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1.
Hum Mutat ; 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31696996

RESUMO

Hereditary spastic paraplegia (HSP) is a group of disorders with predominant symptoms of lower-extremity weakness and spasticity. Despite the delineation of numerous genetic causes of HSP, a significant portion of individuals with HSP remain molecularly undiagnosed. Through exome sequencing, we identified five unrelated families with childhood-onset nonsyndromic HSP, all presenting with progressive spastic gait, leg clonus, and toe walking starting from 7-8 years old. A recurrent two-base pair deletion (c.426_427delGA, p.K143Sfs*15) in the UBAP1 gene was found in four families, and a similar variant (c.475_476delTT, p.F159*) was detected in a fifth family. The variant was confirmed to be de novo in two families and inherited from affected parent in two other families. RNA studies performed in lymphocytes from one patient with the de novo c.426_427delGA variant demonstrated escape of nonsense-mediated decay (NMD) of the UBAP1 mutant transcript, suggesting the generation of a truncated protein. Both variants identified in this study are predicted to result in truncated proteins losing the capacity of binding to ubiquitinated proteins, hence appearing to exhibit a dominant-negative effect on the normal function of the endosome-specific ESCRT-I (endosomal sorting complexes required for transport-I) complex. This article is protected by copyright. All rights reserved.

2.
Mol Psychiatry ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673123

RESUMO

Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by repetitive motor movements and vocal tics. The clinical manifestations of TS are complex and often overlap with other neuropsychiatric disorders. TS is highly heritable; however, the underlying genetic basis and molecular and neuronal mechanisms of TS remain largely unknown. We performed whole-exome sequencing of a hundred trios (probands and their parents) with detailed records of their clinical presentations and identified a risk gene, ASH1L, that was both de novo mutated and associated with TS based on a transmission disequilibrium test. As a replication, we performed follow-up targeted sequencing of ASH1L in additional 524 unrelated TS samples and replicated the association (P value = 0.001). The point mutations in ASH1L cause defects in its enzymatic activity. Therefore, we established a transgenic mouse line and performed an array of anatomical, behavioral, and functional assays to investigate ASH1L function. The Ash1l+/- mice manifested tic-like behaviors and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol. We also found that Ash1l disruption leads to hyper-activation and elevated dopamine-releasing events in the dorsal striatum, all of which could explain the neural mechanisms for the behavioral abnormalities in mice. Taken together, our results provide compelling evidence that ASH1L is a TS risk gene.

3.
Sci Rep ; 9(1): 15935, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685878

RESUMO

MAGEL2 is a maternally imprinted, paternally expressed gene, located in the Prader-Willi region of human chromosome 15. Pathogenic variants in the paternal copy of MAGEL2 cause Schaaf-Yang syndrome (SHFYNG), a neurodevelopmental disorder related to Prader-Willi syndrome (PWS). Patients with SHFYNG, like PWS, manifest neonatal hypotonia, feeding difficulties, hypogonadism, intellectual disability and sleep apnea. However, individuals with SHFYNG have joint contractures, greater cognitive impairment, and higher prevalence of autism than seen in PWS. Additionally, SHFYNG is associated with a lower prevalence of hyperphagia and obesity than PWS. Previous studies have shown that truncating variants in MAGEL2 lead to SHFYNG. However, the molecular pathways involved in manifestation of the SHFYNG disease phenotype are still unknown. Here we show that a Magel2 null mouse model and fibroblast cell lines from individuals with SHFYNG exhibit increased expression of mammalian target of rapamycin (mTOR) and decreased autophagy. Additionally, we show that SHFYNG induced pluripotent stem cell (iPSC)-derived neurons exhibit impaired dendrite formation. Alterations in SHFYNG patient fibroblast lines and iPSC-derived neurons are rescued by treatment with the mTOR inhibitor rapamycin. Collectively, our findings identify mTOR as a potential target for the development of pharmacological treatments for SHFYNG.

