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1.
Am J Hum Genet ; 110(6): 998-1007, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37207645

RESUMO

While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.


Assuntos
Transtorno do Espectro Autista , Transtornos do Neurodesenvolvimento , Síndrome de Prader-Willi , Adolescente , Humanos , Transtorno do Espectro Autista/genética , Hiperfagia/genética , Hiperfagia/complicações , Transtornos do Neurodesenvolvimento/genética , Obesidade/complicações , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Proteínas
2.
Am J Med Genet A ; 194(7): e63531, 2024 07.
Artigo em Inglês | MEDLINE | ID: mdl-38421086

RESUMO

Duplications of the 3q29 cytoband are rare chromosomal copy number variations (CNVs) (overlapping or recurrent ~1.6 Mb 3q29 duplications). They have been associated with highly variable neurodevelopmental disorders (NDDs) with various associated features or reported as a susceptibility factor to the development of learning disabilities and neuropsychiatric disorders. The smallest region of overlap and the phenotype of 3q29 duplications remain uncertain. We here report a French cohort of 31 families with a 3q29 duplication identified by chromosomal microarray analysis (CMA), including 14 recurrent 1.6 Mb duplications, eight overlapping duplications (>1 Mb), and nine small duplications (<1 Mb). Additional genetic findings that may be involved in the phenotype were identified in 11 patients. Focusing on apparently isolated 3q29 duplications, patients present mainly mild NDD as suggested by a high rate of learning disabilities in contrast to a low proportion of patients with intellectual disabilities. Although some are de novo, most of the 3q29 duplications are inherited from a parent with a similar mild phenotype. Besides, the study of small 3q29 duplications does not provide evidence for any critical region. Our data suggest that the overlapping and recurrent 3q29 duplications seem to lead to mild NDD and that a severe or syndromic clinical presentation should warrant further genetic analyses.


Assuntos
Duplicação Cromossômica , Cromossomos Humanos Par 3 , Variações do Número de Cópias de DNA , Fenótipo , Humanos , Feminino , Masculino , Cromossomos Humanos Par 3/genética , Duplicação Cromossômica/genética , Criança , Variações do Número de Cópias de DNA/genética , Pré-Escolar , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Adolescente , Estudos de Coortes , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Adulto , Lactente
3.
Brain ; 146(6): 2285-2297, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-36477332

RESUMO

The blood-brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood-brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype-phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood-brain barrier and impaired neuronal function.


Assuntos
Microcefalia , Animais , Humanos , Microcefalia/genética , Claudina-5/genética , Claudina-5/metabolismo , Peixe-Zebra/metabolismo , Barreira Hematoencefálica/metabolismo , Convulsões/genética , Síndrome
4.
J Med Genet ; 61(1): 47-56, 2023 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-37495270

RESUMO

BACKGROUND: Molecular diagnosis of neurodevelopmental disorders (NDDs) is mainly based on exome sequencing (ES), with a diagnostic yield of 31% for isolated and 53% for syndromic NDD. As sequencing costs decrease, genome sequencing (GS) is gradually replacing ES for genome-wide molecular testing. As many variants detected by GS only are in deep intronic or non-coding regions, the interpretation of their impact may be difficult. Here, we showed that integrating RNA-Seq into the GS workflow can enhance the analysis of the molecular causes of NDD, especially structural variants (SVs), by providing valuable complementary information such as aberrant splicing, aberrant expression and monoallelic expression. METHODS: We performed trio-GS on a cohort of 33 individuals with NDD for whom ES was inconclusive. RNA-Seq on skin fibroblasts was then performed in nine individuals for whom GS was inconclusive and optical genome mapping (OGM) was performed in two individuals with an SV of unknown significance. RESULTS: We identified pathogenic or likely pathogenic variants in 16 individuals (48%) and six variants of uncertain significance. RNA-Seq contributed to the interpretation in three individuals, and OGM helped to characterise two SVs. CONCLUSION: Our study confirmed that GS significantly improves the diagnostic performance of NDDs. However, most variants detectable by GS alone are structural or located in non-coding regions, which can pose challenges for interpretation. Integration of RNA-Seq data overcame this limitation by confirming the impact of variants at the transcriptional or regulatory level. This result paves the way for new routinely applicable diagnostic protocols.


