Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Ann Clin Transl Neurol ; 6(7): 1319-1326, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31353862

RESUMO

A recurrent de novo missense variant in KCNC1, encoding a voltage-gated potassium channel expressed in inhibitory neurons, causes progressive myoclonus epilepsy and ataxia, and a nonsense variant is associated with intellectual disability. We identified three new de novo missense variants in KCNC1 in five unrelated individuals causing different phenotypes featuring either isolated nonprogressive myoclonus (p.Cys208Tyr), intellectual disability (p.Thr399Met), or epilepsy with myoclonic, absence and generalized tonic-clonic seizures, ataxia, and developmental delay (p.Ala421Val, three patients). Functional analyses demonstrated no measurable currents for all identified variants and dominant-negative effects for p.Thr399Met and p.Ala421Val predicting neuronal disinhibition as the underlying disease mechanism.

2.
Genet Med ; 21(12): 2807-2814, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31164752

RESUMO

PURPOSE: Phenotype information is crucial for the interpretation of genomic variants. So far it has only been accessible for bioinformatics workflows after encoding into clinical terms by expert dysmorphologists. METHODS: Here, we introduce an approach driven by artificial intelligence that uses portrait photographs for the interpretation of clinical exome data. We measured the value added by computer-assisted image analysis to the diagnostic yield on a cohort consisting of 679 individuals with 105 different monogenic disorders. For each case in the cohort we compiled frontal photos, clinical features, and the disease-causing variants, and simulated multiple exomes of different ethnic backgrounds. RESULTS: The additional use of similarity scores from computer-assisted analysis of frontal photos improved the top 1 accuracy rate by more than 20-89% and the top 10 accuracy rate by more than 5-99% for the disease-causing gene. CONCLUSION: Image analysis by deep-learning algorithms can be used to quantify the phenotypic similarity (PP4 criterion of the American College of Medical Genetics and Genomics guidelines) and to advance the performance of bioinformatics pipelines for exome analysis.

3.
Am J Hum Genet ; 102(6): 1195-1203, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861108

RESUMO

Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.

4.
Hum Genet ; 137(5): 401-411, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29796876

RESUMO

Intellectual disability (ID) has an estimated prevalence of 1.5-2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism. WES detected a heterozygous de novo 1 bp insertion in the splice donor site of exon 3. Individual 2, a 3-year-old boy, showed ID and pre- and postnatal growth retardation, postnatal mild microcephaly, hyperkinetic and restless behaviour, as well as mild dysmorphism. WES detected a heterozygous de novo frameshift mutation. While ten individuals with ID and de novo variants in FBXO11 have been reported as part of larger studies, only one of the reports has some additional clinical data. Interestingly, the latter individual carries the identical mutation as our individual 2 and also displays ID, intrauterine growth retardation, microcephaly, behavioural anomalies, and dysmorphisms. Thus, we confirm deleterious de novo mutations in FBXO11 as a cause of ID and start the delineation of the associated clinical picture which may also comprise postnatal microcephaly or borderline small head size and behavioural anomalies.

5.
Clin Neuroradiol ; 27(4): 481-483, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28643035

RESUMO

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of inherited neurologic disorders with iron accumulation in the basal ganglia, which share magnetic resonance (MR) imaging characteristics, histopathologic and clinical features. According to the affected basal nuclei, clinical features include extrapyramidal movement disorders and varying degrees of intellectual disability status. The most common NBIA subtype is caused by pathogenic variants in PANK2. The hallmark of MR imaging in patients with PANK2 mutations is an eye-of-the-tiger sign in the globus pallidus. We report a 33-year-old female with a rare subtype of NBIA, called beta-propeller protein-associated neurodegeneration (BPAN) with a hitherto unknown missense variant in WDR45. She presented with BPAN's particular biphasic course of neurological symptoms and with a dominant iron accumulation in the midbrain that enclosed a spotty T2-hyperintensity.


