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2.
Am J Hum Genet ; 104(4): 701-708, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30879638

RESUMO

Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/threonine-protein kinase BRSK2. All probands have a speech delay, and most present with intellectual disability, motor delay, behavioral issues, and autism. Six of the nine variants are predicted to result in loss of function, and computational modeling predicts that the remaining three missense variants are damaging to BRSK2 structure and function. All nine variants are absent from large variant databases, and BRSK2 is, in general, relatively intolerant to protein-altering variation among humans. In all six probands for whom parents were available, the mutations were found to have arisen de novo. Five of these de novo variants were from cohorts with at least 400 sequenced probands; collectively, the cohorts span 3,429 probands, and the observed rate of de novo variation in these cohorts is significantly higher than the estimated background-mutation rate (p = 2.46 × 10-6). We also find that exome sequencing provides lower coverage and appears less sensitive to rare variation in BRSK2 than does genome sequencing; this fact most likely reduces BRSK2's visibility in many clinical and research sequencing efforts. Altogether, our results implicate damaging variation in BRSK2 as a source of neurodevelopmental disease.

3.
Am J Hum Genet ; 104(4): 596-610, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30879640

RESUMO

Mutations in several genes encoding components of the SWI/SNF chromatin remodeling complex cause neurodevelopmental disorders (NDDs). Here, we report on five individuals with mutations in SMARCD1; the individuals present with developmental delay, intellectual disability, hypotonia, feeding difficulties, and small hands and feet. Trio exome sequencing proved the mutations to be de novo in four of the five individuals. Mutations in other SWI/SNF components cause Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, or other syndromic and non-syndromic NDDs. Although the individuals presented here have dysmorphisms and some clinical overlap with these syndromes, they lack their typical facial dysmorphisms. To gain insight into the function of SMARCD1 in neurons, we investigated the Drosophila ortholog Bap60 in postmitotic memory-forming neurons of the adult Drosophila mushroom body (MB). Targeted knockdown of Bap60 in the MB of adult flies causes defects in long-term memory. Mushroom-body-specific transcriptome analysis revealed that Bap60 is required for context-dependent expression of genes involved in neuron function and development in juvenile flies when synaptic connections are actively being formed in response to experience. Taken together, we identify an NDD caused by SMARCD1 mutations and establish a role for the SMARCD1 ortholog Bap60 in the regulation of neurodevelopmental genes during a critical time window of juvenile adult brain development when neuronal circuits that are required for learning and memory are formed.

4.
Am J Psychiatry ; 176(3): 217-227, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30818990

RESUMO

OBJECTIVE:: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS:: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS:: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS:: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

5.
Neurology ; 92(11): e1225-e1237, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30737337

RESUMO

OBJECTIVE: To describe the leukodystrophy caused by pathogenic variants in LARS2 and KARS, encoding mitochondrial leucyl transfer RNA (tRNA) synthase and mitochondrial and cytoplasmic lysyl tRNA synthase, respectively. METHODS: We composed a group of 5 patients with leukodystrophy, in whom whole-genome or whole-exome sequencing revealed pathogenic variants in LARS2 or KARS. Clinical information, brain MRIs, and postmortem brain autopsy data were collected. We assessed aminoacylation activities of purified mutant recombinant mitochondrial leucyl tRNA synthase and performed aminoacylation assays on patients' lymphoblasts and fibroblasts. RESULTS: Patients had a combination of early-onset deafness and later-onset neurologic deterioration caused by progressive brain white matter abnormalities on MRI. Female patients with LARS2 pathogenic variants had premature ovarian failure. In 2 patients, MRI showed additional signs of early-onset vascular abnormalities. In 2 other patients with LARS2 and KARS pathogenic variants, magnetic resonance spectroscopy revealed elevated white matter lactate, suggesting mitochondrial disease. Pathology in one patient with LARS2 pathogenic variants displayed evidence of primary disease of oligodendrocytes and astrocytes with lack of myelin and deficient astrogliosis. Aminoacylation activities of purified recombinant mutant leucyl tRNA synthase showed a 3-fold loss of catalytic efficiency. Aminoacylation assays on patients' lymphoblasts and fibroblasts showed about 50% reduction of enzyme activity. CONCLUSION: This study adds LARS2 and KARS pathogenic variants as gene defects that may underlie deafness, ovarian failure, and leukodystrophy with mitochondrial signature. We discuss the specific MRI characteristics shared by leukodystrophies caused by mitochondrial tRNA synthase defects. We propose to add aminoacylation assays as biochemical diagnostic tools for leukodystrophies.

6.
Hum Mutat ; 40(3): 243-257, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30582250

RESUMO

The PCDH19 gene consists of six exons encoding a 1,148 amino acid transmembrane protein, Protocadherin 19, which is involved in brain development. Heterozygous pathogenic variants in this gene are inherited in an unusual X-linked dominant pattern in which heterozygous females are affected, while hemizygous males are typically unaffected, although they pass on the pathogenic variant to each affected daughter. PCDH19-related disorder is known to cause early-onset epilepsy in females characterized by seizure clusters exacerbated by fever and in most cases, onset is within the first year of life. This condition was initially described in 1971 and in 2008 PCDH19 was identified as the underlying genetic etiology. This condition is the result of pathogenic loss-of-function variants that may be de novo or inherited from an affected mother or unaffected father and cellular interference has been hypothesized to be the culprit. Heterozygous females are symptomatic because of the presence of both wild-type and mutant cells that interfere with one another due to the production of different surface proteins, whereas nonmosaic hemizygous males produce a homogenous population of cells. Here, we review novel pathogenic variants in the PCDH19 gene since 2012 to date, and summarize any genotype-phenotype correlations.

7.
Brain ; 141(12): 3331-3342, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476002

RESUMO

Hereditary spastic paraplegias (HSPs) are rare neurological disorders caused by progressive distal degeneration of the corticospinal tracts. Among the 79 loci and 65 spastic paraplegia genes (SPGs) involved in HSPs, mutations in SPAST, which encodes spastin, responsible for SPG4, are the most frequent cause of both familial and sporadic HSP. SPG4 is characterized by a clinically pure phenotype associated with restricted involvement of the corticospinal tracts and posterior columns of the spinal cord. It is rarely associated with additional neurological signs. However, both age of onset and severity of the disorder are extremely variable. Such variability is both intra- and inter-familial and may suggest incomplete penetrance, with some patients carrying mutations remaining asymptomatic for their entire life. We analysed a cohort of 842 patients with SPG4-HSP to assess genotype-phenotype correlations. Most patients were French (89%) and had a family history of SPG4-HSP (75%). Age at onset was characterized by a bimodal distribution, with high inter-familial and intra-familial variability, especially concerning first-degree relatives. Penetrance of the disorder was 0.9, complete after 70 years of age. Penetrance was lower in females (0.88 versus 0.94 in males, P = 0.01), despite a more diffuse phenotype with more frequent upper limb involvement. Seventy-seven per cent of pathogenic mutations (missense, frameshift, splice site, nonsense, and deletions) were located in the AAA cassette of spastin, impairing its microtubule-severing activity. A comparison of the missense and truncating mutations revealed a significantly lower age at onset for patients carrying missense mutations than those carrying truncating mutations, explaining the bimodal distribution of the age at onset. The age at onset for patients carrying missense mutations was often before 10 years, sometimes associated with intellectual deficiency. Neuropathological examination of a single case showed degeneration of the spinocerebellar and spinocortical tracts, as well as the posterior columns. However, there were numerous small-diameter processes among unusually large myelinated fibres in the corticospinal tract, suggesting marked regeneration. In conclusion, this large cohort of 842 individuals allowed us to identify a significantly younger age at onset in missense mutation carriers and lower penetrance in females, despite a more severe disorder. Neuropathology in one case showed numerous small fibres suggesting regeneration.

8.
Hum Genet ; 137(9): 753-768, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30167850

RESUMO

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.


Assuntos
Proteínas de Transporte/genética , Canalopatias/genética , Deficiências do Desenvolvimento/genética , Marcadores Genéticos , Variação Genética , Proteínas de Membrana/genética , Canais de Sódio/genética , Adolescente , Adulto , Canalopatias/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Adulto Jovem
9.
Brain Dev ; 40(9): 768-774, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29861155

RESUMO

OBJECTIVE: Heterozygous mutations in the ATP1A3 gene are responsible for various neurological disorders, ranging from early-onset alternating hemiplegia of childhood to adult-onset dystonia-parkinsonism. Next generation sequencing allowed the description of other phenotypes, including early-onset epileptic encephalopathy in two patients. We report on three more patients carrying ATP1A3 mutations with a close phenotype and discuss the relationship of this phenotype to alternating hemiplegia of childhood. METHODS: The patients' DNA underwent next generation sequencing. A retrospective analysis of clinical case records is reported. RESULTS: Each of the three patients had an unreported heterozygous de novo sequence variant in ATP1A3. These patients shared a similar phenotype characterized by early-onset attacks of movement disorders, some of which proved to be epileptic, and severe developmental delay. (Hemi)plegic attacks had not been considered before genetic testing. SIGNIFICANCE: Together with the two previously reported cases, our patients confirm that ATP1A3 mutations are associated with a phenotype combining features of early-onset encephalopathy, epilepsy and dystonic fits, as in the most severe forms of alternating hemiplegia of childhood, but in which (hemi)plegic attacks are absent or only suspected retrospectively.


Assuntos
Epilepsia/genética , Transtornos dos Movimentos/genética , Mutação , Convulsões/genética , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Feminino , Hemiplegia/genética , Hemiplegia/fisiopatologia , Humanos , Masculino , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/fisiopatologia , Convulsões/diagnóstico , Convulsões/fisiopatologia
10.
Brain ; 141(5): 1286-1299, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29481671

RESUMO

Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.

11.
J Inherit Metab Dis ; 41(3): 447-456, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29423831

RESUMO

BACKGROUND: In 2009, untargeted metabolomics led to the delineation of a new clinico-biological entity called cerebellar ataxia with elevated cerebrospinal free sialic acid, or CAFSA. In order to elucidate CAFSA, we applied sequentially targeted and untargeted omic approaches. METHODS AND RESULTS: First, we studied five of the six CAFSA patients initially described. Besides increased CSF free sialic acid concentrations, three patients presented with markedly decreased 5-methyltetrahydrofolate (5-MTHF) CSF concentrations. Exome sequencing identified a homozygous POLG mutation in two affected sisters, but failed to identify a causative gene in the three sporadic patients with high sialic acid but low 5-MTHF. Using targeted mass spectrometry, we confirmed that free sialic acid was increased in the CSF of a third known POLG-mutated patient. We then pursued pathophysiological analyses of CAFSA using mass spectrometry-based metabolomics on CSF from two sporadic CAFSA patients as well as 95 patients with an unexplained encephalopathy and 39 controls. This led to the identification of a common metabotype between the two initial CAFSA patients and three additional patients, including one patient with Kearns-Sayre syndrome. Metabolites of the CSF metabotype were positioned in a reconstruction of the human metabolic network, which highlighted the proximity of the metabotype with acetyl-CoA and carnitine, two key metabolites regulating mitochondrial energy homeostasis. CONCLUSION: Our genetic and metabolomics analyses suggest that CAFSA is a heterogeneous entity related to mitochondrial DNA alterations either through POLG mutations or a mechanism similar to what is observed in Kearns-Sayre syndrome.

12.
Hum Mutat ; 39(1): 23-39, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29068161

RESUMO

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Genes DCC , Estudos de Associação Genética , Mutação , Fenótipo , Agenesia do Corpo Caloso , Sequência de Aminoácidos , Sítios de Ligação , Sequência Conservada , Bases de Dados Genéticas , Humanos , Imagem por Ressonância Magnética , Modelos Moleculares , Netrina-1/química , Netrina-1/metabolismo , Ligação Proteica , Conformação Proteica , Domínios Proteicos/genética , Síndrome
13.
J Clin Invest ; 127(11): 3923-3936, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28945198

RESUMO

Netrin-1 is a secreted protein that was first identified 20 years ago as an axon guidance molecule that regulates midline crossing in the CNS. It plays critical roles in various tissues throughout development and is implicated in tumorigenesis and inflammation in adulthood. Despite extensive studies, no inherited human disease has been directly associated with mutations in NTN1, the gene coding for netrin-1. Here, we have identified 3 mutations in exon 7 of NTN1 in 2 unrelated families and 1 sporadic case with isolated congenital mirror movements (CMM), a disorder characterized by involuntary movements of one hand that mirror intentional movements of the opposite hand. Given the diverse roles of netrin-1, the absence of manifestations other than CMM in NTN1 mutation carriers was unexpected. Using multimodal approaches, we discovered that the anatomy of the corticospinal tract (CST) is abnormal in patients with NTN1-mutant CMM. When expressed in HEK293 or stable HeLa cells, the 3 mutated netrin-1 proteins were almost exclusively detected in the intracellular compartment, contrary to WT netrin-1, which is detected in both intracellular and extracellular compartments. Since netrin-1 is a diffusible extracellular cue, the pathophysiology likely involves its loss of function and subsequent disruption of axon guidance, resulting in abnormal decussation of the CST.


Assuntos
Transtornos dos Movimentos/genética , Netrina-1/genética , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Animais , Sequência Conservada , Feminino , Frequência do Gene , Estudos de Associação Genética , Células HEK293 , Células HeLa , Heterozigoto , Humanos , Masculino , Camundongos , Mutação de Sentido Incorreto , Linhagem , Deleção de Sequência
14.
Neuron ; 94(6): 1101-1111.e7, 2017 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-28641109

RESUMO

Tourette syndrome (TS) is a model neuropsychiatric disorder thought to arise from abnormal development and/or maintenance of cortico-striato-thalamo-cortical circuits. TS is highly heritable, but its underlying genetic causes are still elusive, and no genome-wide significant loci have been discovered to date. We analyzed a European ancestry sample of 2,434 TS cases and 4,093 ancestry-matched controls for rare (< 1% frequency) copy-number variants (CNVs) using SNP microarray data. We observed an enrichment of global CNV burden that was prominent for large (> 1 Mb), singleton events (OR = 2.28, 95% CI [1.39-3.79], p = 1.2 × 10-3) and known, pathogenic CNVs (OR = 3.03 [1.85-5.07], p = 1.5 × 10-5). We also identified two individual, genome-wide significant loci, each conferring a substantial increase in TS risk (NRXN1 deletions, OR = 20.3, 95% CI [2.6-156.2]; CNTN6 duplications, OR = 10.1, 95% CI [2.3-45.4]). Approximately 1% of TS cases carry one of these CNVs, indicating that rare structural variation contributes significantly to the genetic architecture of TS.


Assuntos
Moléculas de Adesão Celular Neuronais/genética , Contactinas/genética , Variações do Número de Cópias de DNA , Proteínas do Tecido Nervoso/genética , Síndrome de Tourette/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Razão de Chances , Adulto Jovem
16.
J Med Genet ; 54(7): 460-470, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28377535

RESUMO

BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine. METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care. RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated. CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.


Assuntos
Encefalopatias/genética , Mutação/genética , Receptores de N-Metil-D-Aspartato/genética , Encefalopatias/tratamento farmacológico , Heterozigoto , Humanos , Imagem por Ressonância Magnética , Memantina/uso terapêutico , Terapia de Alvo Molecular , Neuroimagem , Fenótipo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo
17.
Hum Genet ; 136(4): 463-479, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28283832

RESUMO

Subtelomeric 1q43q44 microdeletions cause a syndrome associating intellectual disability, microcephaly, seizures and anomalies of the corpus callosum. Despite several previous studies assessing genotype-phenotype correlations, the contribution of genes located in this region to the specific features of this syndrome remains uncertain. Among those, three genes, AKT3, HNRNPU and ZBTB18 are highly expressed in the brain and point mutations in these genes have been recently identified in children with neurodevelopmental phenotypes. In this study, we report the clinical and molecular data from 17 patients with 1q43q44 microdeletions, four with ZBTB18 mutations and seven with HNRNPU mutations, and review additional data from 37 previously published patients with 1q43q44 microdeletions. We compare clinical data of patients with 1q43q44 microdeletions with those of patients with point mutations in HNRNPU and ZBTB18 to assess the contribution of each gene as well as the possibility of epistasis between genes. Our study demonstrates that AKT3 haploinsufficiency is the main driver for microcephaly, whereas HNRNPU alteration mostly drives epilepsy and determines the degree of intellectual disability. ZBTB18 deletions or mutations are associated with variable corpus callosum anomalies with an incomplete penetrance. ZBTB18 may also contribute to microcephaly and HNRNPU to thin corpus callosum, but with a lower penetrance. Co-deletion of contiguous genes has additive effects. Our results confirm and refine the complex genotype-phenotype correlations existing in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of AKT3, ZBTB18 and HNRNPU in humans.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1 , Ribonucleoproteínas Nucleares Heterogêneas/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Proteínas Repressoras/genética , Humanos
18.
J Pediatr ; 185: 160-166.e1, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28284480

RESUMO

OBJECTIVE: To evaluate the role that chromosomal micro-rearrangements play in patients with both corpus callosum abnormality and intellectual disability, we analyzed copy number variations (CNVs) in patients with corpus callosum abnormality/intellectual disability STUDY DESIGN: We screened 149 patients with corpus callosum abnormality/intellectual disability using Illumina SNP arrays. RESULTS: In 20 patients (13%), we have identified at least 1 CNV that likely contributes to corpus callosum abnormality/intellectual disability phenotype. We confirmed that the most common rearrangement in corpus callosum abnormality/intellectual disability is inverted duplication with terminal deletion of the 8p chromosome (3.2%). In addition to the identification of known recurrent CNVs, such as deletions 6qter, 18q21 (including TCF4), 1q43q44, 17p13.3, 14q12, 3q13, 3p26, and 3q26 (including SOX2), our analysis allowed us to refine the 2 known critical regions associated with 8q21.1 deletion and 19p13.1 duplication relevant for corpus callosum abnormality; report a novel 10p12 deletion including ZEB1 recently implicated in corpus callosum abnormality with corneal dystrophy; and) report a novel pathogenic 7q36 duplication encompassing SHH. In addition, 66 variants of unknown significance were identified in 57 patients encompassed candidate genes. CONCLUSIONS: Our results confirm the relevance of using microarray analysis as first line test in patients with corpus callosum abnormality/intellectual disability.


Assuntos
Agenesia do Corpo Caloso/genética , Variações do Número de Cópias de DNA , Deficiência Intelectual/genética , Adolescente , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 7 , Cromossomos Humanos Par 8 , Feminino , Proteínas Hedgehog/genética , Humanos , Masculino , Análise em Microsséries , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto Jovem , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
19.
Artigo em Inglês | MEDLINE | ID: mdl-27830107

RESUMO

BACKGROUND: Autosomal dominant congenital mirror movements (CMM) is a neurodevelopmental disorder characterized by early onset involuntary movements of one side of the body that mirror intentional movements on the contralateral side; these persist throughout life in the absence of other neurological symptoms. The main culprit genes responsible for this condition are RAD51 and DCC. This condition has only been reported in a few families, and the molecular mechanisms linking RAD51 mutations and mirror movements (MM) are poorly understood. METHODS: We collected demographic, clinical, and genetic data of a new family with CMM due to a truncating mutation of RAD51. We reviewed the literature to identify all reported patients with CMM due to RAD51 mutations. RESULTS: We identified a heterozygous nonsense mutation c.760C>T (p.Arg254*) in eight subjects: four with obvious and disabling MM, and four with a mild phenotype. Including our new family, we identified 32 patients from 6 families with CMM linked to RAD51 variants. DISCUSSION: Our findings further support the involvement of RAD51 in CMM pathogenesis. Possible molecular mechanisms involved in CMM pathogenesis are discussed.

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