Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 90
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Mol Genet Genomic Med ; 7(10): e00861, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31414730

RESUMO

BACKGROUND: Eight different deletions and point variants of the X-chromosomal gene CNKSR2 have been reported in families with males presenting intellectual disability (ID) and epilepsy. Obligate carrier females with a frameshift variant in the N-terminal protein coding part of CNKSR2 or with a deletion of the complete gene are not affected. Only for one C-terminal nonsense variant, two carrier females were mildly affected by seizures without or with mild motor and language delay. METHODS: Exome sequencing was performed in one female child of a Dutch family, presenting seizures, mild ID, facial dysmorphisms, and abnormalities of the extremities. Potential causative variants were validated by Sanger sequencing. X-chromosome-inactivation (XCI) analysis was performed by methylation-sensitive PCR and fragment-length analysis of the androgen-receptor CAG repeat polymorphism. RESULTS: We identified a de novo variant, c.2304G>A (p.(Trp768*)), in the C-terminal protein coding part of the X-chromosomal gene CNKSR2 in a female patient with seizures and mild ID. Sanger sequencing confirmed the presence of this nonsense variant. XCI analysis showed a mild skewing of X inactivation (20:80) in the blood of our patient. Our variant is the second C-terminal-affecting CNKSR2 variant described in neurologically affected females. CONCLUSION: Our results indicate that CNKSR2 nonsense variants in the C-terminal coding part can result in ID with seizures in female variant carriers.

3.
Am J Hum Genet ; 104(5): 914-924, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982611

RESUMO

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506∗ and p.Glu496∗ were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

4.
Genet Med ; 21(9): 2059-2069, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30923367

RESUMO

PURPOSE: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro. METHODS: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs. RESULTS: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001). CONCLUSION: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.

5.
Eur J Hum Genet ; 27(8): 1235-1243, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30914828

RESUMO

Intellectual disability (ID), megalencephaly, frontal predominant pachygyria, and seizures, previously called "thin" lissencephaly, are reported to be caused by recessive variants in CRADD. Among five families of different ethnicities identified, one homozygous missense variant, c.509G>A p.(Arg170His), was of Finnish ancestry. Here we report on the phenotypic variability associated for this potential CRADD founder variant in 22 Finnish individuals. Exome sequencing was used to identify candidate genes in Finnish patients presenting with ID. Targeted Sanger sequencing and restriction enzyme analysis were applied to screen for the c.509G>A CRADD variant in cohorts from Finland. Detailed phenotyping and genealogical studies were performed. Twenty two patients were identified with the c.509G>A p.(Arg170His) homozygous variant in CRADD. The majority of the ancestors originated from Northeastern Finland indicating a founder effect. The hallmark of the disease is frontotemporal predominant pachygyria with mild cortical thickening. All patients show ID of variable severity. Aggressive behavior was found in nearly half of the patients, EEG abnormalities in five patients and megalencephaly in three patients. This study provides detailed data about the phenotypic spectrum of patients with lissencephaly due to a CRADD variant that affects function. High inter- and intrafamilial phenotypic heterogeneity was identified in patients with pachygyria caused by the homozygous CRADD founder variant. The phenotype variability suggests that additional genetic and/or environmental factors play a role in the clinical presentation. Since frontotemporal pachygyria is the hallmark of the disease, brain imaging studies are essential to support the molecular diagnosis for individuals with ID and a CRADD variant.

6.
Am J Hum Genet ; 103(6): 1045-1052, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30526862

RESUMO

We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs∗20), c.1348C>T (p.Arg450∗), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.


Assuntos
Agressão/fisiologia , Nanismo/genética , Variação Genética/genética , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/genética , Microcefalia/genética , Adolescente , Animais , Criança , Drosophila melanogaster/genética , Éxons/genética , Feminino , Técnicas de Inativação de Genes/métodos , Homozigoto , Humanos , Masculino , Linhagem , Fenótipo , RNA Mensageiro/genética , RNA de Transferência/genética
7.
Genet Med ; 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30287925