Assuntos
Transtornos do Neurodesenvolvimento , Humanos , Sequenciamento do Exoma , RNA-Seq , Fluxo de Trabalho , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Mapeamento Cromossômico
5.
Am J Med Genet B Neuropsychiatr Genet ; 195(6): e32970, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38459409

RESUMO

Since 2008, FOXG1 haploinsufficiency has been linked to a severe neurodevelopmental phenotype resembling Rett syndrome but with earlier onset. Most patients are unable to sit, walk, or speak. For years, FOXG1 sequencing was only prescribed in such severe cases, limiting insight into the full clinical spectrum associated with this gene. Next-generation sequencing (NGS) now enables unbiased diagnostics. Through the European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, we gathered data from patients with heterozygous FOXG1 variants presenting a mild phenotype, defined as able to speak and walk independently. We also reviewed data from three previously reported patients meeting our criteria. We identified five new patients with pathogenic FOXG1 missense variants, primarily in the forkhead domain, showing varying nonspecific intellectual disability and developmental delay. These features are not typical of congenital Rett syndrome and were rarely associated with microcephaly and epilepsy. Our findings are consistent with a previous genotype-phenotype analysis by Mitter et al. suggesting the delineation of five different FOXG1 genotype groups. Milder phenotypes were associated with missense variants in the forkhead domain. This information may facilitate prognostic assessments in children carrying a FOXG1 variant and improve the interpretation of new variants identified with genomic sequencing.


Assuntos
Fatores de Transcrição Forkhead , Deficiência Intelectual , Proteínas do Tecido Nervoso , Fenótipo , Síndrome de Rett , Humanos , Fatores de Transcrição Forkhead/genética , Síndrome de Rett/genética , Proteínas do Tecido Nervoso/genética , Feminino , Masculino , Criança , Pré-Escolar , Deficiência Intelectual/genética , Desenvolvimento da Linguagem , Estudos de Associação Genética/métodos , Mutação de Sentido Incorreto/genética , Deficiências do Desenvolvimento/genética , Lactente , Adolescente , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Haploinsuficiência/genética
6.
Am J Hum Genet ; 106(6): 830-845, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32442410

RESUMO

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Craniossinostoses/genética , Transtornos do Neurodesenvolvimento/genética , Osteocondroma/genética , Fatores de Transcrição SOXD/genética , Transporte Ativo do Núcleo Celular , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Criança , Pré-Escolar , Simulação por Computador , Feminino , Variação Estrutural do Genoma/genética , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/diagnóstico , RNA-Seq , Fatores de Transcrição SOXD/química , Fatores de Transcrição SOXD/metabolismo , Síndrome , Transcrição Gênica , Transcriptoma , Translocação Genética/genética
7.
Genet Med ; 25(7): 100835, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36999555

RESUMO

PURPOSE: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder. METHODS: Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae. RESULTS: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions <1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans. CONCLUSION: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.


Assuntos
Lissencefalias Clássicas e Heterotopias Subcorticais em Banda , Deficiência Intelectual , Lisencefalia , Transtornos do Neurodesenvolvimento , Humanos , Animais , Camundongos , Encéfalo/anormalidades , Lisencefalia/genética , Deficiência Intelectual/genética , Proteínas 14-3-3/genética
8.
Genet Med ; 25(8): 100856, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37092537

RESUMO

PURPOSE: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. METHODS: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. RESULTS: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators' recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. CONCLUSION: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.


Assuntos
Microftalmia , Receptores do Ácido Retinoico , Humanos , Receptores do Ácido Retinoico/genética , Receptores do Ácido Retinoico/metabolismo , Retinoides
9.
Ann Neurol ; 92(6): 958-973, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36073542

