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1.
Ann Neurol ; 86(2): 181-192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177578

RESUMO

OBJECTIVE: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. METHODS: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. RESULTS: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. INTERPRETATION: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.

2.
Sci Rep ; 9(1): 1219, 2019 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718709

RESUMO

Inherited retinal diseases (IRDs) are a common cause of visual impairment. IRD covers a set of genetically highly heterogeneous disorders with more than 150 genes associated with one or more clinical forms of IRD. Molecular genetic diagnosis has become increasingly important especially due to expanding number of gene therapy strategies under development. Next generation sequencing (NGS) of gene panels has proven a valuable diagnostic tool in IRD. We present the molecular findings of 677 individuals, residing in Denmark, with IRD and report 806 variants of which 187 are novel. We found that deletions and duplications spanning one or more exons can explain 3% of the cases, and thus copy number variation (CNV) analysis is important in molecular genetic diagnostics of IRD. Seven percent of the individuals have variants classified as pathogenic or likely-pathogenic in more than one gene. Possible Danish founder variants in EYS and RP1 are reported. A significant number of variants were classified as variants with unknown significance; reporting of these will hopefully contribute to the elucidation of the actual clinical consequence making the classification less troublesome in the future. In conclusion, this study underlines the relevance of performing targeted sequencing of IRD including CNV analysis as well as the importance of interaction with clinical diagnoses.

3.
Am J Hum Genet ; 104(2): 213-228, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30639323

RESUMO

Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61%) individuals. In addition to TBX4, the overlapping ∼2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.

4.
Clin Genet ; 2018 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-30417326

RESUMO

Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield.

5.
PLoS Genet ; 14(11): e1007780, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30419018

RESUMO

Clustered copy number variants (CNVs) as detected by chromosomal microarray analysis (CMA) are often reported as germline chromothripsis. However, such cases might need further investigations by massive parallel whole genome sequencing (WGS) in order to accurately define the underlying complex rearrangement, predict the occurrence mechanisms and identify additional complexities. Here, we utilized WGS to delineate the rearrangement structure of 21 clustered CNV carriers first investigated by CMA and identified a total of 83 breakpoint junctions (BPJs). The rearrangements were further sub-classified depending on the patterns observed: I) Cases with only deletions (n = 8) often had additional structural rearrangements, such as insertions and inversions typical to chromothripsis; II) cases with only duplications (n = 7) or III) combinations of deletions and duplications (n = 6) demonstrated mostly interspersed duplications and BPJs enriched with microhomology. In two cases the rearrangement mutational signatures indicated both a breakage-fusion-bridge cycle process and haltered formation of a ring chromosome. Finally, we observed two cases with Alu- and LINE-mediated rearrangements as well as two unrelated individuals with seemingly identical clustered CNVs on 2p25.3, possibly a rare European founder rearrangement. In conclusion, through detailed characterization of the derivative chromosomes we show that multiple mechanisms are likely involved in the formation of clustered CNVs and add further evidence for chromoanagenesis mechanisms in both "simple" and highly complex chromosomal rearrangements. Finally, WGS characterization adds positional information, important for a correct clinical interpretation and deciphering mechanisms involved in the formation of these rearrangements.

6.
Stem Cell Res ; 33: 46-50, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30312873

RESUMO

Bardet-Biedl syndrome (BBS) is genetically heterogeneous with at least 21 genes involved, and BBS10 encodes, together with BBS6 and BBS12, chaperonin-like proteins which are important for the assembly of the multiprotein complex, the BBSome encoded by other BBS genes. Here we describe the successful generation of an induced pluripotent stem cell (iPSC) line KCi002-A from a male with BBS, homozygous for the disease causing variant c.271insT, p.(Cys91fsX95) in BBS10. Resource table.

7.
Eur J Hum Genet ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30291340

RESUMO

Deletions on chromosome 15q14 are a known chromosomal cause of cleft palate, typically co-occurring with intellectual disability, facial dysmorphism, and congenital heart defects. The identification of patients with loss-of-function variants in MEIS2, a gene within this deletion, suggests that these features are attributed to haploinsufficiency of MEIS2. To further delineate the phenotypic spectrum of the MEIS2-related syndrome, we collected 23 previously unreported patients with either a de novo sequence variant in MEIS2 (9 patients), or a 15q14 microdeletion affecting MEIS2 (14 patients). All but one de novo MEIS2 variant were identified by whole-exome sequencing. One variant was found by targeted sequencing of MEIS2 in a girl with a clinical suspicion of this syndrome. In addition to the triad of palatal defects, heart defects, and developmental delay, heterozygous loss of MEIS2 results in recurrent facial features, including thin and arched eyebrows, short alae nasi, and thin vermillion. Genotype-phenotype comparison between patients with 15q14 deletions and patients with sequence variants or intragenic deletions within MEIS2, showed a higher prevalence of moderate-to-severe intellectual disability in the former group, advocating for an independent locus for psychomotor development neighboring MEIS2.

