhancer/gène(s) cible(s). Ces communications moléculaires sont facilitées au sein de domaines d'association topologique (TADs) qui jouent un rôle important dans la régulation transcriptionnelle de manière tissu-spécifique. Par conséquent, toute variation de structure susceptible de réorganiser les TADs (fusion, mélange entre deux TADs ou même création) peut entraîner une altération de l’expression génique. Dans ce contexte, l'objectif du second travail de recherche est de caractériser, au moyen de la capture de conformation de chromosomes à haut débit (Hi-C), les remaniements complexes des patients capables de modifier la structure des TADs. Combinée avec d’autres techniques omiques comme le séquençage longs fragments, les études transcriptomiques ou encore épigénomiques, cette approche permet d'étudier les mécanismes moléculaires sous-jacents sur différents modèles cellulaires dérivés des individus affectés.Ces travaux de recherche mettent en évidence l'impact physiopathologique des variations génétiques ponctuelles et de structure sur les mécanismes de régulation transcriptionnelle et post-transcriptionnelle des gènes cibles et ouvrent la voie à de nouvelles hypothèses biologiques dans le cadre de la recherche translationnelle en pathologie humaine.Gene expression occurs through the transcription process in the nucleus of eukaryotic cells, which produces RNAs, essential intermediates for protein formation. RNA synthesis and fate are controlled by a complex network of factors, among which are regulatory non-coding DNA sequences that ensure precise spatio-temporal regulation of gene expression and heterogeneous nuclear ribonucleoproteins (hnRNP), able to bind RNA molecules and contributing to their maturation, stability, and localization.The current standard approach for molecular exploration of patients with developmental disorders (DD) and/or intellectual disabilities (ID) uses a combination of chromosomal analysis using DNA microarrays, fragile X testing, exome sequencing, and more recently, genome sequencing to establish a molecular diagnosis. These approaches yield a diagnostic yield of less than 50% for DD/ID. However, the analyses sometimes reveal the presence of variations of uncertain significance in candidate genes not yet implicated in human pathology. Functional tests are then necessary to establish a correct genotype-phenotype correlation. In this way, pathogenic variations have been identified in two candidate genes encoding hnRNPs involved in RNA metabolism: PTBP1 and PTBP2. The aim of this first study is to describe the cellular pathophysiological mechanism related to transcriptional defects causing syndromic (for PTBP1) or non-syndromic (for PTBP2) neurodevelopmental impairment using in vitro and in vivo functional molecular approaches including RNA immunoprecipitation sequencing (RIP-seq) in a cohort of affected individuals.In some cases, genomic analysis identifiy complex structural variations that can disrupt the sequence of a dosage-sensitive gene, alter the activity of an enhancer, or exert position effects on gene expression by altering enhancer/target gene interactions. These molecular communications are facilitated within topological associating domains (TADs), which play an important role in tissue-specific transcriptional regulation. Consequently, any structural variation that reorganizes TADs (fusion, shuffling or even new TAD) can lead to an alteration in gene expression. In this context, the goal of this second research project is to characterize, through high-throughput chromosome conformation capture (Hi-C), the complex rearrangements in patients reorganizing the structure of TADs. Combined with other omic techniques such as long fragment sequencing, transcriptomic or epigenomic analysis, this approach allows the study of the underlying molecular mechanisms on different cellular models derived from affected individuals.These research efforts highlight the physiopathological impact of punctual and structural genetic variations on the transcriptional and post-transcriptional regulatory mechanisms of target genes and pave the way for new biological hypotheses in the context of translational research in human pathology
Search from genomic imbalances in a cohort of 20 patients with oral-facial-digital syndromes negative for mutations and large rearrangements in the OFD1 gene.
No full textAutosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital syndrome with short stature and brachymesophalangia
No full textThe 13 subtypes of oral-facial-digital syndrome (OFDS) belong to the heterogeneous group of ciliopathies. Disease-causing genes encode for centrosomal proteins, components of the transition zone or proteins implicated in ciliary signaling. A unique consanguineous family presenting with an unclassified OFDS with skeletal dysplasia and brachymesophalangia was explored. Homozygosity mapping and exome sequencing led to the identification of a homozygous mutation in IFT57, which encodes a protein implicated in ciliary transport. The mutation caused splicing anomalies with reduced expression of the wild-type transcript and protein. Both anterograde ciliary transport and sonic hedgehog signaling were significantly decreased in subjects' fibroblasts compared with controls. Sanger sequencing of IFT57 in 13 OFDS subjects and 12 subjects with Ellis-Van Creveld syndrome was negative. This report identifies the implication of IFT57 in human pathology and highlights the first description of a ciliary transport defect in OFDS, extending the genetic heterogeneity of this subgroup of ciliopathies
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