RESUMO

OBJECTIVE: Rare inherited missense variants in SLC32A1, the gene that encodes the vesicular gamma-aminobutyric acid (GABA) transporter, have recently been shown to cause genetic epilepsy with febrile seizures plus. We aimed to clarify if de novo missense variants in SLC32A1 can also cause epilepsy with impaired neurodevelopment. METHODS: Using exome sequencing, we identified four individuals with a developmental and epileptic encephalopathy and de novo missense variants in SLC32A1. To assess causality, we performed functional evaluation of the identified variants in a murine neuronal cell culture model. RESULTS: The main phenotype comprises moderate-to-severe intellectual disability, infantile-onset epilepsy within the first 18 months of life, and a choreiform, dystonic, or dyskinetic movement disorder. In silico modeling and functional analyses reveal that three of these variants, which are located in helices that line the putative GABA transport pathway, result in reduced quantal size, consistent with impaired filling of synaptic vesicles with GABA. The fourth variant, located in the vesicular gamma-aminobutyric acid N-terminus, does not affect quantal size, but increases presynaptic release probability, leading to more severe synaptic depression during high-frequency stimulation. Thus, variants in vesicular gamma-aminobutyric acid can impair GABAergic neurotransmission through at least two mechanisms, by affecting synaptic vesicle filling and by altering synaptic short-term plasticity. INTERPRETATION: This work establishes de novo missense variants in SLC32A1 as a novel cause of a developmental and epileptic encephalopathy. SUMMARY FOR SOCIAL MEDIA IF PUBLISHED: @platzer_k @lemke_johannes @RamiJamra @Nirgalito @GeneDx The SLC family 32 Member 1 (SLC32A1) is the only protein identified to date, that loads gamma-aminobutyric acid (GABA) and glycine into synaptic vesicles, and is therefore also known as the vesicular GABA transporter (VGAT) or vesicular inhibitory amino acid transporter (VIAAT). Rare inherited missense variants in SLC32A1, the gene that encodes VGAT/vesicular inhibitory amino acid transporter, have recently been shown to cause genetic epilepsy with febrile seizures plus. We aimed to clarify if de novo missense variants in SLC32A1 can also cause epilepsy with impaired neurodevelopment. We report on four individuals with de novo missense variants in SLC32A1 and a developmental and epileptic encephalopathy with infantile onset epilepsy. We establish causality of the variants via in silico modeling and their functional evaluation in a murine neuronal cell culture model. SLC32A1 variants represent a novel genetic etiology in neurodevelopmental disorders with epilepsy and a new GABA-related disease mechanism. ANN NEUROL 2022;92:958-973.


Assuntos
Epilepsia Generalizada , Epilepsia , Convulsões Febris , Animais , Camundongos , Epilepsia Generalizada/genética , Epilepsia/genética , Transmissão Sináptica/genética , Ácido gama-Aminobutírico/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo
10.
Hum Genet ; 141(1): 65-80, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34748075

RESUMO

Pathogenic variants of the myelin transcription factor-1 like (MYT1L) gene include heterozygous missense, truncating variants and 2p25.3 microdeletions and cause a syndromic neurodevelopmental disorder (OMIM#616,521). Despite enrichment in de novo mutations in several developmental disorders and autism studies, the data on clinical characteristics and genotype-phenotype correlations are scarce, with only 22 patients with single nucleotide pathogenic variants reported. We aimed to further characterize this disorder at both the clinical and molecular levels by gathering a large series of patients with MYT1L-associated neurodevelopmental disorder. We collected genetic information on 40 unreported patients with likely pathogenic/pathogenic MYT1L variants and performed a comprehensive review of published data (total = 62 patients). We confirm that the main phenotypic features of the MYT1L-related disorder are developmental delay with language delay (95%), intellectual disability (ID, 70%), overweight or obesity (58%), behavioral disorders (98%) and epilepsy (23%). We highlight novel clinical characteristics, such as learning disabilities without ID (30%) and feeding difficulties during infancy (18%). We further describe the varied dysmorphic features (67%) and present the changes in weight over time of 27 patients. We show that patients harboring highly clustered missense variants in the 2-3-ZNF domains are not clinically distinguishable from patients with truncating variants. We provide an updated overview of clinical and genetic data of the MYT1L-associated neurodevelopmental disorder, hence improving diagnosis and clinical management of these patients.


Assuntos
Variação Genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Criança , Pré-Escolar , Epilepsia/genética , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Feminino , Estudos de Associação Genética , Heterozigoto , Humanos , Lactente , Transtornos do Desenvolvimento da Linguagem/genética , Masculino , Obesidade/genética , Fenótipo , Adulto Jovem
11.
Cytogenet Genome Res ; 162(5): 244-249, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36481557

RESUMO

We report a patient presenting with neurodevelopmental disorder, cleft palate, micrognathia, relatively mild microcephaly (-2 SD), and ventricular septal defect for whom a 9p terminal deletion was identified by aCGH at birth. The analyses of the samples taken prenatally showed that this terminal deletion resulted from the recombination of a dicentric chromosome which was transmitted to the zygote. Indeed, an inverted duplication with terminal deletion of the short arm of chromosome 9 [invdupdel(9p)] was found in a mosaic state in the placenta. To our knowledge, it is the first reported patient with a terminal deletion present in all tested cells of the blood associated with an invdupdel of the same chromosome in the placenta. This case highlights the role of postzygotic breakages of dicentric chromosomes, a possible underestimated mechanism of formation of terminal deletions. It raises the question of genetic counseling in cases of prenatally detected invdupdels.


