Showing papers by "Alain Verloes published in 2022"

Developmental and epileptic encephalopathy related to a heterozygous variant of the RHOBTB2 gene: A case report from French Guiana

Abstract: Here we report a case of developmental and epileptic encephalopathy related to RHOBTB2 gene mutation in a ten‐month old infant in French Guiana. Although the 28 previously reported cases had early‐onset epilepsy and severe intellectual disability, here the reported individual presented with late postnatal onset of microcephaly and the absence of cortical atrophy on MRI. The publication of cases of such a rare form of developmental and epileptic encephalopathy will eventually allow us to better understand the mechanism by which RHOBTB2 misregulation could induce severe and atypical neurological disorders.

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype, a new cohort of 86 patients

Abstract: Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second‐largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype–phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow‐up of patients.

Biallelic THOC6 pathogenic variants: Prenatal phenotype and review of the literature

Abstract: The THOC6 protein is a component of the THO complex. It is involved in mRNA transcription, processing and nuclear export. Interestingly molecular biallelic loss‐of‐function variants of the THOC6 gene were identified in the Beaulieu–Boycott–Innes syndrome (BBIS– OMIM # 613680). This condition was described in 17 patients and is characterized by a moderate to severe intellectual disability, facial dysmorphic features and severe birth defects such as heart, skeletal, ano‐genital and renal congenital malformations.

Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome

Abstract: Abstract Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driver OTUD7A . OTUD7A is an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase function. The OTUD7A protein–protein interaction network included synaptic, axonal, and cytoskeletal proteins and was enriched for ASD and epilepsy risk genes (Ank3, Ank2, SPTAN1, SPTBN1). The interactions between OTUD7A and Ankyrin-G ( Ank3 ) and Ankyrin-B ( Ank2 ) were disrupted by an epilepsy-associated OTUD7A L233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7A L233F/L233F models revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment, while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7A L233F/L233F models revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Furthermore, our study highlights the utility of targeting CNV genes using cell type-specific proteomics to identify shared and unexplored disease mechanisms across NDDs.

De novo NUF2 variant in a novel inherited bone marrow failure syndrome including microcephaly and renal hypoplasia

Abstract: In a patient with severe microcephaly, congenital bone marrow failure, growth retardation, and renal hypoplasia, we identified a likely pathogenic variant in NUF2 that impairs the cell's ability to properly complete mitosis. Interestingly, these clinical features as well as the observed cellular alterations are highly reminiscent of what is reported in Fanconi Anaemia supporting a unifying causal role of the variant in the disease. This case provides the first evidence that a kinetochore defect, previously associated with microcephaly, can be responsible for an inherited bone marrow failure syndrome, highlighting the unique pathological link between neurogenesis and haematopoiesis.

CBP-HSF2 structural and functional interplay in Rubinstein-Taybi neurodevelopmental disorder

Abstract: Abstract Patients carrying autosomal dominant mutations in the histone/lysine acetyl transferases CBP or EP300 develop a neurodevelopmental disorder: Rubinstein-Taybi syndrome (RSTS). The biological pathways underlying these neurodevelopmental defects remain elusive. Here, we unravel the contribution of a stress-responsive pathway to RSTS. We characterize the structural and functional interaction between CBP/EP300 and heat-shock factor 2 (HSF2), a tuner of brain cortical development and major player in prenatal stress responses in the neocortex: CBP/EP300 acetylates HSF2, leading to the stabilization of the HSF2 protein. Consequently, RSTS patient-derived primary cells show decreased levels of HSF2 and HSF2-dependent alteration in their repertoire of molecular chaperones and stress response. Moreover, we unravel a CBP/EP300-HSF2-N-cadherin cascade that is also active in neurodevelopmental contexts, and show that its deregulation disturbs neuroepithelial integrity in 2D and 3D organoid models of cerebral development, generated from RSTS patient-derived iPSC cells, providing a molecular reading key for this complex pathology.

