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1.
J Genet Couns ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553105

RESUMO

As exome sequencing expands as a diagnostic tool, patients and providers have voiced concerns about communicating the breadth and scope of potential results when obtaining informed consent. This study aimed to understand how genetic counselors prioritize essential components of the informed consent process and whether counselor factors influence these decisions. Development of a best-worst scaling experiment was informed by a systematic literature review and two focus groups. In all, 11 choice sets were created using a balanced incomplete block design, where participants selected the most and least important object in each set. Mean best-worst (BW) scores were calculated to summarize the relative importance of each object, and mediation analyses assessed whether responses were associated with genetic counselor factors and attitudes. In all, 342 members of the National Society of Genetic Counselors completed the online survey. Ranking of BW scores suggests that participants prioritize collaborative decision-making, assessing understanding and managing expectations, with the least emphasis placed on discussing technological complexities. Stratified analyses found that counselors more experienced with obtaining informed consent for exome sequencing and those reporting higher perceptions of patients' ability to manage information rated discussing variants of uncertain significance as significantly more important (p < .05). Our results suggest that genetic counselors report intentions to prioritize individual patient needs when obtaining informed consent for exome sequencing. Professional characteristics and attitudes may influence preemptive discussion of uncertain results.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31501260

RESUMO

Neurodevelopmental disorders (NDDs), including global developmental delay (GDD), intellectual disability (ID), and autism spectrum disorder (ASD), represent a continuum of developmental brain dysfunction. Although the etiology of NDD is heterogeneous, genetic variation represents the largest contribution, strongly supporting the recommendation for genetic evaluation in individuals with GDD/ID and ASD. Technological advances now allow for a specific genetic diagnosis to be identified in a substantial portion of affected individuals. This information has important ramifications for treatment, prognosis, and recurrence risk, as well as psychological and social benefits for the family. Genetic counseling is a vital service to enable patients and their families to understand and adapt to the genetic contribution to NDDs. As the demand for genetic evaluation for NDDs increases, genetic counselors will have a predominant role in the ongoing evaluation of NDDs, especially as identification of genetic etiologies has the potential to lead to targeted treatments for NDDs in the future.

4.
Am J Hum Genet ; 105(2): 413-424, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31327508

RESUMO

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

6.
Hum Mutat ; 40(7): 908-925, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30817854

RESUMO

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

7.
Am J Hum Genet ; 104(3): 530-541, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30827496

RESUMO

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.

8.
J Clin Invest ; 129(3): 1240-1256, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620337

RESUMO

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.

9.
SAGE Open Med Case Rep ; 6: 2050313X18807622, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30377530

RESUMO

Pathogenic variants in EEF1A2, a gene encoding a eukaryotic translation elongation factor, have been previously reported in pediatric cases of epileptic encephalopathy and intellectual disability. We report a case of a 17-year-old male with a prior history of epilepsy, autism, intellectual disability, and the abrupt onset of choreo-athetotic movements. The patient was diagnosed with an EEF1A2 variant by whole exome sequencing. His movement disorder responded dramatically to treatment with tetrabenazine. To the best of our knowledge, this is the first report of successful treatment of a hyperkinetic movement disorder in the setting of EEF1A2 mutation. A trial with tetrabenazine should be considered in cases with significant choreoathetosis.

10.
Artigo em Inglês | MEDLINE | ID: mdl-30318729

RESUMO

BACKGROUND: Clinical diagnostic whole-exome sequencing (WES) is a powerful tool for patients with undiagnosed genetic disorders. To demonstrate the clinical utility, we surveyed healthcare providers (HCP) about changes in medical management and treatment, diagnostic testing, reproductive planning, and use of educational services subsequent to WES testing. METHODS: For a period of 18 months, an 18-question survey was sent to HCPs attached to the WES reports. We analyzed the molecular diagnosis, patient clinical features, and the medical management changes reported in the returned surveys. RESULTS: A total of 62 (2.2% of 2,876) surveys were returned, consisting of 37.1% patients with a positive or likely positive pathogenic alteration, 51.6% negative results, 9.7% uncertain findings, and 1 patient (1.6%) with a novel candidate finding. Overall, 100% of the HCPs of patients with positive or likely positive WES results (n = 23) and HCPs of patients with uncertain WES results (n = 6) responded positively to one of the 18 queries. Of note, 37.5% of the HCPs of patients with negative WES results (n = 32) responded positively to at least one query. CONCLUSION: Overall, these data clearly demonstrate the clinical utility of WES by demonstrating the impact on medical management irrespective of the exome result.

11.
J Child Neurol ; 33(13): 825-831, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30185102

RESUMO

GM3 synthase deficiency is due to biallelic pathogenic variants in ST3GAL5, which encodes a sialyltransferase that synthesizes ganglioside GM3. Key features of this rare autosomal recessive condition include profound intellectual disability, failure to thrive and infantile onset epilepsy. We expand the phenotypic spectrum with 3 siblings who were found by whole exome sequencing to have a homozygous pathogenic variant in ST3GAL5, and we compare these cases to those previously described in the literature. The siblings had normal birth history, subsequent developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment. Ichthyosis and self-injurious behavior are newly described in our patients and may influence clinical management. We conclude that GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. Other phenotypic features have variable expressivity, including failure to thrive, epilepsy, regression, vision impairment, and skin findings. Our analysis demonstrates a broader phenotypic range of this potentially under-recognized disorder.