4.
Hum Mol Genet ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31600777

RESUMO

Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS) has been identified as an autosomal-dominant disorder characterized by a complex neurological phenotype, with high prevalence of intellectual disability and optic nerve atrophy/hypoplasia. The syndrome is caused by loss-of-function mutations in NR2F1, which encodes a highly conserved nuclear receptor that serves as a transcriptional regulator. Previous investigations to understand the protein's role in neurodevelopment have mostly used mouse models with constitutive and tissue-specific homozygous knockout of Nr2f1. In order to represent the human disease more accurately, which is caused by heterozygous NR2F1 mutations, we investigated a heterozygous knockout mouse model, and found that this model recapitulates some of the neurological phenotypes of BBSOAS, including altered learning/memory, hearing defects, neonatal hypotonia, and decreased hippocampal volume. The mice showed altered fear memory, and further electrophysiological investigation in hippocampal slices revealed significantly reduced long-term potentiation (LTP) and long-term depression (LTD). These results suggest that a deficit or alteration in hippocampal synaptic plasticity may contribute to the intellectual disability frequently seen in BBSOAS. RNA-Seq analysis revealed significant differential gene expression in the adult Nr2f1+/- hippocampus, including the up-regulation of multiple matrix metalloproteases (MMPs), which are known to be critical for the development and the plasticity of the nervous system. Taken together, our studies highlight the important role of Nr2f1 in neurodevelopment. The discovery of impaired hippocampal synaptic plasticity in the heterozygous mouse model sheds light on the pathophysiology of altered memory and cognitive function in BBSOAS.

5.
eNeuro ; 6(6)2019.
Artigo em Inglês | MEDLINE | ID: mdl-31562178

RESUMO

Rett Syndrome is a neurological disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) and characterized by severe intellectual disability. The cholinergic system is a critical modulator of cognitive ability and is affected in patients with Rett Syndrome. To better understand the importance of MeCP2 function in cholinergic neurons, we studied the effect of selective Mecp2 deletion from cholinergic neurons in mice. Mice with Mecp2 deletion from cholinergic neurons were selectively impaired in assays of recognition memory, a cognitive task largely mediated by the perirhinal cortex (PRH). Deletion of Mecp2 from cholinergic neurons resulted in profound alterations in baseline firing of L5/6 neurons and eliminated the responses of these neurons to optogenetic stimulation of cholinergic input to PRH. Both the behavioral and the electrophysiological deficits of cholinergic Mecp2 deletion were rescued by inhibiting ACh breakdown with donepezil treatment.

6.
Birth Defects Res ; 111(18): 1356-1364, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31313535

RESUMO

BACKGROUND: Few studies have systematically evaluated birth defect co-occurrence patterns, perhaps, in part, due to the lack of software designed to implement large-scale, complex analytic methods. METHODS: We created an R-based platform, "co-occurring defect analysis" (CODA), designed to implement analyses of birth defect co-occurrence patterns in birth defect registries. CODA uses an established algorithm for calculating the observed-to-expected ratio of a given birth defect combination, accounting for the known tendency of birth defects to co-occur nonspecifically. To demonstrate CODA's feasibility, we evaluated the computational time needed to assess 2- to 5-way combinations of major birth defects in the Texas Birth Defects Registry (TBDR) (1999-2014). We report on two examples of pairwise patterns, defects co-occurring with trisomy 21 or with non-syndromic spina bifida, to demonstrate proof-of-concept. RESULTS: We evaluated combinations of 175 major birth defects among 206,784 infants in the TBDR. CODA performed efficiently in the data set, analyzing 1.5 million 5-way combinations in 18 hr. As anticipated, we identified large observed-to-expected ratios for the birth defects that co-occur with trisomy 21 or spina bifida. CONCLUSIONS: CODA is available for application to birth defect data sets and can be used to better understand co-occurrence patterns. Co-occurrence patterns elucidated by using CODA may be helpful for identifying new birth defect associations and may provide etiological insights regarding potentially shared pathogenic mechanisms. CODA may also have wider applications, such as assessing patterns of additional types of co-occurrence patterns in other large data sets (e.g., medical records).

8.
Mol Cell Probes ; 45: 84-88, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30914295

RESUMO

When deciding on which genes to assess in larger Next-Generation Sequencing (NGS) datasets for the molecular genetic diagnosis of intellectual disability (ID), geneticists today have a variety of gene-phenotype databases and expert-curated gene lists available. To quantify their respective completeness, we compare an ID gene selection auto-generated from the Human Phenotype Ontology gene-phenotype association database and expert-curated ID gene lists from three reputable sources (sysID, the DDD consortium and Genomics England) and analyse some of their differences. We give examples of what we regard as genuine gaps ("missing ID genes") for each of these and conclude that a complementary or consensus approach is needed to maximise diagnostic yield in ID patients. We propose several consensus gene lists with ID-associated genes of different confidence levels.