RESUMO

PURPOSE: To characterize new molecular factors implicated in a hereditary congenital facial paresis (HCFP) family and otosclerosis. METHODS: We performed exome sequencing in a four-generation family presenting nonprogressive HCFP and mixed hearing loss (HL). MEPE was analyzed using either Sanger sequencing or molecular inversion probes combined with massive parallel sequencing in 89 otosclerosis families, 1604 unrelated affected subjects, and 1538 unscreened controls. RESULTS: Exome sequencing in the HCFP family led to the identification of a rare segregating heterozygous frameshift variant p.(Gln425Lysfs*38) in MEPE. As the HL phenotype in this family resembled otosclerosis, we performed variant burden and variance components analyses in a large otosclerosis cohort and demonstrated that nonsense and frameshift MEPE variants were significantly enriched in affected subjects (p = 0.0006-0.0060). CONCLUSION: MEPE exerts its function in bone homeostasis by two domains, an RGD and an acidic serine aspartate-rich MEPE-associated (ASARM) motif inhibiting respectively bone resorption and mineralization. All variants associated with otosclerosis are predicted to result in nonsense mediated decay or an ASARM-and-RGD-truncated MEPE. The HCFP variant is predicted to produce an ASARM-truncated MEPE with an intact RGD motif. This difference in effect on the protein corresponds with the presumed pathophysiology of both diseases, and provides a plausible molecular explanation for the distinct phenotypic outcome.

8.
Neurol Genet ; 4(4): e262, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30109272

RESUMO

Objective: To address the relationship between mutations in the DNA strand break repair protein tyrosyl DNA phosphodiesterase 2 (TDP2) and spinocerebellar ataxia autosomal recessive 23 (SCAR23) and to characterize the cellular phenotype of primary fibroblasts from this disease. Methods: We have used exome sequencing, Sanger sequencing, gene editing and cell biology, biochemistry, and subcellular mitochondrial analyses for this study. Results: We have identified a patient in the United States with SCAR23 harboring the same homozygous TDP2 mutation as previously reported in 3 Irish siblings (c.425+1G>A). The current and Irish patients share the same disease haplotype, but the current patient lacks a homozygous variant present in the Irish siblings in the closely linked gene ZNF193, eliminating this as a contributor to the disease. The current patient also displays symptoms consistent with mitochondrial dysfunction, although levels of mitochondrial function in patient primary skin fibroblasts are normal. However, we demonstrate an inability in patient primary fibroblasts to rapidly repair topoisomerase-induced DNA double-strand breaks (DSBs) in the nucleus and profound hypersensitivity to this type of DNA damage. Conclusions: These data confirm the TDP2 mutation as causative for SCAR23 and highlight the link between defects in nuclear DNA DSB repair, developmental delay, epilepsy, and ataxia.

9.
Am J Hum Genet ; 102(4): 685-695, 2018 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-29576219

RESUMO

Biogenesis of the mitochondrial oxidative phosphorylation system, which produces the bulk of ATP for almost all eukaryotic cells, depends on the translation of 13 mtDNA-encoded polypeptides by mitochondria-specific ribosomes in the mitochondrial matrix. These mitoribosomes are dual-origin ribonucleoprotein complexes, which contain mtDNA-encoded rRNAs and tRNAs and ∼80 nucleus-encoded proteins. An increasing number of gene mutations that impair mitoribosomal function and result in multiple OXPHOS deficiencies are being linked to human mitochondrial diseases. Using exome sequencing in two unrelated subjects presenting with sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency, we identified mutations in the gene encoding the mitochondrial ribosomal protein S2, which has not previously been implicated in disease. Characterization of subjects' fibroblasts revealed a decrease in the steady-state amounts of mutant MRPS2, and this decrease was shown by complexome profiling to prevent the assembly of the small mitoribosomal subunit. In turn, mitochondrial translation was inhibited, resulting in a combined OXPHOS deficiency detectable in subjects' muscle and liver biopsies as well as in cultured skin fibroblasts. Reintroduction of wild-type MRPS2 restored mitochondrial translation and OXPHOS assembly. The combination of lactic acidemia, hypoglycemia, and sensorineural hearing loss, especially in the presence of a combined OXPHOS deficiency, should raise suspicion for a ribosomal-subunit-related mitochondrial defect, and clinical recognition could allow for a targeted diagnostic approach. The identification of MRPS2 as an additional gene related to mitochondrial disease further expands the genetic and phenotypic spectra of OXPHOS deficiencies caused by impaired mitochondrial translation.