8.
Stem Cell Res ; 31: 235-239, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30142598

RESUMO

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy with a wide range of symptoms including obesity, retinal dystrophy, polycystic kidney disease, polydactyly, hypogonadism and learning difficulties. Here we describe the successful generation of an induced pluripotent stem cell (iPSC) KCi001-A from a BBS patient compound heterozygous for two disease causing BBS1 variants c.1169T>G, p. (Met390Arg)/c.1135G>C, p.(Gly370Arg). Resource table.

9.
Nat Rev Genet ; 19(10): 649-666, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29995837

RESUMO

Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning.

10.
Am J Med Genet B Neuropsychiatr Genet ; 177(4): 397-405, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29603867

RESUMO

Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses-particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD.

11.
Nat Rev Endocrinol ; 14(4): 229-249, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29377879

RESUMO

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour. Despite recent advances in knowledge, there is marked heterogeneity in clinical diagnostic criteria and care. As detailed in this Consensus Statement, an international consensus group agreed upon 72 recommendations for the clinical and molecular diagnosis and management of BWS, including comprehensive protocols for the molecular investigation, care and treatment of patients from the prenatal period to adulthood. The consensus recommendations apply to patients with Beckwith-Wiedemann spectrum (BWSp), covering classical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly. Although the consensus group recommends a tumour surveillance programme targeted by molecular subgroups, surveillance might differ according to the local health-care system (for example, in the United States), and the results of targeted and universal surveillance should be evaluated prospectively. International collaboration, including a prospective audit of the results of implementing these consensus recommendations, is required to expand the evidence base for the design of optimum care pathways.

12.
Hum Mutat ; 39(3): 345-364, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29250858

RESUMO

Silver-Russell syndrome (SRS) is a clinically and molecularly heterogeneous disorder involving prenatal and postnatal growth retardation, and the term SRS-like is broadly used to describe individuals with clinical features resembling SRS. The main molecular subgroups are loss of methylation of the distal imprinting control region (H19/IGF2:IG-DMR) on 11p15.5 (50%) and maternal uniparental disomy of chromosome 7 (5%-10%). Through a comprehensive literature search, we identified 91 patients/families with various structural and small sequence variants, which were suggested as additional molecular defects leading to SRS/SRS-like phenotypes. However, the molecular and phenotypic data of these patients were not standardized and therefore not comparable, rendering difficulties in phenotype-genotype comparisons. To overcome this challenge, we curated a disease database including (epi)genetic phenotypic data of these patients. The clinical features are scored according to the Netchine-Harbison clinical scoring system (NH-CSS), which has recently been accepted as standard by consensus. The structural and sequence variations are reviewed and where necessary redescribed according to recent recommendations. Our study provides a framework for both research and diagnostic purposes through facilitating a standardized comparison of (epi)genotypes with phenotypes of patients with structural/sequence variants.

13.
Epigenetics ; 13(2): 117-121, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-27911167

RESUMO

The analysis of DNA methylation has become routine in the pipeline for diagnosis of imprinting disorders, with many publications reporting aberrant methylation associated with imprinted differentially methylated regions (DMRs). However, comparisons between these studies are routinely hampered by the lack of consistency in reporting sites of methylation evaluated. To avoid confusion surrounding nomenclature, special care is needed to communicate results accurately, especially between scientists and other health care professionals. Within the European Network for Human Congenital Imprinting Disorders we have discussed these issues and designed a nomenclature for naming imprinted DMRs as well as for reporting methylation values. We apply these recommendations for imprinted DMRs that are commonly assayed in clinical laboratories and show how they support standardized database submission. The recommendations are in line with existing recommendations, most importantly the Human Genome Variation Society nomenclature, and should facilitate accurate reporting and data exchange among laboratories and thereby help to avoid future confusion.

