Bertrand Isidor - Academia.edu (original) (raw)

Papers by Bertrand Isidor

Research paper thumbnail of SFP-18 – Métabolisme – Hypercalprotectinémie-hyperzincémie : un nouveau syndrome autoinflammatoire héréditaire

Archives de Pédiatrie, 2008

Archives de Pédiatrie 2008 ; 15 : p923-p1019 spécifiques aux manifestations généralisées d'allerg... more Archives de Pédiatrie 2008 ; 15 : p923-p1019 spécifiques aux manifestations généralisées d'allergie. L'item « douleurs abdominales » était le symptôme plus souvent associé à un APT positif (p < 0.001) Conclusions -1. Le diagnostic d'APLV est le plus souvent évoqué par les pédiatres devant des symptômes digestifs ou cutanés. 2. Devant une symptomatologie évocatrice, plus des deux tiers des enfants sont placés d'emblée sous régime. 3. Les APT se sont avérés plus sensibles et spécifiques que les IgE spécifiques chez les nourrissons de moins de 6 mois, particulièrement en cas de manifestations digestives et/ou cutanées.

Research paper thumbnail of Hyperzincemia and hypercalprotectinemia: unsuccessful treatment with tacrolimus

Acta Paediatrica, 2008

We report on a 5-year-old boy with hyperzincemia and hypercalprotectinemia. Treatment began with ... more We report on a 5-year-old boy with hyperzincemia and hypercalprotectinemia. Treatment began with Tacrolimus at the age of 4 years and 6 months. Despite an initial correction of clinical and biological symptoms, zincemia and calprotectinemia progressively worsened with secondary reappearance of symptoms. Tacrolimus seems to have a transient effect in the treatment of Hyperzincemia and hyperprolactinemia.

Research paper thumbnail of Cone-rod dystrophy, growth hormone deficiency and spondyloepiphyseal dysplasia: Report of a new case without nephronophtisis

American Journal of Medical Genetics Part A, 2009

Research paper thumbnail of Oncologic phenotype of peripheral neuroblastic tumors associated with PHOX2B non-polyalanine repeat expansion mutations

Pediatric blood & cancer, Jan 16, 2015

Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to periph... more Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail. We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM. Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late-onset hypoventilation with hypothalamic dysfunction (LO-CHS/HD), and six had no other neurocristopathy. Four tumours were "poorly differentiated," and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with ...

Research paper thumbnail of USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder

Molecular cell, Jan 9, 2015

Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis,... more Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insi...

Research paper thumbnail of Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases

The Journal of allergy and clinical immunology, Jan 26, 2015

Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving e... more Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation ...

Research paper thumbnail of A recurrent KCNQ2 pore mutation causing early onset epileptic encephalopathy has a moderate effect on M current but alters subcellular localization of Kv7 channels

Neurobiology of Disease, 2015

Mutations in the KCNQ2 gene encoding the voltage-dependent potassium M channel Kv7.2 subunit caus... more Mutations in the KCNQ2 gene encoding the voltage-dependent potassium M channel Kv7.2 subunit cause either benign epilepsy or early onset epileptic encephalopathy (EOEE). It has been proposed that the disease severity rests on the inhibitory impact of mutations on M current density. Here, we have analyzed the phenotype of 7 patients carrying the p.A294V mutation located on the S6 segment of the Kv7.2 pore domain (Kv7.2(A294V)). We investigated the functional and subcellular consequences of this mutation and compared it to another mutation (Kv7.2(A294G)) associated with a benign epilepsy and affecting the same residue. We report that all the patients carrying the p.A294V mutation presented the clinical and EEG characteristics of EOEE. In CHO cells, the total expression of Kv7.2(A294V) alone, assessed by western blotting, was only 20% compared to wild-type. No measurable current was recorded in CHO cells expressing Kv7.2(A294V) channel alone. Although the total Kv7.2(A294V) expression was rescued to wild-type levels in cells co-expressing the Kv7.3 subunit, the global current density was still reduced by 83% compared to wild-type heteromeric channel. In a configuration mimicking the patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; heterozygous genotype i.e. Kv7.2(A294V)/Kv7.2/Kv7.3, the global current density was reduced by 30%. In contrast to Kv7.2(A294V), the current density of homomeric Kv7.2(A294G) was not significantly changed compared to wild-type Kv7.2. However, the current density of Kv7.2(A294G)/Kv7.2/Kv7.3 and Kv7.2(A294G)/Kv7.3 channels were reduced by 30% and 50% respectively, compared to wild-type Kv7.2/Kv7.3. In neurons, the p.A294V mutation induced a mislocalization of heteromeric mutant channels to the somato-dendritic compartment, while the p.A294G mutation did not affect the localization of the heteromeric channels to the axon initial segment. We conclude that this position is a hotspot of mutation that can give rise to a severe or a benign epilepsy. The p.A294V mutation does not exert a dominant-negative effect on wild-type subunits but alters the preferential axonal targeting of heteromeric Kv7 channels. Our data suggest that the disease severity is not necessarily a consequence of a strong inhibition of M current and that additional mechanisms such as abnormal subcellular distribution of Kv7 channels could be determinant.

Research paper thumbnail of DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

European journal of human genetics : EJHG, Jan 6, 2015

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserve... more Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, inte...

Research paper thumbnail of Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

European Journal of Human Genetics, 2015

The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chrom... more The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

Research paper thumbnail of Patients with isolated oligo/hypodontia caused by RUNX2 duplication

American Journal of Medical Genetics Part A, 2015

Loss-of-function mutations of RUNX2 are responsible for cleidocranial dysplasia, an autosomal dom... more Loss-of-function mutations of RUNX2 are responsible for cleidocranial dysplasia, an autosomal dominant disorder characterized by delayed closure of cranial sutures, aplastic or hypoplastic clavicles, moderate short stature and supernumerary teeth. By contrast, an increased gene dosage is expected for duplication of the entire RUNX2 sequence and thus, a phenotype different from cleidocranial dysplasia. To date, two cousins with a duplication including the entire RUNX2 sequence in addition to MIR586, CLIC5 and the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; half of SUPT3H have been reported. These patients presented with metopic synostosis and hypodontia. Here, we report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. Interestingly, the mother and one child had isolated hypodontia without craniosynostosis, broadening the phenotype observed in patients with such duplications. © 2015 Wiley Periodicals, Inc.

Research paper thumbnail of Muscle MRI abnormalities in X-linked myopathy with excessive autophagy

Muscle & Nerve, 2015

X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive myopathy due to recent... more X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive myopathy due to recently reported mutations in the VMA21 gene. Four men from 2 separate families were studied. The clinical presentation, genetic data, muscle biopsy, and muscle MRI were analyzed. A known VMA21 mutation c.163 + 4A&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;G and a new mutation c.163 + 3A&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;G, respectively were found in the 2 families. The clinical course was characterized by onset in childhood and progressive muscle weakness with a limb-girdle pattern. Muscle biopsy revealed a mild myopathy with an increased number of giant autophagic vacuoles. Whole body muscle MRI showed that pelvic girdle and proximal thighs were the most and earliest affected territories, with sparing of rectus femoris muscles. Muscle changes essentially consisted of degenerative fatty replacement. This study highlights the distinctive MRI pattern of muscle involvement, which can be helpful for diagnosis of XMEA even before muscle biopsy or genetic analysis are performed. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Treacher Collins syndrome: a clinical and molecular study based on a large series of patients

Genetics in medicine : official journal of the American College of Medical Genetics, Jan 19, 2015

Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial developm... more Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encom...

Research paper thumbnail of Redefining the MED13L syndrome

European journal of human genetics : EJHG, Jan 11, 2015

Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator comp... more Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator complex subunit 13-like protein MED13L, a subunit of the CDK8-associated mediator complex that functions in transcriptional regulation through DNA-binding transcription factors and RNA polymerase II. Heterozygous MED13L variants cause transposition of the great arteries and intellectual disability (ID). Here, we report eight patients with predominantly novel MED13L variants who lack such complex congenital heart malformations. Rather, they depict a syndromic form of ID characterized by facial dysmorphism, ID, speech impairment, motor developmental delay with muscular hypotonia and behavioral difficulties. We thereby define a novel syndrome and significantly broaden the clinical spectrum associated with MED13L variants. A prominent feature of the MED13L neurocognitive presentation is profound language impairment, often in combination with articulatory deficits.European Journal of Human Geneti...

Research paper thumbnail of Kabuki Syndrome and Neonatal Cholestasis: Report of a New Case and Review of the Literature

Journal of Pediatric Gastroenterology and Nutrition, 2007

Research paper thumbnail of Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Journal of Medical Genetics, 2014

Research paper thumbnail of Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

The American Journal of Human Genetics, 2014

Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of sever... more Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.