Assuntos
Transtornos Cromossômicos , Fissura Palatina , Recém-Nascido , Gravidez , Feminino , Humanos , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos , Fissura Palatina/genética , Aconselhamento Genético , Cromossomos Humanos Par 9
12.
Genet Med ; 24(4): 905-914, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35027293

RESUMO

PURPOSE: Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features. To refine the phenotype and to better understand the molecular basis of the syndrome, we analyzed clinical data and performed genome-wide DNA methylation analysis of a series of individuals carrying a YY1 variant. METHODS: Clinical data were collected for 13 individuals not yet reported through an international call for collaboration. DNA was collected for 11 of these individuals and 2 previously reported individuals in an attempt to delineate a specific DNA methylation signature in GADEVS. RESULTS: Phenotype in most individuals overlapped with the previously described features. We described 1 individual with atypical phenotype, heterozygous for a missense variant in a domain usually not involved in individuals with YY1 pathogenic missense variations. We also described a specific peripheral blood DNA methylation profile associated with YY1 variants. CONCLUSION: We reported a distinct DNA methylation episignature in GADEVS. We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism. We also highlighted the utility of DNA methylation episignature analysis for classification of variants of unknown clinical significance.


Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Metilação de DNA/genética , Genoma , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Síndrome
13.
Clin Genet ; 101(5-6): 494-506, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35170016

RESUMO

Peters' anomaly (PA) is a rare anterior segment dysgenesis characterized by central corneal opacity and irido-lenticulo-corneal adhesions. Several genes are involved in syndromic or isolated PA (B3GLCT, PAX6, PITX3, FOXE3, CYP1B1). Some copy number variations (CNVs) have also been occasionally reported. Despite this genetic heterogeneity, most of patients remain without genetic diagnosis. We retrieved a cohort of 95 individuals with PA and performed genotyping using a combination of comparative genomic hybridization, whole genome, exome and targeted sequencing of 119 genes associated with ocular development anomalies. Causative genetic defects involving 12 genes and CNVs were identified for 1/3 of patients. Unsurprisingly, B3GLCT and PAX6 were the most frequently implicated genes, respectively in syndromic and isolated PA. Unexpectedly, the third gene involved in our cohort was SOX2, the major gene of micro-anophthalmia. Four unrelated patients with PA (isolated or with microphthalmia) were carrying pathogenic variants in this gene that was never associated with PA before. Here we described the largest cohort of PA patients ever reported. The genetic bases of PA are still to be explored as genetic diagnosis was unavailable for 2/3 of patients. Nevertheless, we showed here for the first time the involvement of SOX2 in PA, offering new evidence for its role in corneal transparency and anterior segment development.


Assuntos
Opacidade da Córnea , Anormalidades do Olho , Segmento Anterior do Olho/anormalidades , Hibridização Genômica Comparativa , Opacidade da Córnea/diagnóstico , Opacidade da Córnea/genética , Opacidade da Córnea/patologia , Variações do Número de Cópias de DNA/genética , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Humanos , Mutação/genética , Fatores de Transcrição SOXB1/genética
14.
Epilepsy Behav ; 126: 108471, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34915430