14.
Scand J Clin Lab Invest ; 77(8): 617-621, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29037082

RESUMO

Fabry disease is an X- linked inherited lysosomal storage disease caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A (α-Gal A). The possible pathological significance of the D313Y variant in the GLA gene has not been verified and it may be a Fabry variant. Our aim was to elucidate whether the presence of the D313Y variant influenced the α-Gal A activity or resulted in Fabry symptoms or Fabry organ involvement. In two Danish families the presence of the D313Y variant did not result in reduced α-Gal A activity or clinical Fabry manifestations in males, and the presence in Fabry females did not significantly enhance the phenotype of a known causative mutation in the GLA gene (G271S). Our findings indicate that the D313Y variant is not causative to nor enhancing Fabry disease phenotype. The D313Y variant in the GLA gene was not disease causative in 2 Danish families. Investigating male family members were crucial in excluding the Fabry phenotype, and thus very important for proper genetic counceling of all family members, as well as overdiagnosing a devastating genetic disease.


Assuntos
Doença de Fabry/genética , Mutação de Sentido Incorreto , alfa-Galactosidase/genética , Adulto , Idoso , Células Cultivadas , Criança , Análise Mutacional de DNA , Doença de Fabry/enzimologia , Feminino , Fibroblastos/enzimologia , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Leucócitos/enzimologia , Masculino , Pessoa de Meia-Idade , Linhagem , Inativação do Cromossomo X , alfa-Galactosidase/metabolismo
15.
Am J Med Genet A ; 173(8): 2108-2125, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28548707

RESUMO

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Síndrome de Lange/genética , Proteínas/genética , Síndrome de Rett/genética , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Lange/diagnóstico , Síndrome de Lange/fisiopatologia , Exoma/genética , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Síndrome de Rett/diagnóstico , Síndrome de Rett/fisiopatologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Adulto Jovem
16.
Mitochondrion ; 34: 103-114, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28263872

RESUMO

Spinocerebellar ataxia type 2 (SCA2) is a rare neurodegenerative disorder caused by a CAG repeat expansion in the ataxin-2 gene. We show increased oxidative stress, abnormalities in the antioxidant system, changes in complexes involved in oxidative phosphorylation and changes in mitochondrial morphology in SCA2 patient fibroblasts compared to controls, and we show that treatment with CoQ10 can partially reverse these changes. Together, our results suggest that oxidative stress and mitochondrial dysfunction may be contributory factors to the pathophysiology of SCA2 and that therapeutic strategies involving manipulation of the antioxidant system could prove to be of clinical benefit.


Assuntos
Fibroblastos/patologia , Mitocôndrias/patologia , Estresse Oxidativo , Ataxias Espinocerebelares/patologia , Ubiquinona/análogos & derivados , Vitaminas/metabolismo , Adolescente , Adulto , Idoso , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ubiquinona/metabolismo , Adulto Jovem
17.
Nat Rev Endocrinol ; 13(2): 105-124, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27585961

RESUMO

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.


Assuntos
Gerenciamento Clínico , Internacionalidade , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/terapia , Hormônio Liberador de Gonadotropina/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Síndrome de Silver-Russell/metabolismo
18.
Front Neurosci ; 10: 531, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27920664

RESUMO

Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by multiple motor and vocal tics. GTS is a complex disorder, with environmental factors and several genes involved. Although variations within a few genes such as AADAC, NRXN1, SLITRK1, HDC, and IMMP2L have been tentatively associated with GTS (in a small number of patients), the causative genes underlying GTS pathophysiology remain unknown. In a previous genome-wide association study (GWAS) a single nucleotide polymorphism (SNP, rs2060546) near the Netrin-4 (NTN4 - MIM 610401) gene was shown to be associated with GTS [odds ratio (OR) = 1.7; p-value = 5.8 × 10-7] thus warranting further investigations. As NTN4 is one of the axon guidance molecules expressed in the central nervous system and it interacts with the encoded proteins of SLIT and WNT genes guiding the growth cone toward its target, it is an attractive candidate susceptibility gene for GTS. In this study we attempted to replicate the association of rs2060546 with GTS by genotyping a Danish cohort of 240 GTS patients and 1006 healthy controls. Our results did not reveal an association (OR = 1.363; p-value = 0.3329) in the Danish cohort alone, which may be due to the small sample size. However, a meta-analysis including the present cohort and a total of 1316 GTS patients and 5023 controls from the GTS GWAS Replication Initiative (GGRI) and the first GTS-GWAS yielded a significant signal (OR = 3.74; p-value = 0.00018) and same direction of effect in the three cohorts. Thus, our study strengthens the evidence of the possible involvement of NTN4 in GTS etiology, suggesting that further studies in even larger samples and functional studies are warranted to investigate the role of this region in GTS pathogenesis.