10.
Circ Res ; 122(6): 846-854, 2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29343526

RESUMO

RATIONALE: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. OBJECTIVE: We describe 2 families, with 4 patients in total, experiencing severe life-threatening orthostatic hypotension because of a novel cause. METHODS AND RESULTS: As in dopamine ß-hydroxylase deficiency, concentrations of norepinephrine and epinephrine in the patients were low. Plasma dopamine ß-hydroxylase activity, however, was normal, and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause. Homozygosity mapping and exome and Sanger sequencing revealed pathogenic homozygous mutations in the gene encoding cytochrome b561 (CYB561); a missense variant c.262G>A, p.Gly88Arg in exon 3 in the Dutch family and a nonsense mutation (c.131G>A, p.Trp44*) in exon 2 in the American family. Expression of CYB561 was investigated using RNA from different human adult and fetal tissues, transcription of RNA into cDNA, and real-time quantitative polymerase chain reaction. The CYB561 gene was found to be expressed in many human tissues, in particular the brain. The CYB561 protein defect leads to a shortage of ascorbate inside the catecholamine secretory vesicles leading to a functional dopamine ß-hydroxylase deficiency. The concentration of the catecholamines and downstream metabolites was measured in brain and adrenal tissue of 6 CYB561 knockout mice (reporter-tagged deletion allele [post-Cre], genetic background C57BL/6NTac). The concentration of norepinephrine and normetanephrine was decreased in whole-brain homogenates of the CYB561(-/-) mice compared with wild-type mice (P<0.01), and the concentration of normetanephrine and metanephrine was decreased in adrenal glands (P<0.01), recapitulating the clinical phenotype. The patients responded favorably to treatment with l-dihydroxyphenylserine, which can be converted directly to norepinephrine. CONCLUSIONS: This study is the first to implicate cytochrome b561 in disease by showing that pathogenic mutations in CYB561 cause an as yet unknown disease in neurotransmitter metabolism causing orthostatic hypotension.

11.
Nat Genet ; 50(1): 120-129, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29255262

RESUMO

Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to H2O2, formaldehyde, and H2S, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a malodor syndrome.

12.
Genet Med ; 20(7): 778-784, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-28837161

RESUMO

PURPOSE: To elucidate the novel molecular cause in two unrelated consanguineous families with autosomal recessive intellectual disability. METHODS: A combination of homozygosity mapping and exome sequencing was used to locate the plausible genetic defect in family F162, while only exome sequencing was followed in the family PKMR65. The protein 3D structure was visualized with the University of California-San Francisco Chimera software. RESULTS: All five patients from both families presented with severe intellectual disability, aggressive behavior, and speech and motor delay. Four of the five patients had microcephaly. We identified homozygous missense variants in LINGO1, p.(Arg290His) in family F162 and p.(Tyr288Cys) in family PKMR65. Both variants were predicted to be pathogenic, and segregated with the phenotype in the respective families. Molecular modeling of LINGO1 suggests that both variants interfere with the glycosylation of the protein. CONCLUSION: LINGO1 is a transmembrane receptor, predominantly found in the central nervous system. Published loss-of-function studies in mouse and zebrafish have established a crucial role of LINGO1 in normal neuronal development and central nervous system myelination by negatively regulating oligodendrocyte differentiation and neuronal survival. Taken together, our results indicate that biallelic LINGO1 missense variants cause autosomal recessive intellectual disability in humans.

13.
Genome Med ; 9(1): 118, 2017 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-29273094

RESUMO

BACKGROUND: The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients. METHODS: Using linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2. RESULTS: The first family comprises two brothers of Dutch non-consanguineous parents presenting with mild ID and behavioral problems. Immunohistochemical analysis of muscle biopsy revealed no significant aberrations, in line with the absence of a muscular phenotype in the affected siblings. The second family includes five affected individuals from an Iranian consanguineous kindred with mild-to-moderate intellectual disability (ID) and epilepsy without any notable neuroimaging, muscle, or eye abnormalities. Complementation assays of the compound heterozygous mutations identified in the two brothers had a comparable effect on the O-glycosylation of α-dystroglycan as previously reported mutations that are associated with severe muscular phenotypes. CONCLUSIONS: In conclusion, we show that mutations in B3GALNT2 can give rise to a novel MDDG syndrome presentation, characterized by ID associated variably with seizure, but without any apparent muscular involvement. Importantly, B3GALNT2 activity does not fully correlate with the severity of the phenotype as assessed by the complementation assay.