RESUMO

AIM: KCNB1 encephalopathy encompasses a broad phenotypic spectrum associating intellectual disability, behavioral disturbances, and epilepsies of various severity. Using standardized parental questionnaires, we aimed to capture the heterogeneity of the adaptive and behavioral features in a series of patients with KCNB1 pathogenic variants. METHODS: We included 25 patients with a KCNB1 encephalopathy, aged from 3.2 to 34.1 years (median = 10 years). Adaptive functioning was assessed in all patients using the French version of the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) questionnaire. We screened global behavior with the Childhood Behavioral Check-List (CBCL, Achenbach) and autism spectrum disorder (ASD) with the Social Communication Questionnaire (SCQ). We used a cluster analysis to identify subgroups of adaptive profiles. RESULTS: VABS-II questionnaire showed pathological adaptive behavior in all participants with a severity of adaptive deficiency ranging from mild in 8/20 to severe in 7/20. Eight out of 16 were at risk of Attention Problems at the CBCL and 13/18 were at risk of autism spectrum disorder (ASD). The adaptive behavior composite score significantly decreased with age (Spearman's Rho=-0.72, p<0.001) but not the equivalent ages, suggesting stagnation and slowing but no regression over time. The clustering analysis identified two subgroups of patients, one showing more severe adaptive behavior. The severity of the epilepsy phenotype predicted the severity of the behavioral profile with a sensitivity of 70% and a specificity of 90.9%. CONCLUSION: This study confirms the deleterious consequences of early-onset epilepsy in addition to the impact of the gene dysfunction in patients with KCNB1 encephalopathy. ASD and attention disorders are frequent. Parental questionnaires should be considered as useful tools for early screening and care adaptation.


Assuntos
Transtorno do Espectro Autista , Encefalopatias , Epilepsia , Deficiência Intelectual , Adaptação Psicológica , Adolescente , Adulto , Transtorno do Espectro Autista/complicações , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/genética , Encefalopatias/complicações , Encefalopatias/epidemiologia , Encefalopatias/genética , Criança , Pré-Escolar , Epilepsia/genética , Humanos , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Canais de Potássio Shab/genética , Adulto Jovem
15.
Hum Genet ; 140(7): 1109-1120, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33944996

RESUMO

Located in the critical 1p36 microdeletion region, the chromodomain helicase DNA-binding protein 5 (CHD5) gene encodes a subunit of the nucleosome remodeling and deacetylation (NuRD) complex required for neuronal development. Pathogenic variants in six of nine chromodomain (CHD) genes cause autosomal dominant neurodevelopmental disorders, while CHD5-related disorders are still unknown. Thanks to GeneMatcher and international collaborations, we assembled a cohort of 16 unrelated individuals harboring heterozygous CHD5 variants, all identified by exome sequencing. Twelve patients had de novo CHD5 variants, including ten missense and two splice site variants. Three familial cases had nonsense or missense variants segregating with speech delay, learning disabilities, and/or craniosynostosis. One patient carried a frameshift variant of unknown inheritance due to unavailability of the father. The most common clinical features included language deficits (81%), behavioral symptoms (69%), intellectual disability (64%), epilepsy (62%), and motor delay (56%). Epilepsy types were variable, with West syndrome observed in three patients, generalized tonic-clonic seizures in two, and other subtypes observed in one individual each. Our findings suggest that, in line with other CHD-related disorders, heterozygous CHD5 variants are associated with a variable neurodevelopmental syndrome that includes intellectual disability with speech delay, epilepsy, and behavioral problems as main features.


Assuntos
DNA Helicases/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Domínio Catalítico , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/genética , Feminino , Genes Dominantes , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Adulto Jovem
16.
Genet Med ; 23(3): 543-554, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33149277

RESUMO

PURPOSE: A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. METHODS: We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC. RESULTS: Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts. CONCLUSION: Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.


Assuntos
Deficiência Intelectual , Transtornos do Neurodesenvolvimento , Actinas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Humanos , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Convulsões
17.
Hum Mutat ; 41(1): 69-80, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31513310

RESUMO

Developmental and epileptic encephalopathies (DEE) refer to a heterogeneous group of devastating neurodevelopmental disorders. Variants in KCNB1 have been recently reported in patients with early-onset DEE. KCNB1 encodes the α subunit of the delayed rectifier voltage-dependent potassium channel Kv 2.1. We review the 37 previously reported patients carrying 29 distinct KCNB1 variants and significantly expand the mutational spectrum describing 18 novel variants from 27 unreported patients. Most variants occur de novo and mainly consist of missense variants located on the voltage sensor and the pore domain of Kv 2.1. We also report the first inherited variant (p.Arg583*). KCNB1-related encephalopathies encompass a wide spectrum of neurodevelopmental disorders with predominant language difficulties and behavioral impairment. Eighty-five percent of patients developed epilepsies with variable syndromes and prognosis. Truncating variants in the C-terminal domain are associated with a less-severe epileptic phenotype. Overall, this report provides an up-to-date review of the mutational and clinical spectrum of KCNB1, strengthening its place as a causal gene in DEEs and emphasizing the need for further functional studies to unravel the underlying mechanisms.


