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1.
Nat Commun ; 10(1): 4679, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31616000

RESUMO

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.

2.
Hum Genet ; 138(2): 187-198, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30656450

RESUMO

Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene-disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.


Assuntos
Actinas/genética , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Doenças Genéticas Inatas/diagnóstico por imagem , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Quadriplegia/genética , Espasmos Infantis/genética , Criança , Pré-Escolar , Cromatina/genética , Metilação de DNA/genética , Feminino , Doenças Genéticas Inatas/genética , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Linhagem , Quadriplegia/diagnóstico por imagem , Espasmos Infantis/diagnóstico por imagem
3.
Eur J Hum Genet ; 27(4): 594-602, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30659260

RESUMO

In recent years, chromosomal microarray analysis has permitted the discovery of rearrangements underlying several neurodevelopmental disorders and still represents the first diagnostic test for unexplained neurodevelopmental disabilities. Here we report a family of consanguineous parents showing psychiatric disorders and their two sons both affected by intellectual disability, ataxia, and behavioral disorder. SNP/CGH array analysis in this family demonstrated in both siblings a biallelic duplication inherited from the heterozygous parents, disrupting the ADGRB3 gene. ADGRB3, also known as BAI3, belongs to the subfamily of adhesion G protein-coupled receptors (adhesion GPCRs) that regulate many aspects of the central nervous system, including axon guidance, myelination, and synapse formation. Single nucleotide polymorphisms and copy number variants involving ADGRB3 have recently been associated with psychiatric disorders. These findings further support this association and also suggest that biallelic variants affecting the function of the ADGRB3 gene may also cause cognitive impairments and ataxia.

4.
Eur J Hum Genet ; 27(5): 738-746, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30679813

RESUMO

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

5.
Genet Med ; 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30190612

RESUMO

PURPOSE: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. METHODS: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. RESULTS: The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. CONCLUSION: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

6.
Gene ; 534(2): 435-9, 2014 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-24120895

RESUMO

Interstitial duplications involving chromosome 11q have rarely been reported in the literature and mainly represent large, cytogenetically detectable rearrangements associated with a wide and variable spectrum of neurodevelopmental disorders. We report on a patient affected by intellectual disability, craniosynostosis, and microcephaly. Array-CGH analysis identified a de novo 290 kb interstitial duplication of chromosome 11q13.3 including the FGF3 and FGF4 genes. Clinical comparison of our patient with those previously reported with overlapping 11q duplications allows us to define the minimal duplicated region associated with craniosynostosis and strongly supports the hypothesis that the constitutional increased dosage of the FGF3 and FGF4 genes is a risk factor for craniosynostosis in humans.


Assuntos
Craniossinostoses/genética , Fator 3 de Crescimento de Fibroblastos/genética , Fator 4 de Crescimento de Fibroblastos/genética , Dosagem de Genes , Criança , Cromossomos Humanos Par 11 , Humanos , Deficiência Intelectual/genética , Masculino , Microcefalia/genética , Fatores de Risco
7.
Mol Cytogenet ; 6(1): 4, 2013 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-23324214

RESUMO

BACKGROUND: The interstitial 6p deletions, involving the 6p22-p24 chromosomal region, are rare events characterized by variable phenotypes and no clear genotype-phenotype correlation has been established so far. RESULTS: High resolution array-CGH identified 1 Mb de novo interstitial deletion in 6p22.3 chromosomal region in a patient affected by severe Intellectual Disability (ID), Autism Spectrum Disorders (ASDs), and electroencephalographic anomalies. This deletion includes ATXN1, DTNBP1, JARID2 and MYLIP genes, known to play an important role in the brain, and the GMPR gene whose function in the nervous system is unknown. CONCLUSIONS: We support the suggestion that ATXN1, DTNBP1, JARID2 and MYLIP are candidate genes for the pathophysiology of ASDs and ID, and we propose that deletion of DTNBP1 and/or JARID2 contributes to the hypotonia phenotype.

8.
BMC Med Genomics ; 3: 28, 2010 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-20602808

RESUMO

BACKGROUND: ATRX is a severe X-linked disorder characterized by mental retardation, facial dysmorphism, urogenital abnormalities and alpha-thalassemia. The disease is caused by mutations in ATRX gene, which encodes a protein belonging to the SWI/SNF DNA helicase family, a group of proteins involved in the regulation of gene transcription at the chromatin level. In order to identify specific genes involved in the pathogenesis of the disease, we compared, by cDNA microarray, the expression levels of approximately 8500 transcripts between ATRX and normal males of comparable age. METHODS: cDNA microarray was performed using total RNA from peripheral blood mononuclear cells of ATRX and normal males. Microarray results were validated by quantitative real-time polymerase chain reaction. RESULTS: cDNA microarray analysis showed that 35 genes had a lower expression (30-35% of controls) while 25 transcripts had a two-fold higher expression in comparison to controls. In the microarray results the probe for oligophrenin-1, a gene known for its involvement in mental retardation, showed a decreased hybridization signal. However, such gene was poorly expressed in blood mononuclear cells and its decrease was not confirmed in the quantitative real-time RT-PCR assay. On the other hand, the expression of an homologous gene, the GTPase regulator associated with the focal adhesion kinase 1/Oligophrenin-1-like (GRAF1/OPHN-1-L), was relatively high in blood mononuclear cells and significantly decreased in ATRX patients. The analysis of the expression pattern of the GRAF1/OPHN-1-L gene in human tissues and organs revealed the predominant brain expression of a novel splicing isoform, called variant-3. CONCLUSIONS: Our data support the hypothesis of a primary role for altered gene expression in ATRX syndrome and suggest that the GRAF1/OPHN-1-L gene might be involved in the pathogenesis of the mental retardation. Moreover a novel alternative splicing transcript of such gene, predominantly expressed in brain tissues, was identified.


Assuntos
Proteínas Ativadoras de GTPase/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Deficiência Intelectual/genética , Talassemia alfa/genética , Adolescente , Processamento Alternativo , Criança , Proteínas Ativadoras de GTPase/metabolismo , Regulação da Expressão Gênica , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , RNA/metabolismo , Síndrome
10.
Am J Hum Genet ; 85(3): 394-400, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19716111

RESUMO

Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.


Assuntos
Cromossomos Humanos X/genética , Eletroencefalografia , Duplicação Gênica , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/complicações , Transtornos do Desenvolvimento da Linguagem/genética , Feminino , Humanos , Masculino , Linhagem
11.
Eur J Med Genet ; 52(1): 67-70, 2009 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18992374

RESUMO

We describe a 7-year-old patient with autism, moderate mental retardation, secondary microcephaly, agenesis of right optic nerve, and dysmorphic features carrying a de novo cryptic deletion of chromosome 2p25.2, detected by aCGH. Pure monosomies of 2p are very rare, and are usually observed as part of more complex aberrations involving other chromosomes. To the best of our knowledge, this is the first case presenting with a severe clinical phenotype and a de novo pure deletion of 2p25.2. The phenotypic effects of this rearrangement and the role of SOX11 gene, removed in our case, are herein discussed.


Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 2 , Transtorno Autístico/genética , Criança , Hibridização Genômica Comparativa , Humanos , Deficiência Intelectual/genética
13.
Nat Genet ; 40(3): 322-8, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18278044

RESUMO

We report a recurrent microdeletion syndrome causing mental retardation, epilepsy and variable facial and digital dysmorphisms. We describe nine affected individuals, including six probands: two with de novo deletions, two who inherited the deletion from an affected parent and two with unknown inheritance. The proximal breakpoint of the largest deletion is contiguous with breakpoint 3 (BP3) of the Prader-Willi and Angelman syndrome region, extending 3.95 Mb distally to BP5. A smaller 1.5-Mb deletion has a proximal breakpoint within the larger deletion (BP4) and shares the same distal BP5. This recurrent 1.5-Mb deletion contains six genes, including a candidate gene for epilepsy (CHRNA7) that is probably responsible for the observed seizure phenotype. The BP4-BP5 region undergoes frequent inversion, suggesting a possible link between this inversion polymorphism and recurrent deletion. The frequency of these microdeletions in mental retardation cases is approximately 0.3% (6/2,082 tested), a prevalence comparable to that of Williams, Angelman and Prader-Willi syndromes.


Assuntos
Cromossomos Humanos Par 15 , Deleção de Genes , Deficiência Intelectual/genética , Convulsões/genética , Adolescente , Criança , Pré-Escolar , Quebra Cromossômica , Feminino , Frequência do Gene , Humanos , Padrões de Herança , Masculino , Linhagem , Receptores Nicotínicos/genética , Síndrome , Receptor Nicotínico de Acetilcolina alfa7
14.
Brain Dev ; 30(6): 425-9, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18166284

RESUMO

Studies of epilepsy associated with chromosomal abnormalities may provide information about clinical and EEG phenotypes and possibly to identify new epilepsy genes. We describe a female patient with intractable focal epilepsy, borderline intellectual functioning, and facial dysmorphisms, in whom genetic study (i.e., karyotype and array-CGH analysis) revealed a distal trisomy 4p and distal monosomy Xq. Although any genetic hypothesis remains speculative, several genes are located in the 4p chromosome segment involved in the rearrangement, some of which may be related to epilepsy.


Assuntos
Cromossomos Humanos Par 4 , Cromossomos Humanos X , Epilepsias Parciais/genética , Monossomia , Trissomia/genética , Adulto , Aberrações Cromossômicas , Eletroencefalografia , Epilepsias Parciais/fisiopatologia , Humanos , Cariotipagem , Masculino
15.
Epilepsia ; 47(5): 830-8, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16686647

RESUMO

PURPOSE: Mental retardation, facial dysmorphisms, and neurologic and brain abnormalities are features of 6q terminal deletions. Epilepsy is frequently associated with this chromosome abnormality, but electroclinical findings are not well delineated. We report five unrelated patients with 6q terminal deletions and a peculiar clinical, EEG, and neuroradiologic picture of epilepsy, mental retardation, and colpocephaly. METHODS: These three male and two female patients underwent general and neurologic examinations, repeated awake and sleep EEGs, and brain magnetic resonance imaging (MRI). A cytogenetic study and fluorescent in situ hybridization (FISH) with chromosome-specific subtelomeric probes were carried out in all cases. RESULTS: All subjects had seizures characterized by vomiting, cyanosis, and head and eye version, with and without loss of consciousness. In four cases, EEGs showed posterior spike-and-wave complexes, which were activated by sleep. No patient had status epilepticus or prolonged seizures. Brain MRI revealed colpocephaly and dysgenesis of the corpus callosum and brainstem in four patients; three of them also had hypertrophic massa intermedia. FISH analysis revealed a 6q terminal deletion in all patients, which ranged between 9 Mb (cases 2 and 3) and 16 Mb (case 4). CONCLUSIONS: We suggest that epilepsy associated with 6q terminal deletions is a new entity. Patients with dysmorphic features associated with focal occipital epilepsy, colpocephaly, and dysgenesis of the corpus callosum, thalami, and brainstem should be considered candidates for testing for 6q subtelomere deletions.