Assuntos
Deficiência Intelectual/genética , Mutação , N-Acetilgalactosaminiltransferases/genética , Fenótipo , Síndrome de Walker-Warburg/genética , Adolescente , Adulto , Linhagem Celular , Criança , Feminino , Genes Recessivos , Genótipo , Humanos , Deficiência Intelectual/patologia , Masculino , N-Acetilgalactosaminiltransferases/metabolismo , Linhagem , Síndrome de Walker-Warburg/patologia
14.
Am J Hum Genet ; 101(3): 428-440, 2017 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-28823707

RESUMO

Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare recessive disorders with prenatal onset, characterized by hypoplasia of pons and cerebellum. Mutations in a small number of genes have been reported to cause PCH, and the vast majority of PCH cases are explained by mutations in TSEN54, which encodes a subunit of the tRNA splicing endonuclease complex. Here we report three families with homozygous truncating mutations in TBC1D23 who display moderate to severe intellectual disability and microcephaly. MRI data from available affected subjects revealed PCH, small normally proportioned cerebellum, and corpus callosum anomalies. Furthermore, through in utero electroporation, we show that downregulation of TBC1D23 affects cortical neuron positioning. TBC1D23 is a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RAB-specific GTPase-activating proteins (TBC/RABGAPs). Members of this protein family negatively regulate RAB proteins and modulate the signaling between RABs and other small GTPases, some of which have a crucial role in the trafficking of intracellular vesicles and are involved in neurological disorders. Here, we demonstrate that dense core vesicles and lysosomal trafficking dynamics are affected in fibroblasts harboring TBC1D23 mutation. We propose that mutations in TBC1D23 are responsible for a form of PCH with small, normally proportioned cerebellum and should be screened in individuals with syndromic pontocereballar hypoplasia.


Assuntos
Doenças Cerebelares/genética , Cerebelo/anormalidades , Proteínas Ativadoras de GTPase/genética , Homozigoto , Microcefalia/genética , Mutação , Malformações do Sistema Nervoso/genética , Neurônios/patologia , Adolescente , Animais , Células Cultivadas , Doenças Cerebelares/patologia , Cerebelo/patologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Masculino , Camundongos , Microcefalia/patologia , Malformações do Sistema Nervoso/patologia , Neuroblastoma/genética , Neuroblastoma/patologia , Crescimento Neuronal , Neurônios/metabolismo , Linhagem
15.
Am J Hum Genet ; 101(1): 139-148, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28686853

RESUMO

We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.


Assuntos
Facies , Marcha/genética , Haploinsuficiência/genética , Deficiência Intelectual/genética , Proteínas/genética , Convulsões/genética , Sequência de Aminoácidos , Sequência de Bases , Pré-Escolar , Deleção Cromossômica , Feminino , Crescimento e Desenvolvimento/genética , Humanos , Deficiência Intelectual/complicações , Masculino , Mutação/genética , Proteínas/química , Estabilidade de RNA/genética , Convulsões/complicações , Síndrome
16.
Hum Mol Genet ; 26(11): 2062-2075, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28369444

RESUMO

Mediator occupies a key role in protein coding genes expression in mediating the contacts between gene specific factors and the basal transcription machinery but little is known regarding the role of each Mediator subunits. Mutations in MED12 are linked with a broad spectrum of genetic disorders with X-linked intellectual disability that are difficult to range as Lujan, Opitz-Kaveggia or Ohdo syndromes. Here, we investigated several MED12 patients mutations (p.R206Q, p.N898D, p.R961W, p.N1007S, p.R1148H, p.S1165P and p.R1295H) and show that each MED12 mutations cause specific expression patterns of JUN, FOS and EGR1 immediate early genes (IEGs), reflected by the presence or absence of MED12 containing complex at their respective promoters. Moreover, the effect of MED12 mutations has cell-type specificity on IEG expression. As a consequence, the expression of late responsive genes such as the matrix metalloproteinase-3 and the RE1 silencing transcription factor implicated respectively in neural plasticity and the specific expression of neuronal genes is disturbed as documented for MED12/p.R1295H mutation. In such case, JUN and FOS failed to be properly recruited at their AP1-binding site. Our results suggest that the differences between MED12-related phenotypes are essentially the result of distinct IEGs expression patterns, the later ones depending on the accurate formation of the transcription initiation complex. This might challenge clinicians to rethink the traditional syndromes boundaries and to include genetic criterion in patients' diagnostic.


Assuntos
Genes Precoces/genética , Complexo Mediador/genética , Anormalidades Múltiplas/genética , Blefarofimose/genética , Blefaroptose/genética , Regulação da Expressão Gênica/genética , Genes Ligados ao Cromossomo X/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Complexo Mediador/metabolismo , Retardo Mental Ligado ao Cromossomo X/genética , Mutação , Fenótipo , Proteínas Repressoras
17.
Hum Mutat ; 38(5): 594-599, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28074630

RESUMO

Next-generation sequencing led to the identification of many potential novel disease genes. The presence of mutations in the same gene in multiple unrelated patients is, however, a priori insufficient to establish that these genes are truly involved in the respective disease. Here, we show how phenotype information can be incorporated within statistical approaches to provide additional evidence for the causality of mutations. We developed a broadly applicable statistical model that integrates gene-specific mutation rates, cohort size, mutation type, and phenotype frequency information to assess the chance of identifying de novo mutations affecting the same gene in multiple patients with shared phenotype features. We demonstrate our approach based on the frequency of phenotype features present in a unique cohort of 6,149 patients with intellectual disability. We show that our combined approach can decrease the number of patients required to identify novel disease genes, especially for patients with combinations of rare phenotypes. In conclusion, we show how integrating genotype-phenotype information can aid significantly in the interpretation of de novo mutations in potential novel disease genes.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Fenótipo , Estudos de Associação Genética/métodos , Genótipo , Humanos , Modelos Genéticos , Modelos Estatísticos , Reprodutibilidade dos Testes
18.
Mol Syndromol ; 9(1): 45-51, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29456483

RESUMO

X-linked Opitz G/BBB syndrome (XLOS) is a multisystemic congenital condition, caused by mutations in the midline-1 gene (MID1), characterized by a large inter- and intrafamilial phenotypic variability and often associated with intellectual disability (ID). We report clinical, genetic, and molecular findings in 4 patients with typical XLOS dysmorphic features belonging to 2 unrelated families. Two novel pathogenic loss-of-function MID1 variants, a maternally inherited c.1656del and a de novo c.1215_1228dup, were identified. Subsequently, we performed a genotype-phenotype analysis using data from 91 male XLOS patients. To test the mutation impact on the phenotype; the type of mutation, the MID1-impaired domain and function were compared with the presence of each of the major clinical features (hypertelorism, clefts of the lip and/or palate, laryngo-tracheo-esophageal abnormalities, hypospadias and ID) and minor clinical features (brain, heart, and anal defects). No statistically significant correlation was found with these features. Further investigations, as well as exhaustive and unequivocal phenotyping, may be required to improve our knowledge of the biological mechanisms underlying this syndrome and to provide more adequate disease management.

19.
Eur J Hum Genet ; 24(3): 392-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26173967

RESUMO

AIMP1/p43 is a multifunctional non-catalytic component of the multisynthetase complex. The complex consists of nine catalytic and three non-catalytic proteins, which catalyze the ligation of amino acids to their cognate tRNA isoacceptors for use in protein translation. To date, two allelic variants in the AIMP1 gene have been reported as the underlying cause of autosomal recessive primary neurodegenerative disorder. Here, we present two consanguineous families from Pakistan and Iran, presenting with moderate to severe intellectual disability, global developmental delay, and speech impairment without neurodegeneration. By the combination of homozygosity mapping and next generation sequencing, we identified two homozygous missense variants, p.(Gly299Arg) and p.(Val176Gly), in the gene AIMP1 that co-segregated with the phenotype in the respective families. Molecular modeling of the variants revealed deleterious effects on the protein structure that are predicted to result in reduced AIMP1 function. Our findings indicate that the clinical spectrum for AIMP1 defects is broader than witnessed so far.


Assuntos
Citocinas/genética , Genes Recessivos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Mutação de Sentido Incorreto/genética , Proteínas de Neoplasias/genética , Degeneração Neural/complicações , Degeneração Neural/genética , Proteínas de Ligação a RNA/genética , Adulto , Sequência de Aminoácidos , Criança , Simulação por Computador , Citocinas/química , Exoma/genética , Família , Feminino , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Proteínas de Neoplasias/química , Linhagem , Estrutura Secundária de Proteína , Proteínas de Ligação a RNA/química , Reprodutibilidade dos Testes , Adulto Jovem
20.
JIMD Rep ; 27: 27-32, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26409464

RESUMO

SUCLA2 encodes for a subunit of succinyl-coenzyme A synthase, the enzyme that reversibly synthesises succinyl-coenzyme A and ATP from succinate, coenzyme A and ADP in the Krebs cycle. Disruption of SUCLA2 function can lead to mitochondrial DNA depletion. Patients with a SUCLA2 mutation present with a rare but distinctive deafness-dystonia syndrome. Additionally, they exhibit elevated levels of the characteristic biochemical markers: methylmalonate, C4-dicarboxylic carnitine and lactate are increased in both plasma and urine. Thus far, eight different disease-causing SUCLA2 mutations, of which six missense mutations and two splice site mutations, have been described in the literature. Here, we present the first patient with an intragenic deletion in SUCLA2 and review the patients described in literature.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA