Phenotypic Variability with SLURP1 Mutations and Diffuse Palmoplantar Keratoderma

Non peer reviewe

TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning

Etude clinique et génétique des anomalies du corps calleux chez le foetus

Corpus callosum is the main cerebral commissure connecting homologous cortical areas in placental mammals. Malformations of corpus callosum (MCC) are the most frequent brain malformation at birth and are present in 5% of patients with neurodevelopmental delay. A good knowledge of genetics of corpus callosum development should pave the way to better clinical correlations for a more accurate genetic counselling. This is the challenge of the next decade. This thesis concerns a cohort of 138 fetuses with MCCs, well classified on neuropathological examination. It allowed 1/ to unravel the genetic causes of MCC through a triple approach combining CGH array, whole exome and NGS panels sequencing, with a considerable increase in the number of causes of MCC identified ; 2/ identification of a new gene in an extreme ciliopathy phenotype; and 3/ identification of novel ZBTB20 mutations , a gene recently identified as responsible for Primrose syndrome, showing that this syndrome is frequent among MCCs and allowing a precise clinico-radiological description of the syndrome. 4/ Several new candidate genes are under study.Le corps calleux (CC) est la principale commissure cérébrale connectant les aires corticales homologues des deux hémisphères chez les vertébrés placentaires. Les malformations du corps calleux (MCC) représentent la malformation cérébrale la plus fréquente à la naissance et sont présentes chez 5% des individus avec anomalie neuro-développementale. Une meilleure connaissance de l’ontogenèse du corps calleux et de ses causes génétiques devrait permettre d’ouvrir la voie à des corrélations cliniques pour un meilleur conseil génétique. Cet aspect constitue probablement l’enjeu de la prochaine décennie concernant les foetus avec MCC. Le travail de thèse a porté sur 138 foetus avec MCC, pour lesquels nous avons fait un examen foeto-neuropathologique et une classification en plusieurs catégories. Au total, ce travail a permis : 1/le démantèlement des causes génétiques des MCC par une triple approche de CGH array, d’exome en trio et de panels ciblés, avec une augmentation considérable des causes identifiables de MCC au sein de cette cohorte, 2/ l’identification et la caractérisation fonctionnelle d’un nouveau gène de ciliopathie dans un phénotype extrême ; 3/ l’identification de 3 nouvelles mutations de ZBTB20, récemment identifié comme responsable du syndrome de Primrose, démontrant que ce syndrome est une cause fréquente de MCC et permettant une description clinico-radiologique plus précise. 4/ L’identification de plusieurs gènes candidats en cours de validation

Clinical and genetic analysis of corpus callosum anomalies in fetuses

Le corps calleux (CC) est la principale commissure cérébrale connectant les aires corticales homologues des deux hémisphères chez les vertébrés placentaires. Les malformations du corps calleux (MCC) représentent la malformation cérébrale la plus fréquente à la naissance et sont présentes chez 5% des individus avec anomalie neuro-développementale. Une meilleure connaissance de l’ontogenèse du corps calleux et de ses causes génétiques devrait permettre d’ouvrir la voie à des corrélations cliniques pour un meilleur conseil génétique. Cet aspect constitue probablement l’enjeu de la prochaine décennie concernant les foetus avec MCC. Le travail de thèse a porté sur 138 foetus avec MCC, pour lesquels nous avons fait un examen foeto-neuropathologique et une classification en plusieurs catégories. Au total, ce travail a permis : 1/le démantèlement des causes génétiques des MCC par une triple approche de CGH array, d’exome en trio et de panels ciblés, avec une augmentation considérable des causes identifiables de MCC au sein de cette cohorte, 2/ l’identification et la caractérisation fonctionnelle d’un nouveau gène de ciliopathie dans un phénotype extrême ; 3/ l’identification de 3 nouvelles mutations de ZBTB20, récemment identifié comme responsable du syndrome de Primrose, démontrant que ce syndrome est une cause fréquente de MCC et permettant une description clinico-radiologique plus précise. 4/ L’identification de plusieurs gènes candidats en cours de validation.Corpus callosum is the main cerebral commissure connecting homologous cortical areas in placental mammals. Malformations of corpus callosum (MCC) are the most frequent brain malformation at birth and are present in 5% of patients with neurodevelopmental delay. A good knowledge of genetics of corpus callosum development should pave the way to better clinical correlations for a more accurate genetic counselling. This is the challenge of the next decade. This thesis concerns a cohort of 138 fetuses with MCCs, well classified on neuropathological examination. It allowed 1/ to unravel the genetic causes of MCC through a triple approach combining CGH array, whole exome and NGS panels sequencing, with a considerable increase in the number of causes of MCC identified ; 2/ identification of a new gene in an extreme ciliopathy phenotype; and 3/ identification of novel ZBTB20 mutations , a gene recently identified as responsible for Primrose syndrome, showing that this syndrome is frequent among MCCs and allowing a precise clinico-radiological description of the syndrome. 4/ Several new candidate genes are under study

Pratiques et attitudes linguistiques des travailleurs sociaux

International audienc

Bothnian Palmoplantar Keratoderma: Further Delineation of the Associated Phenotype

Bothnian palmoplantar keratoderma (PPKB, MIM600231) is an autosomal dominant form of diffuse non-epidermolytic PPK characterized by spontaneous yellowish-white PPK associated with a spongy appearance after water-immersion. It is due to AQP5 heterozygous mutations. We report four patients carrying a novel AQP5 heterozygous mutation (c.125T>A; p.(Ile42Asn)), and belonging to the same French family. Early palmoplantar swelling (before one year of age), pruritus and hyperhidrosis were constant. The PPK was finally characterized as transgrediens, non-progrediens, diffuse PPK with a clear delineation between normal and affected skin. The cutaneous modifications at water-immersion test, “hand-in-the-bucket sign”, were significantly evident after 3 to 6 min of immersion in the children and father, respectively. AQP5 protein is expressed in eccrine sweat glands (ESG), salivary and airway submucosal glands. In PPKB, gain of function mutations seem to widen the channel diameter of ESG and increase water movement. Thus, swelling seems to be induced by hypotonicity with water entrance into cells, while hyperhidrosis is the result of an increased cytosolic calcium concentration

Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome

BACKGROUND: Acrocallosal syndrome (ACLS) is a rare recessive disorder characterised by corpus callosum agenesis or hypoplasia, craniofacial dysmorphism, duplication of the hallux, postaxial polydactyly, and severe mental retardation. Recently, we identified mutations in KIF7, a key component of the Sonic hedgehog pathway, as being responsible for this syndrome. METHODS: We sequenced KIF7 in five suspected ACLS cases, one fetus and four patients, based on facial dysmorphism and brain anomalies. RESULTS: Seven mutations were identified at the KIF7 locus in these five cases, six of which are novel. We describe the first four compound heterozygous cases. In all patients, the diagnosis was suspected based on the craniofacial features, despite the absence of corpus callosum anomaly in one and of polydactyly in another. Hallux duplication was absent in 4/5 cases. CONCLUSIONS: These results show that ACLS has a variable expressivity and can be diagnosed even in the absence of the two major features, namely polydactyly or agenesis or hypoplasia of the corpus callosum. Facial dysmorphism with hypertelorism and prominent forehead in all the cases, as well as vermis dysgenesis with brainstem anomalies (molar tooth sign), strongly indicated the diagnosis. KIF7 should be tested in less typical patients in whom craniofacial features are suggestive of ACLS