Assuntos
Anormalidades Múltiplas/genética , Deleção Cromossômica , Cromossomos Humanos Par 6/genética , Eletroencefalografia/estatística & dados numéricos , Epilepsia/diagnóstico , Epilepsia/genética , Deficiência Intelectual/genética , Ventrículos Laterais/anormalidades , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Adulto , Agenesia do Corpo Caloso , Encéfalo/patologia , Tronco Encefálico/anormalidades , Criança , Pré-Escolar , Epilepsia/patologia , Feminino , Humanos , Hibridização in Situ Fluorescente , Imagem por Ressonância Magnética , Masculino , Exame Neurológico , Convulsões/diagnóstico , Convulsões/genética , Convulsões/patologia , Sono/fisiologia , Síndrome
17.
Haematologica ; 88(10): 1099-105, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14555304

RESUMO

BACKGROUND AND OBJECTIVES: We report on two families in which the beta(0)-thalassemia mutation IVS2+1G-->A occurs either in the homozygous or compound heterozygous condition with other beta-thalassemia determinants. In the first family the proband, homozygous for the IVS2+1 determinant, is asymptomatic and was detected by chance during a screening program for beta-thalassemia. In the second family, the proband is a 43-year old female with a very mild thalassemia intermedia due to compound heterozygosity for the IVS2+1G>A and IVS1+110G>A mutations. Her father was diagnosed as having a thalassemic disorder only during the family studies carried out because of the proband's condition. He is a compound heterozygote for the Sicilian type deltabeta(0)-thalassemia and the IVS2+1 mutation and has a normal level of hemoglobin. DESIGN AND METHODS: In both families, the heterozygous carriers of the IVS2+1G>A have unusually elevated levels of fetal hemoglobin (HbF), and the homozygotes showed 98% HbF, reflecting an increased production of well hemoglobinized F-cells not associated with a significant erythroid expansion. RESULTS: The high HbF levels co-segregate with the beta-thalassemia mutation; the size and structure of both pedigrees do not allow the contribution of unlinked genes to the elevated production of HbF to be assessed. INTERPRETATION AND CONCLUSIONS: We propose that the unusual phenotypes resulting from homozygosity and compound heterozygosity for IVS2+1 are, against the background of a polygenic quantitative control of HbF expression, principally due to elements, such as repetitive sequences or single nucleotide polymorphisms, within or closely linked to the beta-gene cluster. These are potentially implicated in chromatin environment modifications, and could, therefore, be responsible for sustained HbF synthesis during development.


Assuntos
Globinas/genética , Haplótipos/fisiologia , Heterozigoto , Homozigoto , Mutação/genética , Talassemia beta/patologia , Adolescente , Adulto , Feminino , Hemoglobina Fetal/metabolismo , Humanos , Masculino , Linhagem , Talassemia beta/sangue
18.
Hum Mutat ; 21(5): 529-34, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12673795

RESUMO

Molecular defects affecting the ATRX gene lead to the ATRX syndrome (alpha thalassemia/mental retardation syndrome, X-linked), characterized by severe mental retardation, microcephaly, distinct facial dysmorphism, and genital abnormalities, as well as a wide spectrum of other pathological features. Alpha thalassemia is frequent but does not represent a constant characteristic of the syndrome. An expanding phenotype of the ATRX gene (a RAD54 homologue encoding a putative zinc-finger helicase) has been demonstrated as a result of the association of single mutations with specific X-linked mental retardation syndromes. To date, mutational analysis of the gene has been based on direct DNA sequencing or using methods with a lower detection rate. In this paper, we present a broad-range DGGE method for single-step mutation scanning of the entire open reading frame (ORF) and canonical splice sites of the gene. Using this method, we successfully identified five novel sequence changes in the ATRX gene, including four missense mutations (K1733E, R2085C, D2136N, T2169A) and one polymorphism (IVS5+35G>A).


Assuntos
DNA Helicases/genética , Análise Mutacional de DNA/métodos , Eletroforese em Gel de Poliacrilamida/métodos , Proteínas Nucleares/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Cromossomos Humanos X/genética , DNA/química , DNA/genética , Ligação Genética , Humanos , Deficiência Intelectual/complicações , Mutação , Sensibilidade e Especificidade , Síndrome , Proteína Nuclear Ligada ao X , Talassemia alfa/complicações
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