Protocole national de diagnostic et de soins (PNDS) de l’aniridie congénitale : synthèse pour le médecin traitant

Abstract: L’aniridie congénitale est une maladie rare panoculaire qui a fait l’objet d’un protocole national de diagnostic et de soins (PNDS) validé par la HAS. Elle est due dans la plupart des cas à une anomalie du gène PAX6 situé en 11p13. L’aniridie est une maladie autosomique dominante à forte pénétrance potentiellement cécitante. Sa prévalence varie de 1/40 000 naissances à 1/96 000 naissances. Environ un tiers des cas sont sporadiques. Les atteintes oculaires associent une absence d’iris complète ou partielle, une opacification cornéenne avec néovascularisation, un glaucome, une cataracte, une hypoplasie fovéolaire, une hypoplasie papillaire et un ptosis. Ces atteintes coexistent à divers degrés et évoluent avec l’âge. L’aniridie congénitale se manifestent dès les premiers mois par un nystagmus, une déficience visuelle et une photophobie. Il faut éliminer une forme syndromique à type de syndrome WAGR, syndrome WAGRO (du fait du risque de tumeur rénale de Wilms) ou syndrome de Gillespie (ataxie cérébelleuse). Sur le plan systémique, il peut exister un diabète du fait l’expression du gène PAX6 dans le pancréas, et d’autres manifestations extraoculaires. Un bilan initial est réalisé au mieux dans un centre de référence, spécialisé dans les maladies rares en ophtalmologie, avec un suivi annuel. La prise en charge des atteintes oculaires évolutives doit être médico-chirurgicale préventive et curative. La déficience visuelle et la photophobie provoquent un handicap entrainant des difficultés pour la mobilité, les déplacements, la communication, les apprentissages, la motricité fine, l’autonomie, avec des conséquences dans la vie personnelle, scolaire, professionnelle, socio-culturelle et sportive. La prise en charge médico-socio-éducative fait intervenir une équipe multidisciplinaire. Des aides doivent être mises en œuvre pour prévenir et limiter les situations de handicap de la vie quotidienne s’appuyant sur la Commission des droits et de l’autonomie des personnes handicapées (CDAPH) au sein de la Maison départementale des personnes handicapées (MDPH). Le généraliste coordonne la prise en charge multidisciplinaire médicale et paramédicale. Congenital aniridia is a rare panocular disease defined by a national diagnostic and care protocol (PNDS) validated by the HAS. In most cases, it is due to an abnormality in the PAX6 gene, located at 11p13. Aniridia is a potentially blinding autosomal dominant disease with high penetrance. The prevalence varies from 1/40,000 births to 1/96,000 births. Approximately one third of cases are sporadic. Ocular involvement includes complete or partial absence of iris tissue, corneal opacification with neovascularization, glaucoma, cataract, foveal hypoplasia, optic disc hypoplasia and ptosis. These ocular disorders coexist to varying degrees and progress with age. Congenital aniridia manifests in the first months of life as nystagmus, visual impairment and photophobia. A syndromic form such as WAGR syndrome, WAGRO syndrome (due to the risk of renal Wilms tumor) or Gillespie syndrome (cerebellar ataxia) must be ruled out. Systemic associations may include diabetes, due to expression of the PAX6 gene in the pancreas, as well as other extraocular manifestations. Initial assessment is best carried out in a referral center specialized in rare ophthalmologic diseases, with annual follow-up. The management of progressive ocular involvement must be both proactive and responsive, with medical and surgical management. Visual impairment and photophobia result in disability, leading to difficulties in mobility, movement, communication, learning, fine motor skills, and autonomy, with consequences in personal, school, professional, socio-cultural and athletic life. Medico-socio-educational care involves a multidisciplinary team. Disability rehabilitation must be implemented to prevent and limit situations of handicap in activities of daily living, relying on the Commission for the Rights and Autonomy of People with Disabilities (CDAPH) within the Departmental House of People with Disabilities (MDPH). The general practitioner coordinates multidisciplinary medical and paramedical care.