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1.
PLoS One ; 14(11): e0225186, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31725784

RESUMO

Restless legs syndrome is a common complex disorder with different genetic and environmental risk factors. Here we used human cell lines to conduct an RNA-Seq study and observed how the gene showing the most significant association with RLS, MEIS1, acts as a regulator of the expression of many other genes. Some of the genes affected by its expression level are linked to pathways previously reported to be associated with RLS. We found that in cells where MEIS1 expression was either increased or prevented, mineral absorption is the principal dysregulated pathway. The mineral absorption pathway genes, HMOX1 and VDR are involved in iron metabolism and response to vitamin D, respectively. This shows a strong functional link to the known RLS pathways. We observed the same enrichment of the mineral absorption pathway in postmortem brain tissues of RLS patients showing a reduced expression of MEIS1. The expression of genes encoding metallothioneins (MTs) was observed to be dysregulated across the RNA-Seq datasets generated from both human cells and tissues. MTs are highly relevant to RLS as they bind intracellular metals, protect against oxidative stress and interact with ferritins which manage iron level in the central nervous system. Overall, our study suggests that in a subset of RLS patients, the contribution of MEIS1 appears to be associated to its downstream regulation of genes that are more directly involved in pathways that are relevant to RLS. While MTs have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's diseases, this is a first report to propose that they have a role in RLS.

2.
Am J Hum Genet ; 105(4): 854-868, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31585109

RESUMO

Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).

3.
J Hum Genet ; 64(11): 1145-1151, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31515523

RESUMO

More than 80 known or suspected genes/loci have been reported to be involved in hereditary spastic paraplegia (HSP). Genetic and clinical overlap have been reported between HSP and other neurological condition, yet about 50% of HSP patients remain genetically undiagnosed. To identify novel genes involved in HSP, we performed a genetic analysis of 383 HSP patients from 289 families with HSP. Two patients with biallelic SPTAN1 variants were identified; one carried the c.2572G>T p.(Ala858Ser) and c.4283C>G p.(Ala1428Gly) variants, and the second also carried the c.2572G>T p.(Ala858Ser) variant, and an additional variant, c.6990G>C p.(Met2330Ile). In silico predictive and structural analyses suggested that these variants are likely to be deleterious. SPTAN1 was highly intolerant for functional variants (in the top 0.31% of intolerant genes) with much lower observed vs. expected number of loss-of-function variants (8 vs. 142.7, p < 5 × 10-15). Using public databases of animal models and previously published data, we have found previously described zebrafish, mouse, and rat animal models of SPTAN1 deficiency, all consistently showing axonal degeneration, fitting the pathological features of HSP in humans. This study expands the phenotype of SPTAN1 mutations, which at the heterozygous state, when occurred de novo, may cause early infantile epileptic encephalopathy-5 (EIEE5). Our results further suggest that SPTAN1 may cause autosomal recessive HSP, and that it should be included in genetic screening panels for genetically undiagnosed HSP patients.

4.
Proc Natl Acad Sci U S A ; 116(32): 16012-16017, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31332017

RESUMO

The Canadian Inuit have a distinct population background that may entail particular implications for the health of its individuals. However, the number of genetic studies examining this Inuit population is limited, and much remains to be discovered in regard to its genetic characteristics. In this study, we generated whole-exome sequences and genomewide genotypes for 170 Nunavik Inuit, a small and isolated founder population of Canadian Arctic indigenous people. Our study revealed the genetic background of Nunavik Inuit to be distinct from any known present-day population. The majority of Nunavik Inuit show little evidence of gene flow from European or present-day Native American peoples, and Inuit living around Hudson Bay are genetically distinct from those around Ungava Bay. We also inferred that Nunavik Inuit have a small effective population size of 3,000 and likely split from Greenlandic Inuit ∼10.5 kya. Nunavik Inuit went through a bottleneck at approximately the same time and might have admixed with a population related to the Paleo-Eskimos. Our study highlights population-specific genomic signatures in coding regions that show adaptations unique to Nunavik Inuit, particularly in pathways involving fatty acid metabolism and cellular adhesion (CPNE7, ICAM5, STAT2, and RAF1). Subsequent analyses in selection footprints and the risk of intracranial aneurysms (IAs) in Nunavik Inuit revealed an exonic variant under weak negative selection to be significantly associated with IA (rs77470587; P = 4.6 × 10-8).