Research paper thumbnail of Five children with deletions of 1p34.3 encompassing AGO1 and AGO3

European Journal of Human Genetics, 2014

Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or tra... more Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this.

Research paper thumbnail of Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

European Journal of Human Genetics, 2014

Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting... more Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting genes encoding the alpha subunit of these channels have been associated with epilepsy and neuropsychiatric disorders such as autism or schizophrenia. Here we report three patients with a genomic aberration affecting the CACNA2D1 gene encoding the α2δ subunit of these voltage-gated calcium channels. All three patients present with epilepsy and intellectual disability pinpointing the CACNA2D1 gene as an interesting candidate gene for these clinical features. Besides these characteristics, patient 2 also presents with obesity with hyperinsulinism, which is very likely to be caused by deletion of the CD36 gene.European Journal of Human Genetics advance online publication, 30 July 2014; doi:10.1038/ejhg.2014.141.

Research paper thumbnail of P58 Familial frameshift SRY mutation inherited from a mosaic father with hypospadias and cryptorchidy

Reproductive BioMedicine Online, 2010

Research paper thumbnail of Prenatal diagnosis of Larsen syndrome caused by a mutation in the filamin B gene

Prenatal Diagnosis, 2009

Larsen syndrome [OMIM 150 250] is an autosomal dominant skeletal dysplasia characterized by crani... more Larsen syndrome [OMIM 150 250] is an autosomal dominant skeletal dysplasia characterized by craniofacial features, large-joint dislocations and abnormalities of the extremities. Craniofacial anomalies include hypertelorism, prominence of the forehead, a depressed nasal bridge ...

Research paper thumbnail of SFP-18 – Métabolisme – Hypercalprotectinémie-hyperzincémie : un nouveau syndrome autoinflammatoire héréditaire

Archives de Pédiatrie, 2008

Archives de Pédiatrie 2008 ; 15 : p923-p1019 spécifiques aux manifestations généralisées d'allerg... more Archives de Pédiatrie 2008 ; 15 : p923-p1019 spécifiques aux manifestations généralisées d'allergie. L'item « douleurs abdominales » était le symptôme plus souvent associé à un APT positif (p < 0.001) Conclusions -1. Le diagnostic d'APLV est le plus souvent évoqué par les pédiatres devant des symptômes digestifs ou cutanés. 2. Devant une symptomatologie évocatrice, plus des deux tiers des enfants sont placés d'emblée sous régime. 3. Les APT se sont avérés plus sensibles et spécifiques que les IgE spécifiques chez les nourrissons de moins de 6 mois, particulièrement en cas de manifestations digestives et/ou cutanées.

Research paper thumbnail of Hyperzincemia and hypercalprotectinemia: unsuccessful treatment with tacrolimus

Acta Paediatrica, 2008

We report on a 5-year-old boy with hyperzincemia and hypercalprotectinemia. Treatment began with ... more We report on a 5-year-old boy with hyperzincemia and hypercalprotectinemia. Treatment began with Tacrolimus at the age of 4 years and 6 months. Despite an initial correction of clinical and biological symptoms, zincemia and calprotectinemia progressively worsened with secondary reappearance of symptoms. Tacrolimus seems to have a transient effect in the treatment of Hyperzincemia and hyperprolactinemia.

Research paper thumbnail of Cone-rod dystrophy, growth hormone deficiency and spondyloepiphyseal dysplasia: Report of a new case without nephronophtisis

American Journal of Medical Genetics Part A, 2009

Research paper thumbnail of Oncologic phenotype of peripheral neuroblastic tumors associated with PHOX2B non-polyalanine repeat expansion mutations

Pediatric blood & cancer, Jan 16, 2015

Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to periph... more Germline non-polyalanine repeat expansion mutations in PHOX2B (PHOX2B NPARM) predispose to peripheral neuroblastic tumors (PNT), frequently in association with other neurocristopathies: Hirschsprung disease (HSCR) or congenital central hypoventilation syndrome (CCHS). Although PHOX2B polyalanine repeat expansions predispose to a low incidence of benign PNTs, the oncologic phenotype associated with PHOX2B NPARM is still not known in detail. We analyzed prognostic factors, treatment toxicity, and outcome of patients with PNT and PHOX2B NPARM. Thirteen patients were identified, six of whom also had CCHS and/or HSCR, one also had late-onset hypoventilation with hypothalamic dysfunction (LO-CHS/HD), and six had no other neurocristopathy. Four tumours were "poorly differentiated," and nine were differentiated, including five ganglioneuromas, three ganglioneuroblastomas, and one differentiating neuroblastoma, hence illustrating that PHOX2B NPARM are predominantly associated with ...