Assuntos
Distúrbios do Metabolismo do Ferro/diagnóstico por imagem , Distrofias Neuroaxonais/diagnóstico por imagem , Adulto , Encéfalo , Proteínas de Transporte/genética , Feminino , Humanos , Ferro , Distúrbios do Metabolismo do Ferro/complicações , Distúrbios do Metabolismo do Ferro/genética , Imagem por Ressonância Magnética , Mutação de Sentido Incorreto , Distrofias Neuroaxonais/complicações , Distrofias Neuroaxonais/genética , Neurodegeneração Associada a Pantotenato-Quinase
6.
Eur J Hum Genet ; 25(7): 889-893, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28422131

RESUMO

For a large number of individuals with intellectual disability (ID), the molecular basis of the disorder is still unknown. However, whole-exome sequencing (WES) is providing more and more insights into the genetic landscape of ID. In the present study, we performed trio-based WES in 311 patients with unsolved ID and additional clinical features, and identified homozygous CPLX1 variants in three patients with ID from two unrelated families. All displayed marked developmental delay and migrating myoclonic epilepsy, and one showed a cerebellar cleft in addition. The encoded protein, complexin 1, is crucially involved in neuronal synaptic regulation, and homozygous Cplx1 knockout mice have the earliest known onset of ataxia seen in a mouse model. Recently, a homozygous truncating variant in CPLX1 was suggested to be causative for migrating epilepsy and structural brain abnormalities. ID was not reported although it cannot be completely ruled out. However, the currently limited knowledge on CPLX1 suggests that loss of complexin 1 function may lead to a complex but variable clinical phenotype, and our findings encourage further investigations of CPLX1 in patients with ID, developmental delay and myoclonic epilepsy to unravel the phenotypic spectrum of carriers of CPLX1 variants.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Epilepsias Mioclônicas/genética , Deficiência Intelectual/genética , Mutação , Proteínas do Tecido Nervoso/genética , Criança , Pré-Escolar , Epilepsias Mioclônicas/diagnóstico , Feminino , Genes Recessivos , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Fenótipo , Síndrome
7.
Am J Hum Genet ; 100(2): 257-266, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28132689

RESUMO

Phenylketonuria (PKU, phenylalanine hydroxylase deficiency), an inborn error of metabolism, can be detected through newborn screening for hyperphenylalaninemia (HPA). Most individuals with HPA harbor mutations in the gene encoding phenylalanine hydroxylase (PAH), and a small proportion (2%) exhibit tetrahydrobiopterin (BH4) deficiency with additional neurotransmitter (dopamine and serotonin) deficiency. Here we report six individuals from four unrelated families with HPA who exhibited progressive neurodevelopmental delay, dystonia, and a unique profile of neurotransmitter deficiencies without mutations in PAH or BH4 metabolism disorder-related genes. In these six affected individuals, whole-exome sequencing (WES) identified biallelic mutations in DNAJC12, which encodes a heat shock co-chaperone family member that interacts with phenylalanine, tyrosine, and tryptophan hydroxylases catalyzing the BH4-activated conversion of phenylalanine into tyrosine, tyrosine into L-dopa (the precursor of dopamine), and tryptophan into 5-hydroxytryptophan (the precursor of serotonin), respectively. DNAJC12 was undetectable in fibroblasts from the individuals with null mutations. PAH enzyme activity was reduced in the presence of DNAJC12 mutations. Early treatment with BH4 and/or neurotransmitter precursors had dramatic beneficial effects and resulted in the prevention of neurodevelopmental delay in the one individual treated before symptom onset. Thus, DNAJC12 deficiency is a preventable and treatable cause of intellectual disability that should be considered in the early differential diagnosis when screening results are positive for HPA. Sequencing of DNAJC12 may resolve any uncertainty and should be considered in all children with unresolved HPA.


Assuntos
Distonia/genética , Deficiência Intelectual/genética , Fenilcetonúrias/genética , Proteínas Repressoras/genética , Alelos , Sequência de Aminoácidos , Biopterina/análogos & derivados , Biopterina/metabolismo , Estudos de Casos e Controles , Dopamina/deficiência , Dopamina/metabolismo , Éxons , Feminino , Fibroblastos/metabolismo , Deleção de Genes , Estudo de Associação Genômica Ampla , Proteínas de Choque Térmico HSP70/genética , Humanos , Masculino , Linhagem , Fenilalanina/metabolismo , Fenilalanina Hidroxilase/genética , Serotonina/deficiência , Serotonina/metabolismo , Triptofano/metabolismo , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo , Tirosina/metabolismo , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
8.
Am J Med Genet A ; 173(2): 435-443, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27862890