5.
Clin Genet ; 96(3): 199-206, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31038196

RESUMO

Autism spectrum disorder (ASD) is a highly heterogeneous genetic disorder with strong evidence of ASD-association currently available only for a small number of genes. This makes it challenging to identify the underlying genetic cause in many cases of ASD, and there is a continuing need for further discovery efforts. We sequenced whole genomes of 119 deeply phenotyped ASD probands in order to identify likely pathogenic variants. We prioritized variants found in each subject by predicted damage, population frequency, literature evidence, and phenotype concordance. We used Sanger sequencing to determine the inheritance status of high-priority variants where possible. We report five novel de novo damaging variants as well as several likely damaging variants of unknown inheritance; these include two novel de novo variants in the well-established ASD gene SCN2A. The availability of rich phenotypic information and its concordance with the literature allowed us to increase our confidence in pathogenicity of discovered variants, especially in probands without parental DNA. Our results contribute to the documentation of potential pathogenic variants and their associated phenotypes in individuals with ASD.

6.
Mov Disord ; 34(4): 526-535, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30788890

RESUMO

BACKGROUND: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. METHODS: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed. RESULTS: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome. CONCLUSIONS: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30415495

RESUMO

BACKGROUND: Neural tube defects (NTD) are among the most common defects affecting 1:1000 births. They are caused by a failure of neural tube closure during development. Their clinical presentation is diverse and dependent on the site and severity of the original defect on the embryonic axis. The etiology of NTD is multifactorial involving environmental factors and genetic variants that remain largely unknown. METHODS: We have conducted a whole exome sequencing (WES) study in five new NTD families and pooled the results with WES data from three NTD families and 43 trios that were previously investigated by our group. We analyzed the data using biased candidate gene and unbiased gene burden approaches. RESULTS: We identified four novel loss-of-function variants in three genes, MTHFR, DLC1, and ITGB1, previously associated with NTD. Notably, DLC1 carried two protein truncating variants in two independent cases. We also demonstrated an enrichment of variants in MYO1E involved in cytoskeletal remodeling. This enrichment reached borderline significance in a replication cohort supporting the association of this new candidate gene to NTD. CONCLUSION: These data provide some key insights into the pathogenic mechanisms of human NTD and demonstrate the power of next-generation sequencing in deciphering the genetics of this complex trait.

8.
Artigo em Inglês | MEDLINE | ID: mdl-30381913

RESUMO

BACKGROUND: Hereditary spastic paraplegia (HSP) is a group of rare disorders characterized by spastic paraparesis and other symptoms. Often, other diseases can mimic HSP, which may delay diagnosis and treatment. METHODS: Whole exome sequencing was performed in families with clinically suspected HSP without a genetic diagnosis. RESULTS: We report three patients from two families who presented with lower limb spasticity, muscular atrophy, and other neurological symptoms, who were clinically diagnosed with complicated HSP. Whole exome sequencing revealed bi-allelic AAAS nonsense mutations; one individual was homozygous for the p.(Arg478*) mutation, and two siblings were homozygous for the p.(Arg286*) mutation, leading to the diagnosis of triple A syndrome. This rare syndrome is typically characterized by a triad of symptoms: achalasia, adrenal insufficiency, and alacrima, and is often accompanied by other neurological abnormalities. CONCLUSIONS: Our findings suggest that triple A syndrome should be suspected in complicated HSP patients without a known genetic cause, especially if at least one of the main triad of triple A syndrome symptoms is present.