9.
J Autism Dev Disord ; 2018 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-30343463

RESUMO

Truncating variants of the MAGEL2 gene, one of the protein-coding genes within the Prader-Willi syndrome (PWS) critical region on chromosome 15q11, cause Schaaf-Yang syndrome (SYS)-a neurodevelopmental disorder that shares several clinical features with PWS. The current study sought to characterize the neurobehavioral phenotype of SYS in a sample of 9 patients with molecularly-confirmed SYS. Participants received an assessment of developmental/intellectual functioning, adaptive functioning, autism symptomatology, and behavioral/emotional functioning. Compared to individuals with PWS, patients with SYS manifested more severe cognitive deficits, no obsessions or compulsions, and increased rates of autism spectrum disorder.

10.
Am J Med Genet A ; 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30302899

RESUMO

Schaaf-Yang Syndrome (SYS) is a genetic disorder caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13. SYS is a neurodevelopmental disorder that has clinical overlap with Prader-Willi Syndrome in the initial stages of life but becomes increasingly distinct throughout childhood and adolescence. Here, we describe the phenotype of an international cohort of 78 patients with nonsense or frameshift mutations in MAGEL2. This cohort includes 43 individuals that have been reported previously, as well as 35 newly identified individuals with confirmed pathogenic genetic variants. We emphasize that intellectual disability/developmental delay, autism spectrum disorder, neonatal hypotonia, infantile feeding problems, and distal joint contractures are the most consistently shared features of patients with SYS. Our results also indicate that there is a marked prevalence of infantile respiratory distress, gastroesophageal reflux, chronic constipation, skeletal abnormalities, sleep apnea, and temperature instability. While there are many shared features, patients with SYS are characterized by a wide phenotypic spectrum, including a variable degree of intellectual disability, language development, and motor milestones. Our results indicate that the variation in phenotypic severity may depend on the specific location of the truncating mutation, suggestive of a genotype-phenotype association. This evidence may be useful in both prenatal and pediatric genetic counseling.

11.
Genet Med ; 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-30158690

RESUMO

PURPOSE: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective. METHODS: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization. RESULTS: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS. CONCLUSION: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.

12.
J Affect Disord ; 239: 247-252, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30029151

RESUMO

OBJECTIVE: Neuronal nicotinic acetylcholine receptors (nAChRs), specifically the α7 nAChR encoded by the gene CHRNA7, have been implicated in behavior regulation in animal models. In humans, copy number variants (CNVs) of CHRNA7 are found in a range of neuropsychiatric disorders, including mood and anxiety disorders. Here, we aimed to determine the prevalence of CHRNA7 CNVs among adolescents and young adults with major depressive disorder (MDD) and anxiety disorders. METHODS: Twelve to 21 year-old participants with MDD and/or anxiety disorders (34% males, mean ±â€¯std age: 18.9 ±â€¯1.8 years) were assessed for CHRNA7 copy number state using droplet digital PCR (ddPCR) and genomic quantitative PCR (qPCR). Demographic, anthropometric, and clinical data, including the Beck Anxiety Index (BAI), Beck Depression Inventory (BDI), and the Inventory of Depressive Symptoms (IDS) were collected and compared across individuals with and without a CHRNA7 CNV. RESULTS: Of 205 individuals, five (2.4%) were found to carry a CHRNA7 gain, significantly higher than the general population. No CHRNA7 deletions were identified. Clinically, the individuals carrying CHRNA7 duplications did not differ significantly from copy neutral individuals with MDD and/or anxiety disorders. CONCLUSIONS: CHRNA7 gains are relatively prevalent among young individuals with MDD and anxiety disorders (odds ratio = 4.032) without apparent distinguishing clinical features. Future studies should examine the therapeutic potential of α7 nAChR targeting drugs to ameliorate depressive and anxiety disorders.

13.
Am J Hum Genet ; 103(1): 154-162, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29961569

RESUMO

TRAF7 is a multi-functional protein involved in diverse signaling pathways and cellular processes. The phenotypic consequence of germline TRAF7 variants remains unclear. Here we report missense variants in TRAF7 in seven unrelated individuals referred for clinical exome sequencing. The seven individuals share substantial phenotypic overlap, with developmental delay, congenital heart defects, limb and digital anomalies, and dysmorphic features emerging as key unifying features. The identified variants are de novo in six individuals and comprise four distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant that is recurrent in four individuals. These variants affect evolutionarily conserved amino acids and are located in key functional domains. Gene-specific mutation rate analysis showed that the occurrence of the de novo variants in TRAF7 (p = 2.6 × 10-3) and the recurrent de novo c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10-8) in our exome cohort was unlikely to have occurred by chance. In vitro analyses of the observed TRAF7 mutations showed reduced ERK1/2 phosphorylation. Our findings suggest that missense mutations in TRAF7 are associated with a multisystem disorder and provide evidence of a role for TRAF7 in human development.

14.
J Hum Genet ; 63(7): 795-801, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29691480

RESUMO

Multiple genomic disorders result from recurrent deletions or duplications between low copy repeat (LCR) clusters, mediated by nonallelic homologous recombination. These copy number variants (CNVs) often exhibit variable expressivity and/or incomplete penetrance. However, the population prevalence of many genomic disorders has not been estimated accurately. A subset of genomic disorders similarly characterized by CNVs between LCRs have been studied epidemiologically, including Williams-Beuren syndrome (7q11.23), Smith-Magenis syndrome (17p11.2), velocardiofacial syndrome (22q11.21), Prader-Willi/Angelman syndromes (15q11.2q12), 17q12 deletion syndrome, and Charcot-Marie-Tooth neuropathy type 1/hereditary neuropathy with liability to pressure palsy (PMP22, 17q11.2). We have generated a method to estimate prevalence of highly penetrant genomic disorders by (1) leveraging epidemiological data for genomic disorders with previously reported prevalence estimates, (2) obtaining chromosomal microarray data on genomic disorders from a large medical genetics clinic; and (3) utilizing these in a linear regression model to determine the prevalence of this syndromic copy number change among the general population. Using our algorithm, the prevalence for five clinically relevant recurrent genomic disorders: 1q21.1 microdeletion (1/6882 live births) and microduplication syndromes (1/6309), 15q13.3 microdeletion syndrome (1/5525), and 16p11.2 microdeletion (1/3021) and microduplication syndromes (1/4216), were determined. These findings will inform epidemiological strategies for evaluating those conditions, and our method may be useful to evaluate the prevalence of other highly penetrant genomic disorders.


Assuntos
Doença de Charcot-Marie-Tooth/epidemiologia , Síndrome de DiGeorge/epidemiologia , Genoma Humano , Modelos Genéticos , Síndrome de Prader-Willi/epidemiologia , Síndrome de Smith-Magenis/epidemiologia , Síndrome de Williams/epidemiologia , Doença de Charcot-Marie-Tooth/genética , Doença de Charcot-Marie-Tooth/patologia , Deleção Cromossômica , Duplicação Cromossômica , Mapeamento Cromossômico , Variações do Número de Cópias de DNA , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/patologia , Humanos , Análise em Microsséries , Epidemiologia Molecular , Penetrância , Síndrome de Prader-Willi/genética , Síndrome de Prader-Willi/patologia , Prevalência , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/patologia , Síndrome de Williams/genética , Síndrome de Williams/patologia
15.
Eur J Med Genet ; 61(10): 627-630, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29660409

RESUMO

We report a novel patient with the phenotypic characteristics of Schaaf-Yang syndrome. In addition, the patient has a severe chronic digestive malfunction, rendering him dependent on intermittent enteral supplementation. To our knowledge, this is the first report of Schaaf-Yang syndrome associated with severe chronic digestive malfunction manifesting with both a malrotation and signs of a chronic intestinal pseudo-obstruction.

16.
J Med Genet ; 55(5): 307-315, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29496979

RESUMO

BACKGROUND: Nonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties and autism spectrum disorder. Prader-Willi syndrome (PWS) is a genetic disorder characterised by severe infantile hypotonia, hypogonadotrophic hypogonadism, early childhood onset obesity/hyperphagia, developmental delay/intellectual disability and short stature. Scoliosis and growth hormone insufficiency are also prevalent in PWS.There is extensive documentation of the endocrine and metabolic phenotypes for PWS, but not for SYS. This study served to investigate the hormonal, metabolic and body composition phenotype of SYS and its potential overlap with PWS. METHODS: In nine individuals with SYS (5 female/4 male; aged 5-17 years), we measured serum ghrelin, glucose, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3, follicle-stimulating hormone, luteinising hormone, thyroid-stimulating hormone, free T4, uric acid and testosterone, and performed a comprehensive lipid panel. Patients also underwent X-ray and dual-energy X-ray absorptiometry analyses to assess for scoliosis and bone mineral density. RESULTS: Low IGF-1 levels despite normal weight/adequate nutrition were observed in six patients, suggesting growth hormone deficiency similar to PWS. Fasting ghrelin levels were elevated, as seen in individuals with PWS. X-rays revealed scoliosis >10° in three patients, and abnormal bone mineral density in six patients, indicated by Z-scores of below -2 SDs. CONCLUSION: This is the first analysis of the hormonal, metabolic and body composition phenotype of SYS. Our findings suggest that there is marked, but not complete overlap between PWS and SYS.

17.
J Hum Genet ; 63(4): 525-528, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29410510

RESUMO

We report the clinical and biochemical findings from a patient who presented with Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), an autosomal-dominant disorder characterized by optic atrophy, developmental delay and intellectual disability. In addition, the patient also displays hypotonia, stroke-like episodes, and complex IV deficiency of the mitochondrial respiratory chain. Whole-exome sequencing (WES) uncovered a novel heterozygous mutation in the NR2F1 gene (NM_005654:c.286A>G:p.Lys96Glu) that encodes for the COUP transcription factor 1 protein (COUP-TF1). Loss-of-function mutations in this protein have been associated with BBSOAS, and a luciferase reporter assay showed that this variant, in the zinc-finger DNA-binding domain (DBD) of COUP-TF1 protein, impairs its transcriptional activity. The additional features of this patient are more related with mitochondrial diseases that with BBSOAS, indicating a mitochondrial involvement. Finally, our data expand both the genetic and phenotypic spectrum associated with NR2F1 gene mutations.


Assuntos
Fator I de Transcrição COUP/genética , Mitocôndrias/genética , Mutação , Atrofia Óptica/diagnóstico , Atrofia Óptica/genética , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Biomarcadores , Respiração Celular , Eletroencefalografia , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Imagem por Ressonância Magnética , Mitocôndrias/metabolismo , Linhagem , Fenótipo , Síndrome , Sequenciamento Completo do Exoma
18.
Am J Hum Genet ; 102(2): 296-308, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29395075

RESUMO

15q13.3 microdeletion syndrome is characterized by a wide spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, epilepsy, language impairment, abnormal behaviors, neuropsychiatric disorders, and hypotonia. This syndrome is caused by a deletion on chromosome 15q, which typically encompasses six genes. Here, through studies on OTU deubiquitinase 7A (Otud7a) knockout mice, we identify OTUD7A as a critical gene responsible for many of the cardinal phenotypes associated with 15q13.3 microdeletion syndrome. Otud7a-null mice show reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalizations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle. We show that OTUD7A localizes to dendritic spines and that Otud7a-null mice have decreased dendritic spine density compared to their wild-type littermates. Furthermore, frequency of miniature excitatory postsynaptic currents (mEPSCs) is reduced in the frontal cortex of Otud7a-null mice, suggesting a role of Otud7a in regulation of dendritic spine density and glutamatergic synaptic transmission. Taken together, our results suggest decreased OTUD7A dosage as a major contributor to the neurodevelopmental phenotypes associated with 15q13.3 microdeletion syndrome, through the misregulation of dendritic spine density and activity.

19.
Cell ; 172(5): 924-936.e11, 2018 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-29474920

RESUMO

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.

20.
J Hum Genet ; 63(3): 349-356, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29279609

RESUMO

Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental syndrome for which mutations in five causative genes that encode (SMC1A, SMC3, RAD21) or regulate (NIPBL, HDAC8) the cohesin complex, account for ~70% of cases. Herein we report on four female Subjects who were found to carry novel intragenic deletions in HDAC8. In one case, the deletion was found in mosaic state and it was determined to be present in ~38% of blood lymphocytes and in nearly all cells of a buccal sample. All deletions, for which parental blood samples were available, were shown to have arisen de novo. X-chromosome inactivation studies demonstrated marked skewing, suggesting strong selection against the mutated HDAC8 allele. Based on an investigation of the deletion breakpoints, we hypothesize that microhomology-mediated replicative mechanisms may be implicated in the formation of some of these rearrangements. This study broadens the mutational spectrum of HDAC8, provides the first description of a causative HDAC8 somatic mutation and increases the knowledge on possible mutational mechanisms underlying copy number variations in HDAC8. Moreover our findings highlight the clinical utility of considering copy number analysis in HDAC8 as well as the analysis on DNA from more than one tissue as an indispensable part of the routine molecular diagnosis of individuals with CdLS or CdLS-overlapping features.


Assuntos
Síndrome de Lange/diagnóstico , Síndrome de Lange/genética , Estudos de Associação Genética , Histona Desacetilases/genética , Fenótipo , Proteínas Repressoras/genética , Deleção de Sequência , Sequência de Bases , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Éxons , Facies , Feminino , Duplicação Gênica , Humanos , Análise de Sequência de DNA , Inativação do Cromossomo X
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