12.
Brain Sci ; 8(8)2018 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087272

RESUMO

The TUBA1A gene encodes tubulin alpha-1A, a protein that is highly expressed in the fetal brain. Alpha- and beta-tubulin subunits form dimers, which then co-assemble into microtubule polymers: dynamic, scaffold-like structures that perform key functions during neurogenesis, neuronal migration, and cortical organisation. Mutations in TUBA1A have been reported to cause a range of brain malformations. We describe four unrelated patients with the same de novo missense mutation in TUBA1A, c.5G>A, p.(Arg2His), as found by next generation sequencing. Detailed comparison revealed similar brain phenotypes with mild variability. Shared features included developmental delay, microcephaly, hypoplasia of the cerebellar vermis, dysplasia or thinning of the corpus callosum, small pons, and dysmorphic basal ganglia. Two of the patients had bilateral perisylvian polymicrogyria. We examined the effects of the p.(Arg2His) mutation by computer-based protein structure modelling and heterologous expression in HEK-293 cells. The results suggest the mutation subtly impairs microtubule function, potentially by affecting inter-dimer interaction. Based on its sequence context, c.5G>A is likely to be a common recurrent mutation. We propose that the subtle functional effects of p.(Arg2His) may allow for other factors (such as genetic background or environmental conditions) to influence phenotypic outcome, thus explaining the mild variability in clinical manifestations.

13.
Am J Med Genet A ; 2018 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-30151950

RESUMO

KIF26B is a member of the kinesin superfamily with evolutionarily conserved functions in controlling aspects of embryogenesis, including the development of the nervous system, though its function is incompletely understood. We describe an infant with progressive microcephaly, pontocerebellar hypoplasia, and arthrogryposis secondary to the involvement of anterior horn cells and ventral (motor) nerves. We performed whole exome sequencing on the trio and identified a de novo KIF26B missense variant, p.Gly546Ser, in the proband. This variant alters a highly conserved amino acid residue that is part of the phosphate-binding loop motif and motor-like domain and is deemed pathogenic by several in silico methods. Functional analysis of the variant protein in cultured cells revealed a reduction in the KIF26B protein's ability to promote cell adhesion, a defect that potentially contributes to its pathogenicity. Overall, KIF26B may play a critical role in the brain development and, when mutated, cause pontocerebellar hypoplasia with arthrogryposis.

14.
J Clin Neuromuscul Dis ; 19(3): 117-123, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29465611

RESUMO

We report the cases of 2 patients who presented to our Myositis Center with myalgias and elevated creatine kinase levels. Muscle biopsy showed pathological features consistent with mitochondrial myopathy. In both cases, a single large deletion in mitochondrial DNA at low-level heteroplasmy was identified by next-generation sequencing in muscle tissue. In 1 case, the deletion was identified in muscle tissue but not blood. In both cases, the deletion was only identified on next-generation sequencing of muscle mitochondrial DNA and missed on array comparative genome hybridization testing. These cases demonstrate that next-generation sequencing of mitochondrial DNA in muscle tissue is the most sensitive method of molecular diagnosis for mitochondrial myopathy due to mitochondrial DNA deletions.


Assuntos
DNA Mitocondrial/genética , Miopatias Mitocondriais/genética , Deleção de Sequência/genética , Idoso , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/diagnóstico por imagem , Músculo Esquelético/diagnóstico por imagem
15.
Am J Med Genet A ; 176(4): 925-935, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29436146

RESUMO

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

16.
Genet Med ; 20(1): 98-108, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28661489

RESUMO

PurposeThe study aimed at widening the clinical and genetic spectrum and assessing genotype-phenotype associations in FOXG1 syndrome due to FOXG1 variants.MethodsWe compiled 30 new and 53 reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1. We grouped patients according to type and location of the variant. Statistical analysis of molecular and clinical data was performed using Fisher's exact test and a nonparametric multivariate test.ResultsAmong the 30 new patients, we identified 19 novel FOXG1 variants. Among the total group of 83 patients, there were 54 variants: 20 frameshift (37%), 17 missense (31%), 15 nonsense (28%), and 2 in-frame variants (4%). Frameshift and nonsense variants are distributed over all FOXG1 protein domains; missense variants cluster within the conserved forkhead domain. We found a higher phenotypic variability than previously described. Genotype-phenotype association revealed significant differences in psychomotor development and neurological features between FOXG1 genotype groups. More severe phenotypes were associated with truncating FOXG1 variants in the N-terminal domain and the forkhead domain (except conserved site 1) and milder phenotypes with missense variants in the forkhead conserved site 1.ConclusionsThese data may serve for improved interpretation of new FOXG1 sequence variants and well-founded genetic counseling.


Assuntos
Fatores de Transcrição Forkhead/genética , Estudos de Associação Genética , Variação Genética , Proteínas do Tecido Nervoso/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único
17.
Am J Hum Genet ; 101(6): 1013-1020, 2017 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-29220673

RESUMO

Using trio whole-exome sequencing, we have identified de novo heterozygous pathogenic variants in GRIA4 in five unrelated individuals with intellectual disability and other symptoms. GRIA4 encodes an AMPA receptor subunit known as GluR4, which is found on excitatory glutamatergic synapses and is important for learning and memory. Four of the variants are located in the highly conserved SYTANLAAF motif in the transmembrane protein M3, and the fifth is in an extra-cellular domain. Molecular modeling of the altered protein showed that three of the variants in the SYTANLAAF motif orient toward the center of the pore region and most likely lead to disturbance of the gating mechanism. The fourth variant in the SYTANLAAF motif most likely results in reduced permeability. The variant in the extracellular domain potentially interferes with the binding between the monomers. On the basis of clinical information and genetic results, and the fact that other subunits of the AMPA receptor have already been associated with neurodevelopmental disorders, we suggest that pathogenic de novo variants in GRIA4 lead to intellectual disability with or without seizures, gait abnormalities, problems of social behavior, and other variable features.


Assuntos
Transtornos Neurológicos da Marcha/genética , Deficiência Intelectual/genética , Transtornos dos Movimentos/genética , Receptores de AMPA/genética , Convulsões/genética , Adolescente , Adulto , Pré-Escolar , Feminino , Humanos , Masculino , Modelos Moleculares , Comportamento Problema , Comportamento Social , Sequenciamento Completo do Exoma , Adulto Jovem
18.
Neurology ; 89(4): 385-394, 2017 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-28667181

RESUMO

OBJECTIVE: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. METHODS: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. RESULTS: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. CONCLUSIONS: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.


Assuntos
Encefalopatias/genética , Encefalopatias/metabolismo , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Mutação , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Proteínas de Homeodomínio , Humanos , Lactente , Masculino , Modelos Moleculares , Fenótipo , Proteína de Homoeobox de Baixa Estatura , Irmãos , Vesículas Sinápticas/metabolismo , Adulto Jovem
19.
Am J Med Genet A ; 173(9): 2505-2510, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28650581

RESUMO

Pathogenic variants in the mitochondrial aminoacyl tRNA synthetases lead to deficiencies in mitochondrial protein synthesis and are associated with a broad range of clinical presentations usually with early onset and inherited in an autosomal recessive manner. Of the 19 mitochondrial aminoacyl tRNA synthetases, WARS2, encoding mitochondrial tryptophanyl tRNA synthetase, was as of late the only one that had not been associated with disease in humans. A case of a family with pathogenic variants in WARS2 that caused mainly intellectual disability, speech impairment, aggressiveness, and athetosis was recently reported. Here we substantially extend and consolidate the symptomatology of WARS2 by presenting a patient with severe infantile-onset leukoencephalopathy, profound intellectual disability, spastic quadriplegia, epilepsy, microcephaly, short stature, failure to thrive, cerebral atrophy, and periventricular white matter abnormalities. He was found by whole-exome sequencing to have compound heterozygous variants in WARS2, c.938A>T (p.K313M) and c.298_300delCTT (p.L100del). De novo synthesis of proteins inside mitochondria was reduced in the patient's fibroblasts, leading to significantly lower steady-state levels of respiratory chain subunits compared to control and resulting in lower oxygen consumption rates.


Assuntos
Deficiência Intelectual/genética , Leucoencefalopatias/genética , Quadriplegia/genética , Triptofano-tRNA Ligase/genética , Idade de Início , Sequência de Aminoácidos/genética , Humanos , Lactente , Deficiência Intelectual/fisiopatologia , Leucoencefalopatias/fisiopatologia , Masculino , Microcefalia , Mitocôndrias/genética , Mutação , Quadriplegia/fisiopatologia , Patologia da Fala e Linguagem , Adulto Jovem
20.
PLoS Genet ; 13(3): e1006683, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28346496

RESUMO

Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Anormalidades Craniofaciais/genética , Predisposição Genética para Doença/genética , Deformidades Congênitas da Mão/genética , Neoplasias Hematológicas/genética , Deficiência Intelectual/genética , Mutação , Unhas Malformadas/genética , Proteínas Nucleares/genética , Anormalidades Múltiplas/metabolismo , Anormalidades Múltiplas/patologia , Western Blotting , Proteínas de Transporte/metabolismo , Linhagem Celular , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Criança , Pré-Escolar , Anormalidades Craniofaciais/metabolismo , Anormalidades Craniofaciais/patologia , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Mutação em Linhagem Germinativa , Células HEK293 , Deformidades Congênitas da Mão/metabolismo , Deformidades Congênitas da Mão/patologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patologia , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Masculino , Unhas Malformadas/metabolismo , Unhas Malformadas/patologia , Proteínas Nucleares/metabolismo , Fenótipo
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