9.
Artigo em Inglês | MEDLINE | ID: mdl-30378261

RESUMO

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age of 13. The male COS cases have a slightly younger age of onset than female cases. They also present with a higher rate of comorbid developmental disorders. These sex differences are not explained by the frequency of chromosomal abnormalities, and the contribution of other forms of genetic variations remains unestablished. Using a whole-exome sequencing approach, we examined 12 COS trios where the unaffected parents had an affected male child. The sequencing data enabled us to test if the hemizygous variants, transmitted from the unaffected carrying mother, could mediate the phenotype (X-linked recessive inheritance model). Our results revealed that affected children have a significantly greater number of X-linked rare variants than their unaffected fathers. The variants identified in the male probands were mostly found in genes previously linked to other neuropsychiatric diseases like autism, intellectual disability, and epilepsy, including LUZP4, PCDH19, RPS6KA3, and OPHN1. The level of expression of the genes was assessed at different developmental periods in normal brain using the BrainSpan database. This approach revealed that some of them were expressed earlier in males than in females, consistent with the younger age of onset in male COS. In conclusion, this article suggests that X-linked genes might play a role in the pathophysiology of COS. Candidate genes detailed here could explain the higher level of comorbidities and the earlier age of onset observed in a subset of the male COS cases.

10.
Clin Biochem ; 59: 69-77, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29958880

RESUMO

OBJECTIVES: Non-invasive prenatal aneuploidy testing (NIPT) by next-generation sequencing of circulating cell-free DNA in maternal plasma relies on chromosomal ratio (chrratio) measurements to detect aneuploid values that depart from euploid ratios. Diagnostic performances are known to depend on the fraction of fetal DNA (FF) present in maternal plasma, although how this translates into specific quantitative changes in specificity/positive predictive values and which other variables might also be important is not well understood. DESIGN & METHODS: To explore this issue, theoretical relationships between FF and various measures of diagnostic performances were assessed for a range of parameter values. Empirical data from three NIPT assays were then used to validate theoretical calculations. RESULTS: For a given positivity threshold, dramatic changes in specificity and positive predictive values (PPV) as a function of both FF and the coefficient of variation (CV) of the chrratio measurement were observed. Theoretically predicted and observed chrratio z-scores agreed closely, confirming the determinant impact of small changes in both FF and chrratio CV. CONCLUSIONS: Evaluation of NIPT assay performances therefore requires knowledge of the FF distribution in the population in which the test is intended to be used and, in particular, of the precise value of the assay chrratio CV for each chromosome or genomic region of interest. Laboratories offering NIPT testing should carefully measure these parameters to ensure test reliability and clinical usefulness in interpreting individual patients' results.


Assuntos
Aneuploidia , Diagnóstico Pré-Natal/métodos , Adulto , Transtornos Cromossômicos/sangue , Feminino , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Modelos Teóricos , Valor Preditivo dos Testes , Gravidez , Diagnóstico Pré-Natal/estatística & dados numéricos , Reprodutibilidade dos Testes
11.
Mol Psychiatry ; 2018 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-29895895

RESUMO

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia defined as onset before age of 13. Here we report on two unrelated cases diagnosed with both COS and alternating hemiplegia of childhood (AHC), and for whom two distinct pathogenic de novo variants were identified in the ATP1A3 gene. ATP1A3 encodes the α-subunit of a neuron-specific ATP-dependent transmembrane sodium-potassium pump. Using whole exome sequencing data derived from a cohort of 17 unrelated COS cases, we also examined ATP1A3 and all of its interactors known to be expressed in the brain to establish if variants could be identified. This led to the identification of a third case with a possibly damaging missense mutation in ATP1A3 and three others cases with predicted pathogenic missense variants in the FXYD gene family (FXYD1, FXYD6, and FXYD6-FXYD2 readthrough). FXYD genes encode proteins that modulate the ATP-dependant pump function. This report is the first to identify variants in the same pathway for COS. Our COS study illustrates the interest of stratifying a complex condition according to the age of onset for the identification of deleterious variants. Whereas ATP1A3 is a replicated gene in rare neuropediatric diseases, this gene has previously been linked with COS in only one case report. The association with rare variants in FXYD gene family is novel and highlights the interest of exploring these genes in COS as well as in pediatric neurodevelopmental disorders.

