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1.
J Med Genet ; 60(7): 644-654, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36446582

RESUMO

BACKGROUND: KBG syndrome is a highly variable neurodevelopmental disorder and clinical diagnostic criteria have changed as new patients have been reported. Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome, but no genotype-phenotype correlation has been reported. METHODS: 67 patients with KBG syndrome were assessed using a custom phenotypical questionnaire. Manifestations present in >50% of the patients and a 'phenotypical score' were used to perform a genotype-phenotype correlation in 340 patients from our cohort and the literature. RESULTS: Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures. 82.8% of the patients had at least one of seven main comorbidities: hearing loss and/or otitis media, visual problems, cryptorchidism, cardiopathy, feeding difficulties and/or seizures. Associations found included a higher phenotypical score in patients with sequence variants compared with CNVs and a higher frequency of triangular face (71.1% vs 42.5% in CNVs). Short stature was more frequent in patients with exon 9 variants (62.5% inside vs 27.8% outside exon 9), and the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants). Presence of macrodontia and comorbidities were associated with larger deletion sizes and hand anomalies with smaller deletions. CONCLUSION: We present a detailed phenotypical description of KBG syndrome in the largest series reported to date of 67 patients, provide evidence of a genotype-phenotype correlation between some KBG features and specific ANKRD11 variants in 340 patients, and propose updated clinical diagnostic criteria based on our findings.


Assuntos
Anormalidades Múltiplas , Transtorno do Espectro Autista , Doenças do Desenvolvimento Ósseo , Deficiência Intelectual , Anormalidades Dentárias , Masculino , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/genética , Anormalidades Múltiplas/diagnóstico , Doenças do Desenvolvimento Ósseo/genética , Anormalidades Dentárias/genética , Fácies , Transtorno do Espectro Autista/genética , Variações do Número de Cópias de DNA , Proteínas Repressoras/genética , Deleção Cromossômica , Fenótipo , Fatores de Transcrição/genética
2.
Cytogenet Genome Res ; 2023 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-38056433

RESUMO

Introduction The zinc finger BTB domain-containing protein ZBTB18 binds to FOXG1 to form a transcriptional repressive complex involved in neuronal differentiation. Disruption of the components of this complex results in chromosome 1q43-q44 deletion syndrome/intellectual developmental disorder 22 or in FOXG1 syndrome. Case presentation This study reports on five patients with cognitive and behavioral impairment, seizures, microcephaly, and/or congenital brain abnormalities. Whole exome sequencing identified deleterious ZBTB18 variants in three patients and deleterious FOXG1 variants in the remaining patients. We have detected a missense variant within the BTB domain of ZBTB18 in two affected monozygotic twins. In addition, we observed agenesis of the septum pellucidum in a missense FOXG1 carrier with a severe FOXG1 syndrome. Conclusion Although the ZBTB18 zinc finger domains harbor the majority of known deleterious variants, we report a novel de novo rare missense variant within the BTB domain. The agenesis of the septum pellucidum observed in a missense FOXG1 carrier could be considered as a novel clinical feature associated with FOXG1 syndrome. The severe FOXG1 syndrome in this patient contrasts with the milder phenotype expected for a missense. Genetic or environmental factors may explain this phenotypic variability in FOXG1 syndrome.

3.
Am J Med Genet A ; 179(2): 290-294, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30569622

RESUMO

Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) and Genitopatellar syndrome (GTPTS) are very rare conditions caused by KAT6B truncating variants. Because of both syndromes often share common features the associated phenotypes are usually grouped under the term "KAT6B-related disorders." However, particular signs of each syndrome have been reported and their appearance seems to be dependent on where the KAT6B variant is located. Thus, whereas truncating variants associated with SBBYSS have their highest density in the distal part of exon 18, those resulting in GTPTS are distributed between the end of exon 17 and beginning of exon 18. Here, we reported two de novo heterozygous KAT6B truncating variants. The first variant (c.5802delA; p.A1935Pfs*16), identified in a boy with SSBYSS phenotype, resulting in the most distal KAT6B truncating variant reported up-to-date in the scientific literature. The second variant (c.3152delG; p.S1051Tfs*63), located in a region hitherto defined as specific of SBBYSS, seems to cause an overlapping SBBYSS/GTPTS phenotype. The clinical and genetic characterization of these patients could contribute to the understanding of the KAT6B-related disorders.