19.
J Glaucoma ; 25(12): 926-930, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27820421

RESUMO

PURPOSE OF THE STUDY: Primary congenital glaucoma (PCG OMIM 231300) can be caused by pathogenic sequence variations in cytochrome P450, subfamily 1, polypeptide 1 (CYP1B1). The purpose of this study was to investigate the contribution of sequence variations in CYP1B1 in a cohort of individuals with PCG residing in Denmark. METHODS: The study included 37 unrelated individuals with PCG. Individuals were investigated for CYP1B1 mutations by Sanger sequencing of polymerase chain reaction products using BigDye terminators and capillary electrophoresis. RESULTS: A total of 12 mutations were identified and 5 of these were novel. Six were missense mutations; 4 were truncating mutations (2 nonsense and 2 frameshift); 1 was an in-frame deletion and 1 was an in-frame duplication. Mutations in CYP1B1 could fully explain the PCG phenotype in 7 individuals (18%). Five individuals were compound heterozygous or presumed compound heterozygous, 1 was homozygous and 1 was apparently homozygous. Three individuals were heterozygous for sequence variations in CYP1B1 thought to be pathogenic-one of these was p.(Tyr81Asn). Several known sequence variations with presumably no functional effect were found in the cohort. CONCLUSIONS: In this study, we identified 12 CYP1B1 mutations, 5 of which were novel. The frequency of CYP1B1 mutations in this cohort was comparable with other populations. We also detected an individual heterozygous for p.(Tyr81Asn) mutation, previously suggested to cause autosomal dominant primary open-angle glaucoma.


Assuntos
Citocromo P-450 CYP1B1/genética , DNA/genética , Glaucoma de Ângulo Aberto/genética , Pressão Intraocular , Mutação , Citocromo P-450 CYP1B1/metabolismo , Análise Mutacional de DNA , Dinamarca/epidemiologia , Feminino , Glaucoma de Ângulo Aberto/congênito , Glaucoma de Ângulo Aberto/epidemiologia , Humanos , Incidência , Masculino , Mutação de Sentido Incorreto , Fenótipo , Reação em Cadeia da Polimerase
20.
Front Neurosci ; 10: 384, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27601976

RESUMO

Gilles de la Tourette Syndrome (GTS) is characterized by the presence of multiple motor and phonic tics with a fluctuating course of intensity, frequency, and severity. Up to 90% of patients with GTS present with comorbid conditions, most commonly attention-deficit/hyperactivity disorder (ADHD), and obsessive-compulsive disorder (OCD), thus providing an excellent model for the exploration of shared etiology across disorders. TS-EUROTRAIN (FP7-PEOPLE-2012-ITN, Grant Agr.No. 316978) is a Marie Curie Initial Training Network (http://ts-eurotrain.eu) that aims to elucidate the complex etiology of the onset and clinical course of GTS, investigate the neurobiological underpinnings of GTS and related disorders, translate research findings into clinical applications, and establish a pan-European infrastructure for the study of GTS. This includes the challenges of (i) assembling a large genetic database for the evaluation of the genetic architecture with high statistical power; (ii) exploring the role of gene-environment interactions including the effects of epigenetic phenomena; (iii) employing endophenotype-based approaches to understand the shared etiology between GTS, OCD, and ADHD; (iv) establishing a developmental animal model for GTS; (v) gaining new insights into the neurobiological mechanisms of GTS via cross-sectional and longitudinal neuroimaging studies; and (vi) partaking in outreach activities including the dissemination of scientific knowledge about GTS to the public. Fifteen partners from academia and industry and 12 PhD candidates pursue the project. Here, we aim to share the design of an interdisciplinary project, showcasing the potential of large-scale collaborative efforts in the field of GTS. Our ultimate aims are to elucidate the complex etiology and neurobiological underpinnings of GTS, translate research findings into clinical applications, and establish Pan-European infrastructure for the study of GTS and associated disorders.

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