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1.
Ann Neurol ; 2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32337771

RESUMO

OBJECTIVE: To foster trial-readiness of COQ8A-ataxia, we map the clinico-genetic, molecular and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modelling, in vitro mutation analyses, MRI markers, disease progression and CoQ10 response data. RESULTS: 59 patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modelling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs. 53%, p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14/30 patients, and by quantitative longitudinal assessments in 8/11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way towards large-scale natural history studies and treatment trials in COQ8A-ataxia. This article is protected by copyright. All rights reserved.

2.
Mol Syndromol ; 10(4): 195-201, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31602191

RESUMO

Intellectual disability (ID) occurs in approximately 1% of the population. Over the last years, broad sequencing approaches such as whole exome sequencing (WES) substantially contributed to the definition of the molecular defects underlying nonsyndromic ID. Pathogenic variants in HIVEP2, which encodes the human immunodeficiency virus type I enhancer binding protein 2, have recently been reported as a cause of ID, developmental delay, behavioral disorders, and dysmorphic features. HIVEP2 serves as a transcriptional factor regulating NF-ĸB and diverse genes that are essential in neural development. To date, only 8 patients with pathogenic de novo nonsense or frameshift variants and 1 patient with a pathogenic missense variant in HIVEP2 have been reported. By WES, we identified 2 novel truncating HIVEP2 variants, c.6609_6616delTGAGGGTC (p.Glu2204*) and c.6667C>T (p.Arg2223*), in 2 young adults presenting with developmental delay and mild ID without any dysmorphic features, systemic malformations, or behavioral issues.

3.
J Med Genet ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31439721

RESUMO

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT. METHODS: We evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes. RESULTS: We identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes. CONCLUSION: Our findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

5.
Genet Med ; 21(6): 1295-1307, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30349098

RESUMO

PURPOSE: Pathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin-Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting. METHODS: Clinicians entered clinical data in an extensive web-based survey. RESULTS: 79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified. CONCLUSION: There are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Proteínas Cromossômicas não Histona/genética , Exoma , Face/anormalidades , Feminino , Estudos de Associação Genética/métodos , Variação Genética/genética , Deformidades Congênitas da Mão/genética , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Micrognatismo/genética , Pessoa de Meia-Idade , Mutação , Pescoço/anormalidades , Penetrância
6.
Mol Psychiatry ; 24(11): 1748-1768, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-29728705

RESUMO

RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes co-segregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

7.
Am J Med Genet C Semin Med Genet ; 178(2): 198-205, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-30182445

RESUMO

Holoprosencephaly (HPE) has been defined as a distinct clinical entity with characteristic facial gestalt, which may-or may not-be associated with the true brain malformation observed postmortem in autopsy or in pre- or postnatal imaging. Affected families mainly show autosomal dominant inheritance with markedly reduced penetrance and extremely broad clinical variability even between mutation carriers within the same families. We here present advances in prenatal imaging over the last years, increasing the proportion of individuals with HPE identified prenatally including milder HPE forms and more frequently allowing to detect more severe forms already in early gestation. We report the results of diagnostic genetic testing of 344 unrelated patients for HPE at our lab in Germany since the year 2000, which currently with the application of next generation sequencing (NGS) panel sequencing identifies causal mutations for about 31% (12/38) of unrelated individuals with normal chromosomes when compared to about 15% (46/306) using conventional Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). More comprehensive genetic testing by our in house NGS panel sequencing of 10 HPE associated genes (MiSeq™ and NextSeq™500, Illumina, Inc., San Diego, CA) not only allowed to include genes with smaller contribution to the phenotype, but may also unravel additional low frequency or more common genetic variants potentially contributing to the observed large intrafamiliar variability and may ultimately guide our understanding of the individual clinical manifestation of this complex developmental disorder.


Assuntos
Testes Genéticos/métodos , Holoprosencefalia/diagnóstico , Holoprosencefalia/genética , Mutação , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Encéfalo/embriologia , Região Branquial/anormalidades , Região Branquial/diagnóstico por imagem , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Proteínas do Olho/genética , Facies , Feminino , Alemanha , Proteínas Hedgehog/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Holoprosencefalia/diagnóstico por imagem , Proteínas de Homeodomínio/genética , Humanos , Masculino , Microftalmia/diagnóstico , Microftalmia/diagnóstico por imagem , Microftalmia/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Linhagem , Gravidez , Diagnóstico Pré-Natal , Fatores de Transcrição/genética
8.
BMC Med Genet ; 19(1): 144, 2018 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-30111295

RESUMO

BACKGROUND: The PTEN-hamartoma-tumor-syndrome (PHTS) is caused by germline mutations in Phosphatase and Tensin homolog (PTEN) and predisposes to the development of several typical malignancies. Whereas PTEN mutations have been implicated in the occurrence of malignant mesotheliomas, the genetic landscape of verrucous carcinomas (VC) is largely uncharted. Both VC and malignant peritoneal mesotheliomas (MPM) are exceedingly rare and a potential link between these malignancies and PHTS has never been reported. CASE PRESENTATION: We here describe the clinical course of a PHTS patient who, in addition to a typical thyroid carcinoma at the age of 36 years, developed a highly-differentiated oral VC and an epithelioid MPM six years later. The patient with a history of occupational asbestos exposure underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for MPM. The clinical diagnosis of PHTS was consequently corroborated by a germline PTEN deletion. Sequencing of tumor tissue revealed a second hit in PTEN in the thyroid carcinoma and VC, confirmed by a PTEN loss and activation of the PI3K/AKT pathway in immunohistochemistry. Furthermore, additional somatic mutations in the thyroid carcinoma as well as in the VC were detected, whereas the genetics of MPM remained unrevealing. DISCUSSION AND CONCLUSIONS: We here report the very unusual clinical course of a patient with rare tumors that have a germline mutation first hit in PTEN in common. Since this patient was exposed to asbestos and current evidence suggests molecular mechanisms that might render PHTS patients particularly susceptible to mesothelioma, we strongly recommend PHTS patients to avoid even minimal exposure.


Assuntos
Carcinoma Verrucoso/genética , Mutação em Linhagem Germinativa/genética , Neoplasias Pulmonares/genética , Mesotelioma/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Humanos , Doenças Raras
9.
Eur J Hum Genet ; 25(2): 183-191, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27901041

RESUMO

Truncating ASXL3 mutations were first identified in 2013 by Bainbridge et al. as a cause of syndromic intellectual disability in four children with similar phenotypes using whole-exome sequencing. The clinical features - postulated by Bainbridge et al. to be overlapping with Bohring-Opitz syndrome - were developmental delay, severe feeding difficulties, failure to thrive and neurological abnormalities. This condition was included in OMIM as 'Bainbridge-Ropers syndrome' (BRPS, #615485). To date, a total of nine individuals with BRPS have been published in the literature in four reports (Bainbridge et al., Dinwiddie et al, Srivastava et al. and Hori et al.). In this report, we describe six unrelated patients with newly diagnosed heterozygous de novo loss-of-function variants in ASXL3 and concordant clinical features: severe muscular hypotonia with feeding difficulties in infancy, significant motor delay, profound speech impairment, intellectual disability and a characteristic craniofacial phenotype (long face, arched eyebrows with mild synophrys, downslanting palpebral fissures, prominent columella, small alae nasi, high, narrow palate and relatively little facial expression). The majority of key features characteristic for Bohring-Opitz syndrome were absent in our patients (eg, the typical posture of arms, intrauterine growth retardation, microcephaly, trigonocephaly, typical facial gestalt with nevus flammeus of the forehead and exophthalmos). Therefore we emphasize that BRPS syndrome, caused by ASXL3 loss-of-function variants, is a clinically distinct intellectual disability syndrome with a recognizable phenotype distinguishable from that of Bohring-Opitz syndrome.


Assuntos
Deficiências do Desenvolvimento/genética , Insuficiência de Crescimento/genética , Fatores de Transcrição/genética , Adolescente , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Insuficiência de Crescimento/diagnóstico , Feminino , Humanos , Lactente , Masculino , Mutação , Fenótipo , Síndrome
10.
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.

11.
Eur J Hum Genet ; 23(11): 1513-8, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25649377

RESUMO

X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes (AP1S2, ATRX, CUL4B, DLG3, IQSEC2, KDM5C, MED12, OPHN1, SLC9A6, SMC1A, UBE2A, UPF3B and ZDHHC9) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5-10% for X-chromosomal defects in male ID patients.


Assuntos
Epilepsia/genética , Genes Ligados ao Cromossomo X , Sequenciamento de Nucleotídeos em Larga Escala , Deficiência Intelectual/genética , Adolescente , Adulto , Criança , Pré-Escolar , Epilepsia/fisiopatologia , Feminino , Dosagem de Genes , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Mutação , Inativação do Cromossomo X/genética
12.
Am J Med Genet A ; 167A(3): 653-6, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25691419

RESUMO

Isolated interstitial duplications of chromosome band 1q25 are apparently very rare; no patients with detailed molecular and clinical characterization of duplications restricted to this region have been published to date. We report on a 9-year-old girl with mild cognitive deficits, tall stature, macrocephaly and discrete dysmorphic features in whom a de novo interstitial 7.5 Mb duplication of 1q25.1q25.3 was detected by SNP array analysis (arr[hg19] 1q25.1q25.3(173,925,505-181,381,242)x3 dn). The duplicated region was inversely inserted into chromosome band 1q42.2: 46,XX,der(1)(pter→q42.2::q25.3→q25.1::q42.2→qter). Overexpression of one or several of the 87 genes in the duplicated interval was presumably the major causative factor for the clinical manifestations. Reports of additional patients with overlapping duplications will be needed to establish detailed karyotype-phenotype correlations and to gain a better understanding of the underlying pathomechanisms.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Duplicação Cromossômica , Cromossomos Humanos Par 1 , Fenótipo , Criança , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/genética , Hibridização Genômica Comparativa , Facies , Feminino , Estudos de Associação Genética , Humanos , Hibridização in Situ Fluorescente
13.
Eur J Hum Genet ; 22(10): 1233-5, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24801762

RESUMO

Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. It may occur as isodisomy, heterodisomy or a combination of both and may involve only chromosome segments. UPD can affect each chromosome. The incidence is estimated to be around 1:3500 in live births. Some parts of chromosomes are subject to 'parent-of-origin imprinting' and the phenotypic effect in UPD syndromes is mainly due to functional imbalance of imprinted genes. Isodisomy can result in mutation homozygosity in autosomal-recessive inherited diseases. UPD causes several well-defined imprinting syndromes associated with intellectual disability (ID). Although knowledge on frequency and size of UPDs in patients with unexplained ID remains largely unknown as no efficient genome-wide screening technique was available for detection of both isodisomic and heterodisomic UPDs. SNP microarrays have been proven to be capable to detect UPDs through Mendelian errors. The correct subclassification of UPD requires child-parent trio experiments. To further elucidate the role of UPD in patients with unexplained ID, we analyzed a total of 322 child-parent trios. We were not able to detect UPDs (isodisomies and heterodisomies) within our cohort spanning whole chromosomes or chromosomal segments. We conclude that UPD is rare in patients with unexplained ID.


Assuntos
Estudo de Associação Genômica Ampla , Deficiência Intelectual/genética , Dissomia Uniparental/genética , Criança , Cromossomos Humanos Par 7/genética , Variações do Número de Cópias de DNA , Testes Genéticos , Genoma Humano , Impressão Genômica , Homozigoto , Humanos , Pais , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos
14.
Am J Med Genet A ; 164A(9): 2161-71, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24842779

RESUMO

Mutations in WDR62 are associated with primary microcephaly; however, they have been reported with wide phenotypic variability. We report on six individuals with novel WDR62 mutations who illustrate this variability and describe three in greater detail. Of the three, one lacks neuromotor development and has severe pachygyria on MRI, another has only delayed speech and motor development and moderate polymicrogyria, and the third has an intermediate phenotype. We observed a rare copy number change of unknown significance, a 17q25qter duplication, in the first severely affected individual. The 17q25 duplication included an interesting candidate gene, tubulin cofactor D (TBCD), crucial in microtubule assembly and disassembly. Sequencing of the non-duplicated allele showed a TBCD missense mutation, predicted to cause a deleterious p.Phe1121Val substitution. Sequencing of a cohort of five patients with WDR62 mutations, including one with an identical mutation and different phenotype, plus 12 individuals with diagnosis of microlissencephaly and another individual with mild intellectual disability (ID) and a 17q25 duplication, did not reveal TBCD mutations. However, immunostaining with tubulin antibodies of cells from patients with both WDR62 and TBCD mutation showed abnormal tubulin network when compared to controls and cells with only the WDR62 mutation. Therefore, we propose that genetic factors contribute to modify the severity of the WDR62 phenotype and, although based on suggestive evidence, TBCD could function as one of such factors.


Assuntos
Predisposição Genética para Doença , Mutação/genética , Proteínas do Tecido Nervoso/genética , Sequência de Bases , Encéfalo/patologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Proteínas Associadas aos Microtúbulos/genética , Dados de Sequência Molecular , Gravidez , Tubulina (Proteína)/metabolismo
15.
Mol Genet Genomic Med ; 2(2): 176-85, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24689081

RESUMO

Cerebral cavernous malformations (CCM) are prevalent vascular malformations occurring in familial autosomal dominantly inherited or isolated forms. Once CCM are diagnosed by magnetic resonance imaging, the indication for genetic testing requires either a positive family history of cavernous lesions or clinical symptoms such as chronic headaches, epilepsy, neurological deficits, and hemorrhagic stroke or the occurrence of multiple lesions in an isolated case. Following these inclusion criteria, the mutation detection rates in a consecutive series of 105 probands were 87% for familial and 57% for isolated cases. Thirty-one novel mutations were identified with a slight shift towards proportionally more CCM3 mutations carriers than previously published (CCM1: 60%, CCM2: 18%, CCM3: 22%). In-frame deletions and exonic missense variants requiring functional analyses to establish their pathogenicity were rare: An in-frame deletion within the C-terminal FERM domain of CCM1 resulted in decreased protein expression and impaired binding to the transmembrane protein heart of glass (HEG1). Notably, 20% of index cases carrying a CCM mutation were below age 10 and 33% below age 18 when referred for genetic testing. Since fulminant disease courses during the first years of life were observed in CCM1 and CCM3 mutation carriers, predictive testing of minor siblings became an issue.

16.
Neurobiol Aging ; 35(5): 1212.e1-5, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24300238

RESUMO

Targeted high-throughput sequencing of many amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) genes in parallel has the potential to reveal novel ALS- and/or FTD-phenotypes and to provide missing links on the ALS-FTD continuum. For example, although the 43-kDa transactive response DNA binding protein is the major pathologic hallmark linking ALS and FTD, mutations in the gene encoding 43-kDa transactive response DNA binding protein (TARDBP) have been appreciated only as a cause of ALS-phenotypes, but not yet of pure FTD. Thus, the genetic link is not yet well substantiated that TARDBP mutations can cause the full spectrum of the ALS-FTD continuum. High-throughput sequencing of 18 ALS and FTD genes in an index patient presenting with early-onset pure (behavioral) FTD and a positive family history for ALS revealed an established TARDBP mutation, A382T. This finding demonstrates that a TARDPB mutation can cause early-onset pure FTD without evidence for ALS even in advanced FTD disease stages. Moreover, it indicates that TARDPB screening might be considered even in young patients with "pure" neuropsychiatric disturbances and without evidence of neurodegenerative disease in the parental generation.


Assuntos
Proteínas de Ligação a DNA/genética , Demência Frontotemporal/genética , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Adulto , Idoso , Esclerose Amiotrófica Lateral/genética , Feminino , Demência Frontotemporal/diagnóstico , Testes Genéticos/métodos , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores , Tomografia por Emissão de Pósitrons
17.
Am J Med Genet A ; 161A(6): 1409-13, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23613162

RESUMO

Deletions of chromosome band 12q24.33 are rare. We report on a 17-year-old male patient with intellectual disability but no major malformations or dysmorphic features in whom a de novo interstitial 660 kb deletion in 12q24.33 was detected by SNP array analysis. This deletion was secondary to a translocation t(12;14)(q24.3;q13)dn that also led to a small deletion in 14q21.1 and a small duplication in 2p23.1. The deletion overlaps with two previously published larger deletions in patients who suffered from intellectual disability, obesity, and polycystic kidney disease, indicating that haploinsufficiency of one or several of the genes in the deleted interval of the patient reported here causes intellectual deficits, but not obesity or renal problems. The 14 RefSeq genes that are harbored by this deletion include P2RX2, which had previously been proposed as a candidate gene for intellectual disability. Thus, the patient reported here broadens our knowledge of the phenotypic consequences of deletions in 12q24.33 and facilitates genotype-phenotype correlations for chromosome aberrations of this region.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 14/genética , Haploinsuficiência/genética , Deficiência Intelectual/genética , Doenças Renais Policísticas/genética , Adolescente , Bandeamento Cromossômico , Hibridização Genômica Comparativa , Estudos de Associação Genética , Humanos , Deficiência Intelectual/diagnóstico , Cariótipo , Masculino , Fenótipo , Doenças Renais Policísticas/diagnóstico , Polimorfismo de Nucleotídeo Único , Translocação Genética
18.
Am J Med Genet A ; 161A(4): 860-4, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23520119

RESUMO

Mutations or deletions of ACSL4 (FACL4, OMIM 300157) are a rare cause of non-syndromic X-linked intellectual disability. We report on a 10-year-old male patient with moderate intellectual disability, sensorineural hearing loss, facial dysmorphism, pyloric stenosis, and intestinal obstruction in whom a de novo Xq22.3-q23 deletion was detected by SNP array analysis. The deleted 1.56 Mb interval harbored ACSL4 and eight neighboring genes (GUCY2F, NXT2, KCNE1L, TMEM164, MIR3978, AMMECR1, SNORD96B, and RGAG1). In contrast to previously reported patients with chromosome aberrations in the region of the AMME complex (Alport syndrome, intellectual disability, midface hypoplasia, and elliptocytosis, OMIM 300194), this deletion did not contain the Alport syndrome gene COL4A5, suggesting that loss of one or several of the other genes in this interval is responsible for the clinical problems. In summary, the patient reported here broadens our knowledge of the phenotypic consequences of deletions of chromosome region Xq22.3-q23 and provides further proof for ACSL4 as an X-linked intellectual disability gene.


Assuntos
Deleção Cromossômica , Cromossomos Humanos X , Coenzima A Ligases/genética , Deficiência Intelectual/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Criança , Facies , Deleção de Genes , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Hibridização in Situ Fluorescente , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único
19.
Am J Med Genet A ; 158A(10): 2587-90, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22965684

RESUMO

Interstitial deletions of the short arm of chromosome 3 are rare. We report on a 3-year-old girl with intellectual disability, muscular hypotonia, strabismus, and facial anomalies in whom an interstitial 1.24 Mb deletion in 3p25.3-p26.1 was detected by SNP array analysis. The deleted region harbors 11 RefSeq genes including CAV3 and SRGAP3/MEGAP, which had been associated with muscle disorders and intellectual disability, respectively. The deletion overlaps with a slightly larger deletion in a girl with a more complex phenotype including congenital heart defect and epilepsy, which indicates that haploinsufficiency of one or several of the genes in the deleted interval causes intellectual deficits, but not heart defects or epilepsy. Thus, the patient broadens our knowledge of the phenotypic consequences of deletions in 3p25.3-p26.1 and facilitates genotype-phenotype correlations for chromosome aberrations of this region.


Assuntos
Cromossomos Humanos Par 3 , Deficiência Intelectual/genética , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 3/genética , Hibridização Genômica Comparativa , Feminino , Proteínas Ativadoras de GTPase/genética , Estudos de Associação Genética , Humanos , Polimorfismo de Nucleotídeo Único
20.
J Med Genet ; 49(9): 547-53, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22844132

RESUMO

Among the clusters of imprinted genes in humans, one of the most relevant regions involved in human growth is localised in 11p15. Opposite epigenetic and genomic disturbances in this chromosomal region contribute to two distinct imprinting disorders associated with disturbed growth, Silver-Russell and Beckwith-Wiedemann syndromes. Due to the complexity of the 11p15 imprinting regions and their interactions, the interpretation of the copy number variations in that region is complicated. The clinical outcome in case of microduplications or microdeletions is therefore influenced by the size, the breakpoint positions and the parental inheritance of the imbalance as well as by the imprinting status of the affected genes. Based on their own new cases and those from the literature, the authors give an overview on the genotype-phenotype correlation in chromosomal rearrangements in 11p15 as the basis for a directed genetic counselling. The detailed characterisation of patients and families helps to further delineate risk figures for syndromes associated with 11p15 disturbances. Furthermore, these cases provide us with profound insights in the complex regulation of the (imprinted) factors localised in 11p15.


Assuntos
Cromossomos Humanos Par 11/genética , Variações do Número de Cópias de DNA/genética , Impressão Genômica/genética , Adulto , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Adulto Jovem
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