Research paper thumbnail of USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder

Molecular cell, Jan 9, 2015

Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis,... more Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insi...

Research paper thumbnail of Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases

The Journal of allergy and clinical immunology, Jan 26, 2015

Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving e... more Hyperzincemia and hypercalprotectinemia (Hz/Hc) is a distinct autoinflammatory entity involving extremely high serum concentrations of the proinflammatory alarmin myeloid-related protein (MRP) 8/14 (S100A8/S100A9 and calprotectin). We sought to characterize the genetic cause and clinical spectrum of Hz/Hc. Proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene sequencing was performed in 14 patients with Hz/Hc, and their clinical phenotype was compared with that of 11 patients with pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. PSTPIP1-pyrin interactions were analyzed by means of immunoprecipitation and Western blotting. A structural model of the PSTPIP1 dimer was generated. Cytokine profiles were analyzed by using the multiplex immunoassay, and MRP8/14 serum concentrations were analyzed by using an ELISA. Thirteen patients were heterozygous for a missense mutation in the PSTPIP1 gene, resulting in a p.E250K mutation, and 1 carried a mutation ...

Research paper thumbnail of A recurrent KCNQ2 pore mutation causing early onset epileptic encephalopathy has a moderate effect on M current but alters subcellular localization of Kv7 channels

Neurobiology of Disease, 2015

Mutations in the KCNQ2 gene encoding the voltage-dependent potassium M channel Kv7.2 subunit caus... more Mutations in the KCNQ2 gene encoding the voltage-dependent potassium M channel Kv7.2 subunit cause either benign epilepsy or early onset epileptic encephalopathy (EOEE). It has been proposed that the disease severity rests on the inhibitory impact of mutations on M current density. Here, we have analyzed the phenotype of 7 patients carrying the p.A294V mutation located on the S6 segment of the Kv7.2 pore domain (Kv7.2(A294V)). We investigated the functional and subcellular consequences of this mutation and compared it to another mutation (Kv7.2(A294G)) associated with a benign epilepsy and affecting the same residue. We report that all the patients carrying the p.A294V mutation presented the clinical and EEG characteristics of EOEE. In CHO cells, the total expression of Kv7.2(A294V) alone, assessed by western blotting, was only 20% compared to wild-type. No measurable current was recorded in CHO cells expressing Kv7.2(A294V) channel alone. Although the total Kv7.2(A294V) expression was rescued to wild-type levels in cells co-expressing the Kv7.3 subunit, the global current density was still reduced by 83% compared to wild-type heteromeric channel. In a configuration mimicking the patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; heterozygous genotype i.e. Kv7.2(A294V)/Kv7.2/Kv7.3, the global current density was reduced by 30%. In contrast to Kv7.2(A294V), the current density of homomeric Kv7.2(A294G) was not significantly changed compared to wild-type Kv7.2. However, the current density of Kv7.2(A294G)/Kv7.2/Kv7.3 and Kv7.2(A294G)/Kv7.3 channels were reduced by 30% and 50% respectively, compared to wild-type Kv7.2/Kv7.3. In neurons, the p.A294V mutation induced a mislocalization of heteromeric mutant channels to the somato-dendritic compartment, while the p.A294G mutation did not affect the localization of the heteromeric channels to the axon initial segment. We conclude that this position is a hotspot of mutation that can give rise to a severe or a benign epilepsy. The p.A294V mutation does not exert a dominant-negative effect on wild-type subunits but alters the preferential axonal targeting of heteromeric Kv7 channels. Our data suggest that the disease severity is not necessarily a consequence of a strong inhibition of M current and that additional mechanisms such as abnormal subcellular distribution of Kv7 channels could be determinant.

Research paper thumbnail of DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies

European journal of human genetics : EJHG, Jan 6, 2015

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserve... more Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, inte...

Research paper thumbnail of Ten new cases further delineate the syndromic intellectual disability phenotype caused by mutations in DYRK1A

European Journal of Human Genetics, 2015

The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chrom... more The dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) gene, located on chromosome 21q22.13 within the Down syndrome critical region, has been implicated in syndromic intellectual disability associated with Down syndrome and autism. DYRK1A has a critical role in brain growth and development primarily by regulating cell proliferation, neurogenesis, neuronal plasticity and survival. Several patients have been reported with chromosome 21 aberrations such as partial monosomy, involving multiple genes including DYRK1A. In addition, seven other individuals have been described with chromosomal rearrangements, intragenic deletions or truncating mutations that disrupt specifically DYRK1A. Most of these patients have microcephaly and all have significant intellectual disability. In the present study, we report 10 unrelated individuals with DYRK1A-associated intellectual disability (ID) who display a recurrent pattern of clinical manifestations including primary or acquired microcephaly, ID ranging from mild to severe, speech delay or absence, seizures, autism, motor delay, deep-set eyes, poor feeding and poor weight gain. We identified unique truncating and non-synonymous mutations (three nonsense, four frameshift and two missense) in DYRK1A in nine patients and a large chromosomal deletion that encompassed DYRK1A in one patient. On the basis of increasing identification of mutations in DYRK1A, we suggest that this gene be considered potentially causative in patients presenting with ID, primary or acquired microcephaly, feeding problems and absent or delayed speech with or without seizures.

Research paper thumbnail of Patients with isolated oligo/hypodontia caused by RUNX2 duplication

American Journal of Medical Genetics Part A, 2015

Loss-of-function mutations of RUNX2 are responsible for cleidocranial dysplasia, an autosomal dom... more Loss-of-function mutations of RUNX2 are responsible for cleidocranial dysplasia, an autosomal dominant disorder characterized by delayed closure of cranial sutures, aplastic or hypoplastic clavicles, moderate short stature and supernumerary teeth. By contrast, an increased gene dosage is expected for duplication of the entire RUNX2 sequence and thus, a phenotype different from cleidocranial dysplasia. To date, two cousins with a duplication including the entire RUNX2 sequence in addition to MIR586, CLIC5 and the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; half of SUPT3H have been reported. These patients presented with metopic synostosis and hypodontia. Here, we report on a family with an affected mother and three affected children. The four patients carried a 285 kb duplication identified by array comparative genomic hybridization. The duplication includes the entire sequence of RUNX2 and the 5&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; half of SUPT3H. We confirmed the duplication by real-time quantitative PCR in the four patients. Two children presented with the association of metopic craniosynostosis and oligo/hypodontia previously described, confirming the phenotype caused by RUNX2 duplication. Interestingly, the mother and one child had isolated hypodontia without craniosynostosis, broadening the phenotype observed in patients with such duplications. © 2015 Wiley Periodicals, Inc.

Research paper thumbnail of Muscle MRI abnormalities in X-linked myopathy with excessive autophagy

Muscle & Nerve, 2015

X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive myopathy due to recent... more X-linked myopathy with excessive autophagy (XMEA) is an X-linked recessive myopathy due to recently reported mutations in the VMA21 gene. Four men from 2 separate families were studied. The clinical presentation, genetic data, muscle biopsy, and muscle MRI were analyzed. A known VMA21 mutation c.163 + 4A&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;G and a new mutation c.163 + 3A&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;G, respectively were found in the 2 families. The clinical course was characterized by onset in childhood and progressive muscle weakness with a limb-girdle pattern. Muscle biopsy revealed a mild myopathy with an increased number of giant autophagic vacuoles. Whole body muscle MRI showed that pelvic girdle and proximal thighs were the most and earliest affected territories, with sparing of rectus femoris muscles. Muscle changes essentially consisted of degenerative fatty replacement. This study highlights the distinctive MRI pattern of muscle involvement, which can be helpful for diagnosis of XMEA even before muscle biopsy or genetic analysis are performed. This article is protected by copyright. All rights reserved.

Research paper thumbnail of Treacher Collins syndrome: a clinical and molecular study based on a large series of patients

Genetics in medicine : official journal of the American College of Medical Genetics, Jan 19, 2015

Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial developm... more Treacher Collins/Franceschetti syndrome (TCS; OMIM 154500) is a disorder of craniofacial development belonging to the heterogeneous group of mandibulofacial dysostoses. TCS is classically characterized by bilateral mandibular and malar hypoplasia, downward-slanting palpebral fissures, and microtia. To date, three genes have been identified in TCS:,TCOF1, POLR1D, and POLR1C. We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. Phenotype-genotype correlations were investigated for 19 clinical features, between TCOF1 and POLR1D, and the type of mutation or its localization in the TCOF1 gene. We identified 92/146 patients (63%) with a molecular anomaly within TCOF1, 9/146 (6%) within POLR1D, and none within POLR1C. Among the atypical negative patients (with intellectual disability and/or microcephaly), we identified four patients carrying a mutation in EFTUD2 and two patients with 5q32 deletion encom...

Research paper thumbnail of Redefining the MED13L syndrome

European journal of human genetics : EJHG, Jan 11, 2015

Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator comp... more Congenital cardiac and neurodevelopmental deficits have been recently linked to the mediator complex subunit 13-like protein MED13L, a subunit of the CDK8-associated mediator complex that functions in transcriptional regulation through DNA-binding transcription factors and RNA polymerase II. Heterozygous MED13L variants cause transposition of the great arteries and intellectual disability (ID). Here, we report eight patients with predominantly novel MED13L variants who lack such complex congenital heart malformations. Rather, they depict a syndromic form of ID characterized by facial dysmorphism, ID, speech impairment, motor developmental delay with muscular hypotonia and behavioral difficulties. We thereby define a novel syndrome and significantly broaden the clinical spectrum associated with MED13L variants. A prominent feature of the MED13L neurocognitive presentation is profound language impairment, often in combination with articulatory deficits.European Journal of Human Geneti...

Research paper thumbnail of Kabuki Syndrome and Neonatal Cholestasis: Report of a New Case and Review of the Literature

Journal of Pediatric Gastroenterology and Nutrition, 2007

Research paper thumbnail of Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Journal of Medical Genetics, 2014

Research paper thumbnail of Mutations in SLC13A5 Cause Autosomal-Recessive Epileptic Encephalopathy with Seizure Onset in the First Days of Life

The American Journal of Human Genetics, 2014

Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of sever... more Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.

Research paper thumbnail of Five children with deletions of 1p34.3 encompassing AGO1 and AGO3

European Journal of Human Genetics, 2014

Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or tra... more Small RNAs (miRNA, siRNA, and piRNA) regulate gene expression through targeted destruction or translational repression of specific messenger RNA in a fundamental biological process called RNA interference (RNAi). The Argonaute proteins, which derive from a highly conserved family of genes found in almost all eukaryotes, are critical mediators of this process. Four AGO genes are present in humans, three of which (AGO 1, 3, and 4) reside in a cluster on chromosome 1p35p34. The effects of germline AGO variants or dosage alterations in humans are not known, however, prior studies have implicated dysregulation of the RNAi mechanism in the pathogenesis of several neurodevelopmental disorders. We describe five patients with hypotonia, poor feeding, and developmental delay who were found to have microdeletions of chromosomal region 1p34.3 encompassing the AGO1 and AGO3 genes. We postulate that haploinsufficiency of AGO1 and AGO3 leading to impaired RNAi may be responsible for the neurocognitive deficits present in these patients. However, additional studies with rigorous phenotypic characterization of larger cohorts of affected individuals and systematic investigation of the underlying molecular defects will be necessary to confirm this.

Research paper thumbnail of Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability

European Journal of Human Genetics, 2014

Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting... more Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting genes encoding the alpha subunit of these channels have been associated with epilepsy and neuropsychiatric disorders such as autism or schizophrenia. Here we report three patients with a genomic aberration affecting the CACNA2D1 gene encoding the α2δ subunit of these voltage-gated calcium channels. All three patients present with epilepsy and intellectual disability pinpointing the CACNA2D1 gene as an interesting candidate gene for these clinical features. Besides these characteristics, patient 2 also presents with obesity with hyperinsulinism, which is very likely to be caused by deletion of the CD36 gene.European Journal of Human Genetics advance online publication, 30 July 2014; doi:10.1038/ejhg.2014.141.

Research paper thumbnail of P58 Familial frameshift SRY mutation inherited from a mosaic father with hypospadias and cryptorchidy

Reproductive BioMedicine Online, 2010

Research paper thumbnail of Prenatal diagnosis of Larsen syndrome caused by a mutation in the filamin B gene

Prenatal Diagnosis, 2009

Larsen syndrome [OMIM 150 250] is an autosomal dominant skeletal dysplasia characterized by crani... more Larsen syndrome [OMIM 150 250] is an autosomal dominant skeletal dysplasia characterized by craniofacial features, large-joint dislocations and abnormalities of the extremities. Craniofacial anomalies include hypertelorism, prominence of the forehead, a depressed nasal bridge ...