Assuntos
Anormalidades Múltiplas/genética , Blefarofimose/genética , Hipotireoidismo Congênito/genética , Anormalidades Craniofaciais/genética , Cardiopatias Congênitas/genética , Histona Acetiltransferases/genética , Deficiência Intelectual/genética , Instabilidade Articular/genética , Rim/anormalidades , Patela/anormalidades , Transtornos Psicomotores/genética , Escroto/anormalidades , Anormalidades Urogenitais/genética , Anormalidades Múltiplas/fisiopatologia , Blefarofimose/fisiopatologia , Criança , Hipotireoidismo Congênito/fisiopatologia , Anormalidades Craniofaciais/fisiopatologia , Éxons/genética , Fácies , Cardiopatias Congênitas/fisiopatologia , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Instabilidade Articular/fisiopatologia , Rim/fisiopatologia , Masculino , Mutação , Patela/fisiopatologia , Fenótipo , Transtornos Psicomotores/fisiopatologia , Escroto/fisiopatologia , Anormalidades Urogenitais/fisiopatologia
4.
Hum Mutat ; 39(8): 1126-1138, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29851191

RESUMO

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.


Assuntos
Epilepsia/metabolismo , Éxons/genética , Transtornos do Crescimento/metabolismo , Deficiência Intelectual/metabolismo , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Criança , Pré-Escolar , Epilepsia/genética , Feminino , Transtornos do Crescimento/genética , Células HEK293 , Células HeLa , Humanos , Deficiência Intelectual/genética , Masculino , Mutação de Sentido Incorreto/genética , Isoformas de Proteínas/genética , Transporte de RNA/genética , Transporte de RNA/fisiologia , Proteínas de Ligação a RNA/genética
5.
BMC Psychiatry ; 18(1): 40, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29422022

RESUMO

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition in childhood (5.3% to 7.1% worldwide prevalence), with substantial overall financial burden to children/adolescents, their families, and society. The aims of this study were to describe the clinical characteristics of children and adolescents with ADHD in Spain, estimate the associated direct/indirect costs of the disorder, and assess whether the characteristics and financial costs differed between children/adolescents adequately responding to currently available pharmacotherapies compared with children/adolescents for whom pharmacotherapies failed. METHODS: This was a multicenter, cross-sectional, descriptive analysis conducted in 15 health units representative of the overall Spanish population. Data on demographic characteristics, socio-occupational status, social relationships, clinical variables of the disease, and pharmacological and non-pharmacological treatments received were collected in 321 children and adolescents with ADHD. Direct and indirect costs were estimated over one year from both a health care system and a societal perspective. RESULTS: The estimated average cost of ADHD per year per child/adolescent was €5733 in 2012 prices; direct costs accounted for 60.2% of the total costs (€3450). Support from a psychologist/educational psychologist represented 45.2% of direct costs and 27.2% of total costs. Pharmacotherapy accounted for 25.8% of direct costs and 15.5% of total costs. Among indirect costs (€2283), 65.2% was due to caregiver expenses. The total annual costs were significantly higher for children/adolescents who responded poorly to pharmacological treatment (€7654 versus €5517; P = 0.024), the difference being mainly due to significantly higher direct costs, particularly with larger expenses for non-pharmacological treatment (P = 0.012). CONCLUSIONS: ADHD has a significant personal, familial, and financial impact on the Spanish health system and society. Successful pharmacological intervention was associated with lower overall expenses in the management of the disorder.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/economia , Efeitos Psicossociais da Doença , Custos de Cuidados de Saúde/estatística & dados numéricos , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Cuidadores/economia , Criança , Estudos Transversais , Demografia , Emprego/economia , Feminino , Humanos , Masculino , Espanha/epidemiologia
6.
Am J Med Genet A ; 167(6): 1369-73, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25898976

RESUMO

The 8q21.11 microdeletion syndrome (OMIM # 614230) has been recently described and is primarily characterized by intellectual disability and facial dysmorphism. We describe here a male patient of 9 years 9 months of age with moderate intellectual disability and dysmorphic facial features. A high resolution copy number variation analysis, performed with the Affymetrix Cytogenetics Whole-Genome 2.7 M SNP array, allowed the identification of a heterozygous 7.069 Mb microdeletion at chromosome 8q21.11-q21.13. Clinical comparison of our patient with literature shows many similarities. However, the whole facial appearance of our patient, especially the elongated rather than rounded face and the absence of a wide nasal bridge and epicanthal folds, confers him a phenotype similar only to a subset, but not to the majority, of the hitherto described patients.


Assuntos
Anormalidades Múltiplas/genética , Deficiência Intelectual/genética , Monossomia , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Criança , Cromossomos Humanos Par 8 , Variações do Número de Cópias de DNA , Fácies , Heterozigoto , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Síndrome
7.
Am J Med Genet A ; 167(6): 1315-22, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25847113

RESUMO

We detail here the clinical description and the family genetic study of a male patient with global developmental delay, disruptive and obsessive behaviors and minor dysmorphic features and a combination of two rare genetic variants: a maternally inherited 16p13.11-p12.3 duplication and a de novo 12p12.1 deletion affecting SOX5. The 16p13.11 microduplication has been implicated in several neurodevelopmental and behavioral disorders and is characterized by variable expressivity and incomplete penetrance. The causes of this variation in phenotypic expression are not fully clear, representing a challenge in genetic diagnosis and counseling. However, several authors have proposed the two-hit model as one of the underlying mechanisms for this phenotypic heterogeneity. Our data could also support this two-hit model in which the 16p13.11-p12.3 duplication might contribute to the phenotype, not only as a single event but also in association with the SOX5 deletion. The SOX5 gene plays important roles in various developmental processes and has been associated with several neurodevelopmental disorders, mainly intellectual disability, developmental delay and language and/or speech delay as well as with behavior problems and dysmorphic features. However, many of the physical features and behavioral manifestations as well as language deficiencies present in our patient are consistent with those previously reported for SOX5 deletions. Patients carrying multiple genomic variants, as the one presented here, illustrate the difficulty in analyzing genotypes when the contribution of each variant results in overlapping phenotypes and/or, alternatively, in the modification of the clinical manifestations defined by the coexisting variant.


Assuntos
Duplicação Cromossômica , Deficiências do Desenvolvimento/genética , Deleção de Genes , Transtornos do Desenvolvimento da Linguagem/genética , Comportamento Obsessivo/genética , Fatores de Transcrição SOXD/genética , Criança , Cromossomos Humanos Par 16 , Deficiências do Desenvolvimento/patologia , Deficiências do Desenvolvimento/fisiopatologia , Fácies , Genótipo , Humanos , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos do Desenvolvimento da Linguagem/fisiopatologia , Masculino , Modelos Genéticos , Comportamento Obsessivo/patologia , Comportamento Obsessivo/fisiopatologia , Linhagem , Fenótipo
8.
Am J Med Genet A ; 167A(12): 3113-20, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26284580

RESUMO

The few proximal 4q chromosomal aberrations identified in patients with neurodevelopmental phenotypes that have been published to date are variable in type, size and breakpoints and, therefore, encompass different chromosome bands and genes, making the establishment of genotype-phenotype correlations a challenging task. Here, microarray-based copy number analysis allowed us the detection of two novel and partially overlapping deletions in two unrelated families. In Family 1, a 4q13.1-q13.2 deletion of 3.84 Mb was identified in a mother with mild intellectual disability and in her two children, both with mild intellectual disability and attention deficit hyperactivity disorder. In Family 2, a de novo 4q13.2-q13.3 deletion of 6.81 Mb was detected in a female patient, born to unaffected parents, with a diagnosis of mild intellectual disability, behavioral disorder and facial dysmorphism. The shortest region of overlap between these two aberrations is located at chromosome 4q13.2 and includes 17 genes amongst of which we suggest UBA6 (ubiquitin-like modifier-activating enzyme 6) as a strong candidate gene for these phenotypes.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 4/genética , Deficiência Intelectual/genética , Transtornos Mentais/genética , Enzimas Ativadoras de Ubiquitina/genética , Adulto , Criança , Hibridização Genômica Comparativa , Família , Feminino , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/patologia , Masculino , Transtornos Mentais/patologia , Fenótipo , Prognóstico
9.
Parkinsonism Relat Disord ; 80: 165-174, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33022436

RESUMO

OBJECTIVE: To perform phenotype and genotype characterization in myoclonus-dystonia patients and to validate clinical rating tools. METHOD: Two movement disorders experts rated patients with the Burke-Fahn-Marsden and Unified-Myoclonus rating scales using a video-recording protocol. Clinimetric analysis was performed. SGCE mutations were screened by Sanger sequencing and multiplex ligation-dependent probe amplification. RESULTS: 48 patients were included and 43/48 rated. Mean age at assessment was 12.9±10.5 years (range 3-51) and 88% were ≤18 years of age. Myoclonus was a universal sign with a rostro-caudal severity-gradient. Myoclonus increased in severity and spread to lower limbs during action tests. Stimulus-evoked myoclonus was observed in 86.8% cases. Dystonia was common but mild. It had a focal distribution and was action-induced, causing writer's cramp (69%) and gait dystonia (34%). The severity of both myoclonus and dystonia had a strong impact on hand writing and walking difficulties. The Unified Myoclonus Rating scale showed the best clinimetric properties for the questionnaire, action myoclonus and functional subscales, and exceeded the Burke-Fahn-Marsden scale in its utility in assessing functional impairment in MDS patients. Twenty-one different SGCE mutations were identified in 45/48 patients, eleven being novel (most prevalent p. Val187*, founder mutation in Canary Islands). CONCLUSION: This study quantifies the severity of the motor phenotype in SGCE-myoclonus dystonia syndrome, with a special focus on children, and identifies disabilities in gross and fine motor tasks that are essential for childhood development. Our results contribute to the knowledge of SGCE-related MDS in the early stage of evolution, where disease-modifying therapies could be initiated in order to prevent long-term social and physical burdens.


Assuntos
Distúrbios Distônicos/genética , Distúrbios Distônicos/fisiopatologia , Destreza Motora/fisiologia , Sarcoglicanas/genética , Adolescente , Adulto , Criança , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Distúrbios Distônicos/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Índice de Gravidade de Doença , Adulto Jovem
10.
Med Clin (Barc) ; 133(19): 745-9, 2009 Nov 21.
Artigo em Espanhol | MEDLINE | ID: mdl-19892372

RESUMO

BACKGROUND AND OBJECTIVE: Brain creatine (Cr) deficiencies are a group of inborn errors of metabolism that are characterized by an absence or severe reduction of brain Cr. Clinically, these patients can display psychomotor/mental retardation and language disorders, commonly associated with epilepsy or movement disorders. Three metabolic defects are known: two affect synthesis - guanidinoacetate metiltransferase (GAMT) and glycine amidinotransferase (AGAT) deficiencies- and one affect the Cr transporter (CRTR). We present the first three Spanish patients with GAMT deficiency, and we compare their clinical phenotype and treatment response with other published cases. PATIENTS AND METHOD: The three patients presented mental retardation, epilepsy and autistic behaviour. Patient 1 also had severe chorea. Diagnosis was done by biochemical and genetic procedures (guanidinoacetate quantification, determination of GAMT activity and mutation analysis in the GAMT gene). RESULTS: An increase of guanidinoacetate was detected in urine and plasma. Brain magnetic resonance spectroscopy revealed low Cr levels. Enzymatic studies revealed a decreased GAMT activity in fibroblasts. Molecular analysis detected pathogenic mutations in the GAMT gene. After the deficiency was confirmed, the patients started treatment with Cr. In addition, patient 2 and 3 received an arginine-restricted diet and ornithine supplements. All them showed a partial improvement. CONCLUSIONS: Patients with GAMT deficiency have an unspecific but relatively constant clinical presentation. Brain Cr deficiency should be considered in patients with mental retardation of unknown aetiology, specially in those with movement disorders or epilepsy. Early diagnosis is important in cases with known treatment such as GAMT deficiency.


Assuntos
Encefalopatias Metabólicas/genética , Creatina/deficiência , Guanidinoacetato N-Metiltransferase/genética , Mutação , Adolescente , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/tratamento farmacológico , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espanha
11.
Med Clin (Barc) ; 130(15): 577-9, 2008 Apr 26.
Artigo em Espanhol | MEDLINE | ID: mdl-18462636

RESUMO

BACKGROUND AND OBJECTIVE: Alternating hemiplegia of childhood (AHC) is a rare disease of unknown etiology characterized by early onset of recurrent episodes of hemiplegia, tonic or dystonic attacks and abnormal ocular movements with a fatal outcome to severe encephalopathy. Our aim was to describe the clinical manifestations, precipitating factors, complementary studies results, long-term outcome and response to treatment in a series of AHC patients. PATIENTS AND METHOD: Descriptive, retrospective and multicenter study in 17 Spanish patients aged between 1-24 years who fulfilled diagnostic criteria of AHC. RESULTS: Twelve cases fulfilled criteria of typical AHC and 5 were atypical. Mean age at diagnosis was 26 months and 47% cases had a family history of migraine. Mean age at onset of hemiplegic attacks was 9.3 months. Symptoms disappeared during sleep and precipitating factors were present in 94% cases. Most patients developed mental retardation with ataxia and dysarthria. Work-up tests (metabolic, neurophysiologic and radiologic) were normal or nonspecific. In 3 patients mutations in CACNA1A, ATP1A2 were ruled out. Positive responses to flunarizine was observed in 81%. CONCLUSIONS: The characteristic clinical symptoms are still the clue to make the diagnosis of this disease, with a lack of genetic, biochemical or radiological specific studies. Early diagnosis avoids invasive tests, repeating procedures, using ineffective and potentially toxic treatments, and allows to start treatment with flunarizine without delay. More genetic studies are needed in broader series of patients.


Assuntos
Hemiplegia/diagnóstico , Hemiplegia/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Espanha
12.
Gene ; 626: 189-199, 2017 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-28506748

RESUMO

Intellectual disability (ID) is a complex and phenotypically heterogeneous neurodevelopmental disorder characterized by significant deficits in cognitive and adaptive skills, debuting during the developmental period. In the last decade, microarray-based copy number variation (CNV) analysis has been proved as a strategy particularly useful in the discovery of loci and candidate genes associated with these phenotypes and is widely used in the clinics with a diagnostic purpose. In this study, we evaluated the usefulness of two genome-wide high density SNP microarrays -Cytogenetics Whole-Genome 2.7M SNP array (n=126 patients; Group 1) and CytoScan High-Density SNP array (n=447 patients; Group 2)- in the detection of clinically relevant CNVs in a cohort of ID patients from Galicia (NW Spain). In 159 (27.7%) patients, we detected 186 rare exonic chromosomal imbalances, that were grouped into the following classes: Clinically relevant (67/186; 36.0%), of unknown clinical significance (93/186; 50.0%) and benign (26/186; 14.0%). The 67 pathogenic CNVs were identified in 64 patients, which means an overall diagnostic yield of 11.2%. Overall, we confirmed that ID is a genetically heterogeneous condition and emphasized the importance of using genome-wide high density SNP microarrays in the detection of its genetic causes. Additionally, we provided clinical and molecular data of patients with pathogenic or likely pathogenic CNVs and discussed the potential implication in neurodevelopmental disorders of genes located within these variants.


Assuntos
Variações do Número de Cópias de DNA , Deficiência Intelectual/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Polimorfismo de Nucleotídeo Único , Espanha
13.
Clin Case Rep ; 3(6): 415-23, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26185640

RESUMO

We report on a male patient with severe autistic disorder, lack of oral language, and dysmorphic features who carries a rare interstitial microdeletion of 4.96 Mb at chromosome 6q14.1-q15. The patient also harbors a maternally inherited copy number gain of 1.69 Mb at chromosome Xp22.31, whose pathogenicity is under debate.

14.
Med Clin (Barc) ; 143(1): 25-8, 2014 Jul 07.
Artigo em Espanhol | MEDLINE | ID: mdl-24768197

RESUMO

BACKGROUND AND OBJECTIVE: Alternating hemiplegia in childhood (AHC) is a disease characterized by recurrent episodes of hemiplegia, tonic or dystonic crisis and abnormal ocular movements. Recently, mutations in the ATP1A3 gene have been identified as the causal mechanism of AHC. The objective is to describe a series of 16 patients with clinical and genetic diagnosis of AHC. PATIENTS AND METHOD: It is a descriptive, retrospective, multicenter study of 16 patients with clinical diagnosis of AHC in whom mutations in ATP1A3 were identified. RESULTS: Six heterozygous, de novo mutations were found in the ATP1A3 gene. The most frequent mutation was G2401A in 8 patients (50%) followed by G2443A in 3 patients (18.75%), G2893A in 2 patients (12.50%) and C2781G, G2893C and C2411T in one patient, respectively (6.25% each). CONCLUSIONS: In the studied population with AHC, de novo mutations were detected in 100% of patients. The most frequent mutations were D801N y la E815K, as reported in other series.


Assuntos
Distúrbios Distônicos/genética , Hemiplegia/genética , Mutação de Sentido Incorreto , Transtornos da Motilidade Ocular/genética , Mutação Puntual , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Análise Mutacional de DNA , Dieta Cetogênica , Distúrbios Distônicos/dietoterapia , Transportador 2 de Aminoácido Excitatório , Feminino , Proteínas de Transporte de Glutamato da Membrana Plasmática/genética , Hemiplegia/dietoterapia , Heterozigoto , Humanos , Masculino , Transtornos da Motilidade Ocular/dietoterapia , Estudos Retrospectivos , ATPase Trocadora de Sódio-Potássio/fisiologia , Espanha , Adulto Jovem
15.
Orphanet J Rare Dis ; 9: 59, 2014 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-24767253

RESUMO

BACKGROUND: With over 50 different disorders and a combined incidence of up to 1/3000 births, lysosomal storage diseases (LSDs) constitute a major public health problem and place an enormous burden on affected individuals and their families. Many factors make LSD diagnosis difficult, including phenotype and penetrance variability, shared signs and symptoms, and problems inherent to biochemical diagnosis. Developing a powerful diagnostic tool could mitigate the protracted diagnostic process for these families, lead to better outcomes for current and proposed therapies, and provide the basis for more appropriate genetic counseling. METHODS: We have designed a targeted resequencing assay for the simultaneous testing of 57 lysosomal genes, using in-solution capture as the enrichment method and two different sequencing platforms. A total of 84 patients with high to moderate-or low suspicion index for LSD were enrolled in different centers in Spain and Portugal, including 18 positive controls. RESULTS: We correctly diagnosed 18 positive blinded controls, provided genetic diagnosis to 25 potential LSD patients, and ended with 18 diagnostic odysseys. CONCLUSION: We report the assessment of a next-generation-sequencing-based approach as an accessory tool in the diagnosis of LSDs, a group of disorders which have overlapping clinical profiles and genetic heterogeneity. We have also identified and quantified the strengths and limitations of next generation sequencing (NGS) technology applied to diagnosis.


Assuntos
Doenças por Armazenamento dos Lisossomos/diagnóstico , Análise de Sequência de DNA , Humanos , Doenças por Armazenamento dos Lisossomos/genética
16.
PLoS One ; 6(4): e18348, 2011 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-21526175

RESUMO

BACKGROUND: There are several known autosomal genes responsible for Ras/MAPK pathway syndromes, including Noonan syndrome (NS) and related disorders (such as LEOPARD, neurofibromatosis type 1), although mutations of these genes do not explain all cases. Due to the important role played by the mitochondrion in the energetic metabolism of cardiac muscle, it was recently proposed that variation in the mitochondrial DNA (mtDNA) genome could be a risk factor in the Noonan phenotype and in hypertrophic cardiomyopathy (HCM), which is a common clinical feature in Ras/MAPK pathway syndromes. In order to test these hypotheses, we sequenced entire mtDNA genomes in the largest series of patients suffering from Ras/MAPK pathway syndromes analyzed to date (n = 45), most of them classified as NS patients (n = 42). METHODS/PRINCIPAL FINDINGS: The results indicate that the observed mtDNA lineages were mostly of European ancestry, reproducing in a nutshell the expected haplogroup (hg) patterns of a typical Iberian dataset (including hgs H, T, J, and U). Three new branches of the mtDNA phylogeny (H1j1, U5b1e, and L2a5) are described for the first time, but none of these are likely to be related to NS or Ras/MAPK pathway syndromes when observed under an evolutionary perspective. Patterns of variation in tRNA and protein genes, as well as redundant, private and heteroplasmic variants, in the mtDNA genomes of patients were as expected when compared with the patterns inferred from a worldwide mtDNA phylogeny based on more than 8700 entire genomes. Moreover, most of the mtDNA variants found in patients had already been reported in healthy individuals and constitute common polymorphisms in human population groups. CONCLUSIONS/SIGNIFICANCE: As a whole, the observed mtDNA genome variation in the NS patients was difficult to reconcile with previous findings that indicated a pathogenic role of mtDNA variants in NS.


Assuntos
DNA Mitocondrial/genética , Evolução Molecular , Genoma Humano/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Mutação/genética , Proteínas ras/genética , Núcleo Celular/genética , Análise Mutacional de DNA , Humanos , Fases de Leitura Aberta/genética , Filogenia , Filogeografia , RNA de Transferência/genética , Síndrome
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