Assuntos
Epilepsia/diagnóstico , Epilepsia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Canais de Potássio Shab/genética , Alelos , Estudos de Associação Genética/métodos , Genótipo , Humanos , Fenótipo , Canais de Potássio Shab/química , Canais de Potássio Shab/metabolismo , Relação Estrutura-Atividade
18.
Am J Hum Genet ; 101(6): 985-994, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29198724

RESUMO

Bone morphogenetic protein 2 (BMP2) in chromosomal region 20p12 belongs to a gene superfamily encoding TGF-ß-signaling proteins involved in bone and cartilage biology. Monoallelic deletions of 20p12 are variably associated with cleft palate, short stature, and developmental delay. Here, we report a cranioskeletal phenotype due to monoallelic truncating and frameshift BMP2 variants and deletions in 12 individuals from eight unrelated families that share features of short stature, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. De novo occurrence and autosomal-dominant inheritance of variants, including paternal mosaicism in two affected sisters who inherited a BMP2 splice-altering variant, were observed across all reported families. Additionally, we observed similarity to the human phenotype of short stature and skeletal anomalies in a heterozygous Bmp2-knockout mouse model, suggesting that haploinsufficiency of BMP2 could be the primary phenotypic determinant in individuals with predicted truncating variants and deletions encompassing BMP2. These findings demonstrate the important role of BMP2 in human craniofacial, skeletal, and cardiac development and confirm that individuals heterozygous for BMP2 truncating sequence variants or deletions display a consistent distinct phenotype characterized by short stature and skeletal and cardiac anomalies without neurological deficits.


Assuntos
Proteína Morfogenética Óssea 2/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Nanismo/genética , Haploinsuficiência/genética , Cardiopatias Congênitas/genética , Animais , Osso e Ossos/embriologia , Criança , Pré-Escolar , Cromossomos Humanos Par 20/genética , Fissura Palatina/genética , Modelos Animais de Doenças , Feminino , Coração/embriologia , Humanos , Lactente , Masculino , Camundongos , Camundongos Knockout , Fator de Crescimento Transformador beta/genética
19.
Genet Med ; 22(11): 1838-1850, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32694869

RESUMO

PURPOSE: Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown. METHODS: By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes. RESULTS: Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification. CONCLUSION: We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.


Assuntos
Blefarofimose , Hipotricose , Deficiência Intelectual , Fácies , Deformidades Congênitas do Pé , Humanos , Deficiência Intelectual/genética , Fenótipo , Fatores de Transcrição/genética
20.
Am J Med Genet A ; 182(9): 2133-2138, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32633079

RESUMO

Deletions in the 12q21 region are rare and non-recurrent CNVs. To date, only 11 patients with deletions in this region have been reported in the literature. These patients most often presented with syndromic intellectual deficiency, ventriculomegaly or hydrocephalus, ectodermal abnormalities, growth retardation and renal and cardiac malformations, suggesting a recognizable microdeletion syndrome. We report three new patients with overlapping deletions of the 12q21 region, including the smallest deletion reported to date and the first case characterized by array CGH during pregnancy. We describe specific clinical findings and shared facial features as developmental delay, ectodermal abnormalities, ventriculomegaly or hydrocephalus, axial hypotonia or spastic diplegia, growth retardation, heart defect, hydronephrosis, ureteral reflux or horseshoe kidney, large thorax or pectus excavatum, syndactyly of 2-3 toes, pterygium coli or excess nuchal skin, large anterior fontanel, low set ears, prominent forehead, short-upturned nose with nostril hypoplasia, microretrognathia and hypertelorism. These new patients and a comprehensive review of the literature allow us to define a minimum critical region spanning 1.6 Mb in 12q21. By screening the critical region using prediction tools, we identified two candidate genes: SYT1and PPP1R12A.


Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Fosfatase de Miosina-de-Cadeia-Leve/genética , Sinaptotagmina I/genética , Anormalidades Múltiplas/patologia , Adulto , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 12/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Fácies , Feminino , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Hidrocefalia/complicações , Hidrocefalia/genética , Hidrocefalia/patologia , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Gravidez
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