12.
Hum Genome Var ; 5: 18001, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29844917

RESUMO

Brain arteriovenous malformations (AVMs) are abnormal connections between arteries and veins that can result in hemorrhagic stroke. A genetic basis for AVMs is suspected, and we investigated potential mutations in a 14-year-old girl who developed a recurrent brain AVM. Whole-exome sequencing (WES) of AVM lesion tissue and blood was performed accompanied by in silico modeling, protein expression observation in lesion tissue and zebrafish modeling. A stop-gain mutation (c.C739T:p.R247X) in the gene SMAD family member 9 (SMAD9) was discovered. In the human brain tissue, immunofluorescent staining demonstrated a vascular predominance of SMAD9 at the protein level. Vascular SMAD9 was markedly reduced in AVM peri-nidal blood vessels, which was accompanied by a decrease in phosphorylated SMAD4, a downstream effector protein of the bone morphogenic protein signaling pathway. Zebrafish modeling (Tg kdrl:eGFP) of the morpholino splice site and translation-blocking knockdown of SMAD9 resulted in abnormal cerebral artery-to-vein connections with morphologic similarities to human AVMs. Orthogonal trajectories of evidence established a relationship between the candidate mutation discovered in SMAD9 via WES and the clinical phenotype. Replication in similar rare cases of recurrent AVM, or even more broadly sporadic AVM, may be informative in building a more comprehensive understanding of AVM pathogenesis.

13.
BMC Pediatr ; 18(1): 138, 2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29665810

RESUMO

After publication of the original article [1] it was brought to our attention that author Bouchra Ouled Amar Bencheikh was incorrectly included as Bouchra Oulad Amar Bencheikh.

14.
PLoS Genet ; 14(4): e1007285, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29649218

RESUMO

Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from limited accuracy. We show that this is in part due to the non-uniformity of read coverage, even after intra-sample normalization. To improve on this, we developed PopSV, an algorithm that uses multiple samples to control for technical variation and enables the robust detection of CNVs. Using WGS and PopSV, we performed a comprehensive characterization of CNVs in 198 individuals affected with epilepsy and 301 controls. For both large and small variants, we found an enrichment of rare exonic events in epilepsy patients, especially in genes with predicted loss-of-function intolerance. Notably, this genome-wide survey also revealed an enrichment of rare non-coding CNVs near previously known epilepsy genes. This enrichment was strongest for non-coding CNVs located within 100 Kbp of an epilepsy gene and in regions associated with changes in the gene expression, such as expression QTLs or DNase I hypersensitive sites. Finally, we report on 21 potentially damaging events that could be associated with known or new candidate epilepsy genes. Our results suggest that comprehensive sequence-based profiling of CNVs could help explain a larger fraction of epilepsy cases.


Assuntos
Variações do Número de Cópias de DNA , Epilepsia/genética , Estudos de Casos e Controles , Estudos de Coortes , Humanos , Locos de Características Quantitativas , Sequenciamento Completo do Genoma
15.
Sci Rep ; 8(1): 4356, 2018 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-29531279

RESUMO

Intracranial Aneurysm (IA) is a common disease with a worldwide prevalence of 1-3%. In the French-Canadian (FC) population, where there is an important founder effect, the incidence of IA is higher and is frequently seen in families. In this study, we genotyped a cohort of 257 mostly familial FC IA patients and 1,992 FC controls using the Illumina NeuroX SNP-chip. The most strongly associated loci were tested in 34 Inuit IA families and in 32 FC IA patients and 106 FC controls that had been exome sequenced (WES). After imputation, one locus at 3p14.2 (FHIT, rs1554600, p = 4.66 × 10-9) reached a genome-wide significant level of association and a subsequent validation in Nunavik Inuit cohort further confirmed the significance of the FHIT variant association (rs780365, FBAT-O, p = 0.002839). Additionally, among the other promising loci (p < 5 × 10-6), the one at 3q13.2 (rs78125721, p = 4.77 × 10-7), which encompasses CCDC80, also showed an increased mutation burden in the WES data (CCDC80, SKAT-O, p = 0.0005). In this study, we identified two new potential IA loci in the FC population: FHIT, which is significantly associated with hypertensive IA, and CCDC80, which has potential genetic and functional relevance to IA pathogenesis, providing evidence on the additional risk loci for familial IA. We also replicated the previous IA GWAS risk locus 18q11.2, and suggested a potential locus at 8p23.1 that warrants further study.

16.
BMC Pediatr ; 18(1): 90, 2018 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-29486744

RESUMO

BACKGROUND: Epilepsy regroups a common and diverse set of chronic neurological disorders that are characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Epilepsies have a highly heterogeneous background with a strong genetic contribution and various mode of inheritance. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy. The variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the causal genetic mutation, making diagnosis, genetic counseling and treatment decisions difficult. We report the description of a Moroccan family referred to our genetic department with X-linked epileptic seizures as the only initial diagnosis. CASE PRESENTATION: Knowing the new contribution of Next-Generation Sequencing (NGS) for clinical investigation, and given the heterogeneity of this group of disorders we performed a Whole-Exome Sequencing (WES) analysis and co-segregation study in several members of this large family. We detected a novel pathogenic PLP1 missense mutation c.251C > A (p.Ala84Asp) allowing us to make a diagnosis of Pelizaeus-Merzbacher Disease for this family. CONCLUSION: This report extends the spectrum of PLP1 mutations and highlights the diagnostic utility of NGS to investigate this group of heterogeneous disorders.


Assuntos
Mutação de Sentido Incorreto , Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/diagnóstico , Doença de Pelizaeus-Merzbacher/genética , Sequenciamento Completo do Exoma , Pré-Escolar , Família , Feminino , Marcadores Genéticos , Humanos , Masculino , Marrocos , Linhagem
17.
Cancer Res ; 77(16): 4517-4529, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28646019

RESUMO

RAD51D is a key player in DNA repair by homologous recombination (HR), and RAD51D truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating RAD51D variants to cancer predisposition remains uncertain. Using deep sequencing and case-control genotyping studies, we show that in French Canadians, the missense RAD51D variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D-XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic RAD51D missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense RAD51D variants. Cancer Res; 77(16); 4517-29. ©2017 AACR.


Assuntos
Proteínas de Ligação a DNA/genética , Mutação de Sentido Incorreto , Neoplasias Ovarianas/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias Ovarianas/patologia , Linhagem , Polimorfismo de Nucleotídeo Único
18.
Hum Mutat ; 38(6): 716-724, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28276201

RESUMO

Neural tube defects, including spina bifida, are among the most common birth defects caused by failure of neural tube closure during development. They have a complex etiology involving largely undetermined environmental and genetic factors. Previous studies in mouse models have implicated the transcription factor Grhl3 as an important factor in the pathogenesis of spina bifida. In the present study, we conducted a resequencing analysis of GRHL3 in a cohort of 233 familial and sporadic cases of spina bifida. We identified two novel truncating variants: one homozygous frameshift variant, p.Asp16Aspfs*10, in two affected siblings and one heterozygous intronic splicing variant, p.Ala318Glyfs*26. We also identified five missense variants, one of which was demonstrated to reduce the activation of gene targets in a luciferase reporter assay. With the previously identified p.Arg391Cys variant, eight variants were found in GRHL3. Comparison of the variant rate between our cohort and the ExAC database identified a significant enrichment of deleterious variants in GRHL3 in the whole gene and the transactivation region in spina bifida patients. These data provide strong evidence for a role of GRHL3 as a predisposing factor to spina bifida and will help dissect the complex etiology and pathogenic mechanisms of these malformations.


Assuntos
Proteínas de Ligação a DNA/genética , Defeitos do Tubo Neural/genética , Disrafismo Espinal/genética , Fatores de Transcrição/genética , Animais , Feminino , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Camundongos , Mutação de Sentido Incorreto/genética , Defeitos do Tubo Neural/fisiopatologia , Linhagem , Deleção de Sequência/genética , Disrafismo Espinal/fisiopatologia , Sequenciamento Completo do Exoma
19.
Neurobiol Aging ; 53: 194.e9-194.e11, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28153381

RESUMO

Variants in the RIC3 gene have recently been suggested as a novel cause of Parkinson's disease (PD). Herein, the entire RIC3 gene was sequenced in a French-Canadian and French sample series of 535 PD patients and 527 unaffected controls. The effect of single variants and the combined effect of variants were calculated. Sequence Kernel association tests (SKAT, SKAT-O) were done on the entire gene level, and on the different domains and exons of RIC3. A total of 28 common and rare variants were identified in patients and controls. No significant association was found between any variant and haplotype in RIC3 and PD, and there was no over-representation of RIC3 variants at the entire gene, domain, or exon levels in patients versus controls. Our results do not support a role for RIC3 mutations as a common cause of PD in the French-Canadian and French populations.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação/genética , Doença de Parkinson/genética , Adulto , Canadá , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade
20.
J Hum Genet ; 62(4): 465-471, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28003643

RESUMO

Kaufman oculo-cerebro-facial syndrome (KOS) is caused by recessive UBE3B mutations and presents with microcephaly, ocular abnormalities, distinctive facial morphology, low cholesterol levels and intellectual disability. We describe a child with microcephaly, brachycephaly, hearing loss, ptosis, blepharophimosis, hypertelorism, cleft palate, multiple renal cysts, absent nails, small or absent terminal phalanges, absent speech and intellectual disability. Syndromes that were initially considered include DOORS syndrome, Coffin-Siris syndrome and Dubowitz syndrome. Clinical investigations coupled with karyotype analysis, array-comparative genomic hybridization, exome and Sanger sequencing were performed to characterize the condition in this child. Sanger sequencing was negative for the DOORS syndrome gene TBC1D24 but exome sequencing identified a homozygous deletion in UBE3B (NM_183415:c.3139_3141del, p.1047_1047del) located within the terminal portion of the HECT domain. This finding coupled with the presence of characteristic features such as brachycephaly, ptosis, blepharophimosis, hypertelorism, short palpebral fissures, cleft palate and developmental delay allowed us to make a diagnosis of KOS. In conclusion, our findings highlight the importance of considering KOS as a differential diagnosis for patients under evaluation for DOORS syndrome and expand the phenotype of KOS to include small or absent terminal phalanges, nails, and the presence of hallux varus and multicystic dysplastic kidneys.


Assuntos
Anormalidades Múltiplas/genética , Diagnóstico Diferencial , Anormalidades do Olho/genética , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Ubiquitina-Proteína Ligases/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adulto , Proteínas de Transporte/genética , Criança , Pré-Escolar , Eczema/diagnóstico , Eczema/genética , Eczema/fisiopatologia , Anormalidades do Olho/diagnóstico , Anormalidades do Olho/fisiopatologia , Face/anormalidades , Face/fisiopatologia , Facies , Feminino , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética , Transtornos do Crescimento/fisiopatologia , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Cariótipo , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/fisiopatologia , Masculino , Microcefalia/diagnóstico , Microcefalia/fisiopatologia , Micrognatismo/diagnóstico , Micrognatismo/genética , Micrognatismo/fisiopatologia , Mutação , Pescoço/anormalidades , Pescoço/fisiopatologia , Patologia Molecular , Análise de Sequência de DNA
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