RESUMO

Loss-of-function mutations and deletions of the SOX2 gene are known to cause uni- and bilateral anophthalmia and microphthalmia as well as related disorders such as anophthalmia-esophageal-genital syndrome. Thus, anophthalmia/microphthalmia is the primary indication for targeted, "phenotype first" analyses of SOX2. However, SOX2 mutations are also associated with a wide range of non-ocular abnormalities, such as postnatal growth retardation, structural brain anomalies, hypogenitalism, and developmental delay. The present report describes three patients without anophthalmia/microphthalmia and loss-of-function mutations or microdeletions of SOX2 who had been investigated in a "genotype first" manner due to intellectual disability/developmental delay using whole exome sequencing or chromosomal microarray analyses. This result prompted us to perform SOX2 Sanger sequencing in 192 developmental delay/intellectual disability patients without anophthalmia or microphthalmia. No additional SOX2 loss-of-function mutations were detected in this cohort, showing that SOX2 is clearly not a major cause of intellectual disability without anophthalmia/microphthalmia. In our three patients and four further, reported "genotype first" SOX2 microdeletion patients, anophthalmia/microphthalmia was present in less than half of the patients. Thus, SOX2 is another example of a gene whose clinical spectrum is broadened by the generation of "genotype first" findings using hypothesis-free, genome-wide methods. © 2016 Wiley Periodicals, Inc.


Assuntos
Estudos de Associação Genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Fenótipo , Mutação Puntual , Fatores de Transcrição SOXB1/genética , Deleção de Sequência , Encéfalo/anormalidades , Pré-Escolar , Hibridização Genômica Comparativa , Exoma , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/genética , Facies , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Recém-Nascido , Imagem por Ressonância Magnética/métodos , Masculino , Polimorfismo de Nucleotídeo Único , Sistema de Registros
9.
Eur J Hum Genet ; 24(12): 1739-1745, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27436265

RESUMO

Recently, germline variants of the transcriptional co-regulator gene TCF20 have been implicated in the aetiology of autism spectrum disorders (ASD). However, the knowledge about the associated clinical picture remains fragmentary. In this study, two individuals with de novo TCF20 sequence variants were identified in a cohort of 313 individuals with intellectual disability of unknown aetiology, which was analysed by whole exome sequencing using a child-parent trio design. Both detected variants - one nonsense and one frameshift variant - were truncating. A comprehensive clinical characterisation of the patients yielded mild intellectual disability, postnatal tall stature and macrocephaly, obesity and muscular hypotonia as common clinical signs while ASD was only present in one proband. The present report begins to establish the clinical picture of individuals with de novo nonsense and frameshift variants of TCF20 which includes features such as proportionate overgrowth and muscular hypotonia. Furthermore, intellectual disability/developmental delay seems to be fully penetrant amongst known individuals with de novo nonsense and frameshift variants of TCF20, whereas ASD is shown to be incompletely penetrant. The transcriptional co-regulator gene TCF20 is hereby added to the growing number of genes implicated in the aetiology of both ASD and intellectual disability. Furthermore, such de novo variants of TCF20 may represent a novel differential diagnosis in the overgrowth syndrome spectrum.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Códon sem Sentido , Mutação da Fase de Leitura , Gigantismo/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Fatores de Transcrição/genética , Adolescente , Transtorno do Espectro Autista/genética , Diagnóstico Diferencial , Exoma , Gigantismo/diagnóstico , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Megalencefalia/diagnóstico , Penetrância , Síndrome
10.
Nat Genet ; 48(8): 877-87, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27399968

RESUMO

Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.


Assuntos
Córtex Cerebral/patologia , Haploinsuficiência/genética , Deficiência Intelectual/patologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Mutação/genética , Neurogênese/fisiologia , Proteínas Repressoras/genética , Anormalidades Múltiplas , Adolescente , Adulto , Agenesia do Corpo Caloso/genética , Agenesia do Corpo Caloso/patologia , Animais , Córtex Cerebral/metabolismo , Criança , Pré-Escolar , Deleção Cromossômica , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Fenótipo , Proteínas Repressoras/metabolismo , Síndrome , Adulto Jovem
11.
Eur J Hum Genet ; 24(4): 556-61, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26153216

RESUMO

Intellectual disability (ID) affects 2-3% of the population. In the past, many genetic causes of ID remained unidentified due to its vast heterogeneity. Recently, whole exome sequencing (WES) studies have shown that de novo variants underlie a significant portion of sporadic cases of ID. Applying WES to patients with ID or global developmental delay at different centers, we identified three individuals with distinct de novo variants in HIVEP2 (human immunodeficiency virus type I enhancer binding protein), which belongs to a family of zinc-finger-containing transcriptional proteins involved in growth and development. Two of the variants were nonsense changes, and one was a 1 bp deletion resulting in a premature stop codon that was reported previously without clinical detail. In silico prediction programs suggest loss-of-function in the mutated allele leading to haploinsufficiency as a putative mechanism in all three individuals. All three patients presented with moderate-to-severe ID, minimal structural brain anomalies, hypotonia, and mild dysmorphic features. Growth parameters were in the normal range except for borderline microcephaly at birth in one patient. Two of the patients exhibited behavioral anomalies including hyperactivity and aggression. Published functional data suggest a neurodevelopmental role for HIVEP2, and several of the genes regulated by HIVEP2 are implicated in brain development, for example, SSTR-2, c-Myc, and genes of the NF-κB pathway. In addition, HIVEP2-knockout mice exhibit several working memory deficits, increased anxiety, and hyperactivity. On the basis of the genotype-phenotype correlation and existing functional data, we propose HIVEP2 as a causative ID gene.


Assuntos
Códon sem Sentido , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Fatores de Transcrição/genética , Pré-Escolar , Exoma , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Masculino , Adulto Jovem
12.
Birth Defects Res A Clin Mol Teratol ; 106(1): 16-26, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26680650

RESUMO

BACKGROUND: For the majority of congenital brain malformations, the underlying cause remains unknown. Recent studies have implicated rare copy number variations (CNVs) in their etiology. METHODS: Here, we used array-based molecular karyotyping to search for causative CNVs in 33 fetuses of terminated pregnancies with prenatally detected brain malformations and additional extracerebral anomalies. RESULTS: In 11 fetuses, we identified 15 CNVs (0.08 Mb to 29.59 Mb), comprising four duplications and eleven deletions. All larger CNVs (> 5 Mb) had also been detected by prenatal conventional karyotyping. None of these CNVs was present in our 1307 healthy in-house controls (frequency < 0.0008). Among these CNVs, we prioritized six chromosomal regions (1q25.1, 5q35.1, 6q25.3-qter, 11p14.3, 15q11.2-q13.1, 18q21.1) due to their previous association with human brain malformations or owing to the presence of a single gene expressed in human brain. Prioritized genes within these regions were UBTD2, SKA1, SVIP, and, most convincingly, GPR52. However, re-sequencing of GPR52 in 100 samples from fetuses with brain malformations or patients with intellectual disability and brain malformations revealed no disease-causing mutation. CONCLUSION: Our study suggests chromosomal regions 1q25.1, 5q35.1, 6q25.3-qter, 11p14.3, 15q11.2-q13.1, and 18q21.1 to be involved in human brain development. Within three of these regions, we suggest UBTD2, GPR52, and SKA1 as possible candidate genes. Because the overall detection rate of array-based molecular karyotyping was slightly higher (23%) than that of conventional prenatal karyotyping (20%), we suggest it's use for prenatal diagnostic testing in fetuses with nonisolated brain malformations.


Assuntos
Encéfalo/metabolismo , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Deficiência Intelectual/genética , Malformações do Sistema Nervoso/genética , Adulto , Encéfalo/anormalidades , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Feminino , Feto , Dosagem de Genes , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Cariotipagem/instrumentação , Cariotipagem/métodos , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , Malformações do Sistema Nervoso/diagnóstico , Malformações do Sistema Nervoso/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Diagnóstico Pré-Natal , Ubiquitinas/genética , Ubiquitinas/metabolismo
13.
Mol Cytogenet ; 8: 72, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26421060

RESUMO

BACKGROUND: Most microdeletions involving chromosome sub-bands 9q33.3-9q34.11 to this point have been detected by analyses focused on STXBP1, a gene known to cause early infantile epileptic encephalopathy 4 and other seizure phenotypes. Loss-of-function mutations of STXBP1 have also been identified in some patients with intellectual disability without epilepsy. Consequently, STXBP1 is widely assumed to be the gene causing both seizures and intellectual disability in patients with 9q33.3-q34.11 microdeletions. RESULTS: We report five patients with overlapping microdeletions of chromosome 9q33.3-q34.11, four of them previously unreported. Their common clinical features include intellectual disability, psychomotor developmental delay with delayed or absent speech, muscular hypotonia, and strabismus. Microcephaly and short stature are each present in four of the patients. Two of the patients had seizures. De novo deletions range from 1.23 to 4.13 Mb, whereas the smallest deletion of 432 kb in patient 3 was inherited from her mother who is reported to have mild intellectual disability. The smallest region of overlap (SRO) of these deletions in 9q33.3 does not encompass STXBP1, but includes two genes that have not been previously associated with disease, RALGPS1 and GARNL3. Sequencing of the two SRO genes RALGPS1 and GARNL3 in at least 156 unrelated patients with mild to severe idiopathic intellectual disability detected no causative mutations. Gene expression analyses in our patients demonstrated significantly reduced expression levels of GARNL3, RALGPS1 and STXBP1 only in patients with deletions of the corresponding genes. Thus, reduced expression of STXBP1 was ruled out as a cause for seizures in our patient whose deletion did not encompass STXBP1. CONCLUSIONS: We suggest that microdeletions of this region on chromosome 9q cause a clinical spectrum including intellectual disability, developmental delay especially concerning speech, microcephaly, short stature, mild dysmorphisms, strabismus, and seizures of incomplete penetrance, and may constitute a new contiguous gene deletion syndrome which cannot completely be explained by deletion of STXBP1.

14.
Am J Hum Genet ; 97(3): 493-500, 2015 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-26340335

RESUMO

CHAMP1 encodes a protein with a function in kinetochore-microtubule attachment and in the regulation of chromosome segregation, both of which are known to be important for neurodevelopment. By trio whole-exome sequencing, we have identified de novo deleterious mutations in CHAMP1 in five unrelated individuals affected by intellectual disability with severe speech impairment, motor developmental delay, muscular hypotonia, and similar dysmorphic features including short philtrum and a tented upper and everted lover lip. In addition to two frameshift and one nonsense mutations, we found an identical nonsense mutation, c.1192C>T (p.Arg398*), in two affected individuals. All mutations, if resulting in a stable protein, are predicted to lead to the loss of the functionally important zinc-finger domains in the C terminus of the protein, which regulate CHAMP1 localization to chromosomes and the mitotic spindle, thereby providing a mechanistic understanding for their pathogenicity. We thus establish deleterious de novo mutations in CHAMP1 as a cause of intellectual disability.


Assuntos
Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Proteínas Cromossômicas não Histona/genética , Códon sem Sentido/genética , Deficiência Intelectual/genética , Fosfoproteínas/genética , Distúrbios da Fala/genética , Sequência de Bases , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Análise de Sequência de DNA
15.
Ann Clin Transl Neurol ; 2(5): 492-509, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26000322

RESUMO

OBJECTIVE: Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency. METHODS: Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay. RESULTS: Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial ß-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation. INTERPRETATION: In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the ß-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.

16.
J Neurol Sci ; 349(1-2): 105-9, 2015 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-25592411

RESUMO

BACKGROUND: Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of diseases presenting with movement disorders and brain iron deposits. In addition to NBIA subtypes caused by mutations in PANK2 and PLA2G6, mutations in the C19orf12 gene were recently described as the third frequent cause of NBIA (called mitochondrial membrane protein-associated neurodegeneration, MPAN). Additionally, the X-linked gene WDR45 was found causative for a special subtype named static encephalopathy in childhood with neurodegeneration in adulthood (also called BPAN); however, analysis of this gene in a broader spectrum of NBIA has not been reported yet. METHODS: In a heterogeneous cohort of 69 patients with suspected NBIA that did not carry mutations in PANK2 and PLA2G6, the coding region of C19orf12 was evaluated by Sanger sequencing. The WDR45 gene was analyzed via high resolution melting and subsequent sequence analysis. RESULTS: Previously described homozygous C19orf12 mutations were found in 3/69 NBIA patients (4.3%). Analysis of the WDR45 gene revealed a novel heterozygous missense mutation in one female NBIA patient showing psychomotor retardation with secondary decline. CONCLUSIONS: C19orf12 mutations were confirmed in our heterogeneous NBIA cohort, while WDR45 mutations appear to be restricted to the subtype showing encephalopathy in childhood with neurodegeneration in adulthood.


Assuntos
Encéfalo/patologia , Proteínas de Transporte/genética , Ferro/metabolismo , Doenças Neurodegenerativas/genética , Adolescente , Adulto , Criança , Feminino , Fosfolipases A2 do Grupo VI/genética , Heterozigoto , Humanos , Masculino , Mutação de Sentido Incorreto , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fatores de Risco , Adulto Jovem
17.
Hum Genet ; 134(1): 97-109, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25326669

RESUMO

Recently, de novo heterozygous loss-of-function mutations in beta-catenin (CTNNB1) were described for the first time in four individuals with intellectual disability (ID), microcephaly, limited speech and (progressive) spasticity, and functional consequences of CTNNB1 deficiency were characterized in a mouse model. Beta-catenin is a key downstream component of the canonical Wnt signaling pathway. Somatic gain-of-function mutations have already been found in various tumor types, whereas germline loss-of-function mutations in animal models have been shown to influence neuronal development and maturation. We report on 16 additional individuals from 15 families in whom we newly identified de novo loss-of-function CTNNB1 mutations (six nonsense, five frameshift, one missense, two splice mutation, and one whole gene deletion). All patients have ID, motor delay and speech impairment (both mostly severe) and abnormal muscle tone (truncal hypotonia and distal hypertonia/spasticity). The craniofacial phenotype comprised microcephaly (typically -2 to -4 SD) in 12 of 16 and some overlapping facial features in all individuals (broad nasal tip, small alae nasi, long and/or flat philtrum, thin upper lip vermillion). With this detailed phenotypic characterization of 16 additional individuals, we expand and further establish the clinical and mutational spectrum of inactivating CTNNB1 mutations and thereby clinically delineate this new CTNNB1 haploinsufficiency syndrome.


Assuntos
Deficiência Intelectual/genética , Microcefalia/genética , Mutação/genética , beta Catenina/genética , Criança , Pré-Escolar , Feminino , Seguimentos , Haploinsuficiência , Humanos , Lactente , Deficiência Intelectual/patologia , Masculino , Microcefalia/patologia , Fenótipo , Síndrome
18.
Eur J Hum Genet ; 23(6): 753-60, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25138099

RESUMO

Intellectual disability (ID) has an estimated prevalence of 2-3%. Due to its extreme heterogeneity, the genetic basis of ID remains elusive in many cases. Recently, whole exome sequencing (WES) studies revealed that a large proportion of sporadic cases are caused by de novo gene variants. To identify further genes involved in ID, we performed WES in 250 patients with unexplained ID and their unaffected parents and included exomes of 51 previously sequenced child-parents trios in the analysis. Exome analysis revealed de novo intragenic variants in SET domain-containing 5 (SETD5) in two patients. One patient carried a nonsense variant, and the other an 81 bp deletion located across a splice-donor site. Chromosomal microarray diagnostics further identified four de novo non-recurrent microdeletions encompassing SETD5. CRISPR/Cas9 mutation modelling of the two intragenic variants demonstrated nonsense-mediated decay of the resulting transcripts, pointing to a loss-of-function (LoF) and haploinsufficiency as the common disease-causing mechanism of intragenic SETD5 sequence variants and SETD5-containing microdeletions. In silico domain prediction of SETD5, a predicted SET domain-containing histone methyltransferase (HMT), substantiated the presence of a SET domain and identified a novel putative PHD domain, strengthening a functional link to well-known histone-modifying ID genes. All six patients presented with ID and certain facial dysmorphisms, suggesting that SETD5 sequence variants contribute substantially to the microdeletion 3p25.3 phenotype. The present report of two SETD5 LoF variants in 301 patients demonstrates a prevalence of 0.7% and thus SETD5 variants as a relatively frequent cause of ID.


Assuntos
Códon sem Sentido , Deficiência Intelectual/genética , Metiltransferases/genética , Fenótipo , Adolescente , Sequência de Aminoácidos , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Exoma , Feminino , Humanos , Masculino , Metiltransferases/química , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Estrutura Terciária de Proteína , Síndrome , Adulto Jovem
19.
Lancet ; 380(9854): 1674-82, 2012 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-23020937

RESUMO

BACKGROUND: The genetic cause of intellectual disability in most patients is unclear because of the absence of morphological clues, information about the position of such genes, and suitable screening methods. Our aim was to identify de-novo variants in individuals with sporadic non-syndromic intellectual disability. METHODS: In this study, we enrolled children with intellectual disability and their parents from ten centres in Germany and Switzerland. We compared exome sequences between patients and their parents to identify de-novo variants. 20 children and their parents from the KORA Augsburg Diabetes Family Study were investigated as controls. FINDINGS: We enrolled 51 participants from the German Mental Retardation Network. 45 (88%) participants in the case group and 14 (70%) in the control group had de-novo variants. We identified 87 de-novo variants in the case group, with an exomic mutation rate of 1·71 per individual per generation. In the control group we identified 24 de-novo variants, which is 1·2 events per individual per generation. More participants in the case group had loss-of-function variants than in the control group (20/51 vs 2/20; p=0·022), suggesting their contribution to disease development. 16 patients carried de-novo variants in known intellectual disability genes with three recurrently mutated genes (STXBP1, SYNGAP1, and SCN2A). We deemed at least six loss-of-function mutations in six novel genes to be disease causing. We also identified several missense alterations with potential pathogenicity. INTERPRETATION: After exclusion of copy-number variants, de-novo point mutations and small indels are associated with severe, sporadic non-syndromic intellectual disability, accounting for 45-55% of patients with high locus heterogeneity. Autosomal recessive inheritance seems to contribute little in the outbred population investigated. The large number of de-novo variants in known intellectual disability genes is only partially attributable to known non-specific phenotypes. Several patients did not meet the expected syndromic manifestation, suggesting a strong bias in present clinical syndrome descriptions. FUNDING: German Ministry of Education and Research, European Commission 7th Framework Program, and Swiss National Science Foundation.


Assuntos
Exoma/genética , Deficiência Intelectual/genética , Mutação/genética , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino
20.
Am J Hum Genet ; 90(5): 847-55, 2012 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-22541559

RESUMO

With a prevalence between 1 and 3%, hereditary forms of intellectual disability (ID) are among the most important problems in health care. Particularly, autosomal-recessive forms of the disorder have a very heterogeneous molecular basis, and genes with an increased number of disease-causing mutations are not common. Here, we report on three different mutations (two nonsense mutations, c.679C>T [p.Gln227(∗)] and c.1114C>T [p.Gln372(∗)], as well as one splicing mutation, g.6622224A>C [p.Ile179Argfs(∗)192]) that cause a loss of the tRNA-methyltransferase-encoding NSUN2 main transcript in homozygotes. We identified the mutations by sequencing exons and exon-intron boundaries within the genomic region where the linkage intervals of three independent consanguineous families of Iranian and Kurdish origin overlapped with the previously described MRT5 locus. In order to gain further evidence concerning the effect of a loss of NSUN2 on memory and learning, we constructed a Drosophila model by deleting the NSUN2 ortholog, CG6133, and investigated the mutants by using molecular and behavioral approaches. When the Drosophila melanogaster NSUN2 ortholog was deleted, severe short-term-memory (STM) deficits were observed; STM could be rescued by re-expression of the wild-type protein in the nervous system. The humans homozygous for NSUN2 mutations showed an overlapping phenotype consisting of moderate to severe ID and facial dysmorphism (which includes a long face, characteristic eyebrows, a long nose, and a small chin), suggesting that mutations in this gene might even induce a syndromic form of ID. Moreover, our observations from the Drosophila model point toward an evolutionarily conserved role of RNA methylation in normal cognitive development.


Assuntos
Códon sem Sentido , Genes Recessivos , Deficiência Intelectual/genética , Metiltransferases/genética , Adolescente , Adulto , Animais , Criança , Clonagem Molecular , Consanguinidade , Drosophila/genética , Éxons , Feminino , Ligação Genética , Genótipo , Homozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Metiltransferases/metabolismo , Pessoa de Meia-Idade , Linhagem , Fenótipo , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA