Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.169
Filtrar
1.
Medicine (Baltimore) ; 99(45): e23033, 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33157955

RESUMO

INTRODUCTION: Microdeletion syndromes occur from deletion of 5Mb of a chromosome in approximately 5% of patients with unexplained intellectual disability. Interstitial microdeletions at bands 1p33 and 1p32.2 of the short arm of chromosome 1 are rare and have not been previously reported in relation to disease. PATIENT CONCERNS: We present a case of a 39-month boy with Pierre Robin sequence, development delay/intellectual disability, growth retardation, short stature, leukoencephalopathy, craniofacial dysplasia, and speech delay. The child was referred to the Child health care department in October 2014 for his delayed language development and aggravated aggression. DIAGNOSIS: Molecular diagnostic testing with G-band karyotyping was normal but clinical microarray analysis detected a 10 Mb microdeletion at 1p33p32.2. INTERVENTIONS: The patient received rehabilitation. OUTCOMES: Three candidate genes were pinpointed to the deleted area, including ORC1, SCP2, and DAB1. Phenotype-genotype analysis suggested that these three genes are likely to be responsible for the main phenotypes observed in the patient, such as microcephaly, growth retardation, short stature, leukoencephalopathy, and development delay/intellectual disability. CONCLUSIONS: The spectrum of phenotypes this case presented with are likely to be caused by 1p33p32.2 deletion which could represent a new microdeletion syndrome.


Assuntos
Cariotipagem/métodos , Análise em Microsséries/métodos , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Proteínas de Transporte/genética , Criança , Pré-Escolar , Deleção Cromossômica , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , Nanismo/diagnóstico , Nanismo/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Complexo de Reconhecimento de Origem/genética , Fenótipo , Síndrome de Pierre Robin/reabilitação
2.
Nat Commun ; 11(1): 4593, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929070

RESUMO

Gene-targeted animal models that are generated by injecting Cas9 and sgRNAs into zygotes are often accompanied by undesired double-strand break (DSB)-induced byproducts and random biallelic targeting due to uncontrollable Cas9 targeting activity. Here, we establish a parental allele-specific gene-targeting (Past-CRISPR) method, based on the detailed observation that pronuclear transfer-mediated cytoplasmic dilution can effectively terminate Cas9 activity. We apply this method in embryos to efficiently target the given parental alleles of a gene of interest and observed little genomic mosaicism because of the spatiotemporal control of Cas9 activity. This method allows us to rapidly explore the function of individual parent-of-origin effects and to construct animal models with a single genomic change. More importantly, Past-CRISPR could also be used for therapeutic applications or disease model construction.


Assuntos
Alelos , Sistemas CRISPR-Cas/genética , Núcleo Celular/genética , Edição de Genes , Terapia de Substituição Mitocondrial , Animais , Sequência de Bases , Modelos Animais de Doenças , Nanismo/genética , Perda do Embrião/genética , Feminino , Marcação de Genes , Genes Dominantes , Impressão Genômica , Heterozigoto , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Reprodutibilidade dos Testes , Fatores de Tempo
3.
Am J Hum Genet ; 107(4): 753-762, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32910914

RESUMO

Lamin B1 plays an important role in the nuclear envelope stability, the regulation of gene expression, and neural development. Duplication of LMNB1, or missense mutations increasing LMNB1 expression, are associated with autosomal-dominant leukodystrophy. On the basis of its role in neurogenesis, it has been postulated that LMNB1 variants could cause microcephaly. Here, we confirm this hypothesis with the identification of de novo mutations in LMNB1 in seven individuals with pronounced primary microcephaly (ranging from -3.6 to -12 SD) associated with relative short stature and variable degree of intellectual disability and neurological features as the core symptoms. Simplified gyral pattern of the cortex and abnormal corpus callosum were noted on MRI of three individuals, and these individuals also presented with a more severe phenotype. Functional analysis of the three missense mutations showed impaired formation of the LMNB1 nuclear lamina. The two variants located within the head group of LMNB1 result in a decrease in the nuclear localization of the protein and an increase in misshapen nuclei. We further demonstrate that another mutation, located in the coil region, leads to increased frequency of condensed nuclei and lower steady-state levels of lamin B1 in proband lymphoblasts. Our findings collectively indicate that de novo mutations in LMNB1 result in a dominant and damaging effect on nuclear envelope formation that correlates with microcephaly in humans. This adds LMNB1 to the growing list of genes implicated in severe autosomal-dominant microcephaly and broadens the phenotypic spectrum of the laminopathies.


Assuntos
Nanismo/genética , Deficiência Intelectual/genética , Lamina Tipo B/genética , Microcefalia/genética , Mutação , Lâmina Nuclear/genética , Sequência de Aminoácidos , Sequência de Bases , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Nanismo/diagnóstico por imagem , Nanismo/metabolismo , Nanismo/patologia , Feminino , Expressão Gênica , Humanos , Lactente , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/metabolismo , Deficiência Intelectual/patologia , Lamina Tipo B/metabolismo , Linfócitos/metabolismo , Linfócitos/patologia , Imagem por Ressonância Magnética , Masculino , Microcefalia/diagnóstico por imagem , Microcefalia/metabolismo , Microcefalia/patologia , Lâmina Nuclear/metabolismo , Lâmina Nuclear/patologia
4.
Medicine (Baltimore) ; 99(34): e21635, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846772

RESUMO

INTRODUCTION: The present study is carried out to review the clinical data and gene detection results of a pediatric patient with short stature, and to summarize the relationship between clinical phenotype and genotype of the child with Aggrecan (ACAN) gene mutation. PATIENT CONCERNS: Our study was started with the observation and follow-up of a 5-year-4-month-old full-term child with short stature accompanied by central precocious puberty (CPP). DIAGNOSIS: Gene sequencing showed that there was a new heterozygous mutation C.2164C >G(p.P722A) in exon 11 of ACAN gene, which was inherited from her father. INTERVENTIONS: The child was treated by growth hormone for 6 months with mild growth, and accelerated bone age (BA) after the presence of precocious puberty. The child was diagnosed with CPP, and was provided with combined gonadotropinreleasing hormone (GnRH) therapy. OUTCOMES: The height of the pediatric patient was 99.4 cm (-3.13SDS) on admission, which was 111.9 cm (-2.08SDS) at the age of 6 years and 10 months, with a growth rate of 8.1 cm/year. There was no significant increase in BA of the pediatric patient after 1 year of follow-up. CONCLUSION: Literature review indicated that the clinical manifestations of ACAN gene mutation are the most common in idiopathic short stature, most of which are familial inheritance and can also be sporadic. Some children may also have osteoarthritis, disc herniation or degeneration. In most cases, children may have advanced BA, and retardation of BA is also found in some cases. To sum up, growth hormone combined with GnRH analogue treatment can effectively improve body height of children by postponing their adolescence. Meanwhile, ACAN gene mutation shall be considered for small-for-gestational-age children without significant growth catch-up and with family history.


Assuntos
Agrecanas/genética , Nanismo/genética , Puberdade Precoce/genética , Pré-Escolar , Nanismo/complicações , Feminino , Seguimentos , Genótipo , Humanos , Fenótipo , Puberdade Precoce/complicações
5.
Gene ; 761: 145027, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-32758583

RESUMO

OBJECTIVES: Oliver-McFarlane syndrome (OMCS) is an autosomal recessive inherited disease resulting from PNPLA6 mutations that results in intellectual impairment and profound short stature. To obtain a better understanding of the genotype-phenotype correlations for PNPLA6-related disorders, we reported the 14th OMCS case and summarized all the reported cases of OMCS. METHODS: We collected clinical biochemical and data and brain MRI data and used whole-exon gene detection and analysis tools to evaluate the pathogenicity of the variants, including PolyPhen-2 and Mutation Taster, and we also generated three-dimensional protein structures and visualized the effects of altered residues with I-TASSER and PyMOL Viewer software. RESULTS: The patient presented with trichomegaly and multiple pituitary hormone deficiencies. Brain MRI showed small pituitary and bilateral paraventricular leukomalacia. Novel variants (c.1491G > T and c.3367G > A) in the PNPLA6 gene were detected in the proband and verified by direct sequencing. Amino acid residues of Gln497 and Gly1123 are predicted to be damaging and destroy the three-dimensional protein structures of the protein. In follow-up, this patient could neither walk nor hold his head erect and had not spoken one word at the age of one year and ten months. Moreover, there is no obvious hot spot mutation in any of the reported allelic variants. Interestingly, the majority of mutations are located in the phospholipid esterase domain, which is responsible for esterase activity. CONCLUSIONS: We identified two novel variants of the PNPLA6 gene in an OMCS patient, which will help to better understand the function of PNPLA6 and genotype-phenotype correlations for PNPLA6-related disorders.


Assuntos
Blefaroptose/diagnóstico , Blefaroptose/genética , Nanismo/diagnóstico , Nanismo/genética , Hipertricose/diagnóstico , Hipertricose/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Fosfolipases/genética , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/genética , Alelos , China , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Frequência do Gene/genética , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Mutação , Fenótipo , Fosfolipases/metabolismo
6.
PLoS One ; 15(7): e0235655, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32628740

RESUMO

Biallelic variants in RNU4ATAC, a non-coding gene transcribed into the minor spliceosome component U4atac snRNA, are responsible for three rare recessive developmental diseases, namely Taybi-Linder/MOPD1, Roifman and Lowry-Wood syndromes. Next-generation sequencing of clinically heterogeneous cohorts (children with either a suspected genetic disorder or a congenital microcephaly) recently identified mutations in this gene, illustrating how profoundly these technologies are modifying genetic testing and assessment. As RNU4ATAC has a single non-coding exon, the bioinformatic prediction algorithms assessing the effect of sequence variants on splicing or protein function are irrelevant, which makes variant interpretation challenging to molecular diagnostic laboratories. In order to facilitate and improve clinical diagnostic assessment and genetic counseling, we present i) an update of the previously reported RNU4ATAC mutations and an analysis of the genetic variations affecting this gene using the Genome Aggregation Database (gnomAD) resource; ii) the pathogenicity prediction performances of scores computed based on an RNA structure prediction tool and of those produced by the Combined Annotation Dependent Depletion tool for the 285 RNU4ATAC variants identified in patients or in large-scale sequencing projects; iii) a method, based on a cellular assay, that allows to measure the effect of RNU4ATAC variants on splicing efficiency of a minor (U12-type) reporter intron. Lastly, the concordance of bioinformatic predictions and cellular assay results was investigated.


Assuntos
RNA Nuclear Pequeno/metabolismo , Spliceossomos/metabolismo , Criança , Bases de Dados Genéticas , Nanismo/genética , Nanismo/patologia , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/patologia , Fibroblastos/citologia , Fibroblastos/metabolismo , Variação Genética , Humanos , Microcefalia/genética , Microcefalia/patologia , Conformação de Ácido Nucleico , Osteocondrodisplasias/genética , Osteocondrodisplasias/patologia , Processamento de RNA , RNA Nuclear Pequeno/química , RNA Nuclear Pequeno/genética
7.
Pediatrics ; 146(2)2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32709737

RESUMO

Establishing the diagnosis of hereditary fructose intolerance (HFI) remains difficult despite the availability of specific molecular genetic testing of the ALDOB gene. This is attributable, at least in part, to the lack of a specific and practical biomarker. We report the incidental diagnosis of HFI as a consequence of nontargeted genetic testing ordered for alternative indications in 5 patients, including 3 children and 2 adults. Two of the children were diagnosed with HFI after extensive evaluations that ultimately involved clinical or research exome sequencing. The third child was diagnosed with HFI during subsequent genetic testing of at-risk family members. Both adults learned to avoid fructose and remained asymptomatic of HFI before diagnosis. One was diagnosed with HFI during preconception, nontargeted expanded carrier screening. For the other, concern for HFI was initially raised by indeterminate direct-to-consumer genetic testing results. None of these patients presented with infantile acute liver failure or other acute decompensation. Our findings suggest that the emphasis of classic teaching on infantile liver failure after first exposure to fructose may be inadvertently increasing the likelihood of missing cases of HFI characterized by other manifestations. HFI is likely underdiagnosed and should be considered for patients with nonspecific findings as well as for individuals with significant aversion to sweets.


Assuntos
Intolerância à Frutose/diagnóstico , Adulto , Idoso , Doenças Assintomáticas , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Triagem e Testes Direto ao Consumidor , Nanismo/genética , Insuficiência de Crescimento/genética , Feminino , Preferências Alimentares , Intolerância à Frutose/genética , Frutose-Bifosfato Aldolase/genética , Frutas/efeitos adversos , Testes Genéticos , Humanos , Achados Incidentais , Infertilidade Feminina , Masculino , Cuidado Pré-Concepcional , Verduras/efeitos adversos , Sequenciamento Completo do Exoma
8.
Eur J Endocrinol ; 183(2): C9-C10, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32413843

RESUMO

Short stature is one of the most common causes for referrals to pediatric endocrinologists. However, in a majority of the children, no underlying cause can be identified and the child instead receives the unhelpful diagnosis of idiopathic short stature (ISS), often after extensive work-up and testing. Recent advances in genetic methodology have allowed for the identification of a number of different monogenic conditions within the large cohort of ISS children. Isolated short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (MIM#165800) due to heterozygous aggrecan gene mutations exemplifies how this progress is changing the way we assess, counsel and treat children with non-endocrine growth disorders.


Assuntos
Agrecanas/genética , Estatura/genética , Nanismo/genética , Transtornos do Crescimento/genética , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Mutação/genética
9.
Gene ; 753: 144816, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32473250

RESUMO

Hemizygosity of the MIR17HG gene encoding the miR-17 ~ 92 cluster is associated with Feingold syndrome 2 characterized by intellectual disability, skeletal abnormalities, short stature, and microcephaly. Here, we report on a female with a de novo 13q31.3 microduplication encompassing MIR17HG but excluding GPC5. She presented developmental delay, skeletal and digital abnormalities, and features such as tall stature and macrocephaly mirroring those of Feingold syndrome 2 patients. The limited extent of the proband's rearrangement to the miR cluster and the corresponding normal expression level of the neighboring GPC5 in her cells, together with previously described data on affected individuals of two families carrying overlapping duplications of the miR-17 ~ 92 cluster that comprise part of GPC5, who likewise presented macrocephaly, developmental delay, as well as skeletal, digital and stature abnormalities, allow to define a new syndrome due to independent microduplication of the miR-17 ~ 92 cluster.


Assuntos
Transtornos Cromossômicos/genética , Pálpebras/anormalidades , Deficiência Intelectual/genética , Deformidades Congênitas dos Membros/genética , MicroRNAs/genética , Microcefalia/genética , Fístula Traqueoesofágica/genética , Adolescente , Deleção Cromossômica , Cromossomos Humanos Par 13/genética , Hibridização Genômica Comparativa/métodos , Deficiências do Desenvolvimento/genética , Nanismo/genética , Feminino , Duplicação Gênica/genética , Glipicanas/genética , Glipicanas/metabolismo , Humanos , Fenótipo
10.
Anim Genet ; 51(3): 466-469, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32239744

RESUMO

Fifteen cases of chondrodysplasia characterized by disproportionate dwarfism occurred in the progeny of a single Holstein bull. A de novo mutation event in the germline of the sire was suspected as cause. Whole-genome sequencing revealed a single protein-changing variant in the stop codon of FGFR3 gene on chromosome 6. Sanger sequencing of EDTA blood proved that this variant occurred de novo and segregates perfectly with the observed phenotype in the affected cattle family. FGFR3 is an important regulator gene in bone formation owing to its key role in the bone elongation induced by FGFR3-dimers. The detected paternally inherited stop-lost variant in FGFR3 is predicted to add 93 additional amino acids to the protein's C-terminus. This study provides a second example of a dominant FGFR3 stop-lost variant as a pathogenic mutation of a severe form of chondrodysplasia. Even though FGFR3 is known to be associated with dwarfism and growth disorders in human and sheep, this study is the first to describe FGFR3-associated chondrodysplasia in cattle.


Assuntos
Doenças dos Bovinos/genética , Nanismo/veterinária , Mutação em Linhagem Germinativa/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Animais , Bovinos , Nanismo/genética , Masculino , Mutação , Fenótipo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo
11.
PLoS One ; 15(3): e0229564, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32119688

RESUMO

The introduction of high-yielding semi-dwarf varieties of wheat into cultivation has led to a "green revolution." This has required intensive research into various sources of dwarfism in wheat. However, there has been very little advancement in research on dwarfing genes in rye in comparison to wheat or barley. So far, three dominant dwarfing genes (Ddw1, Ddw3, and Ddw4) and three recessive genes (ct1, ct2, and np) have been characterized and precisely mapped in rye. There is no complete catalog of dwarfing genes available in rye. This paper presents an identification of the source of dwarfism and preliminary characterization of the new recessive gene dw9 from the BK-1 line. The gene was mapped on the long arm of the 6R chromosome and belongs to the GA-insensitive group. The initial characterization of the influence of this gene on morphological traits shows that it significantly affects the decrease of yielding trait parameters. A full evaluation can be performed after detailed breeding studies.


Assuntos
Nanismo/genética , Secale/genética , Biometria/métodos , Mapeamento Cromossômico/métodos , Cromossomos de Plantas/genética , Resistência à Doença/genética , Genes de Plantas/genética , Genes Recessivos/genética , Fenótipo , Melhoramento Vegetal/métodos , Doenças das Plantas/genética
12.
Anim Genet ; 51(3): 420-422, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32065671

RESUMO

Homozygous and compound heterozygous Miniature horses for ACAN alleles D1, D2, D3* and D4 exhibit chondrodysplastic dwarfism (OMIA 001271-9796). In a previous study, the carrier rate for these four alleles, combined, was 26.2%. The purpose of this study was to investigate whether carriers of these dwarfism-causing alleles had a shorter withers height than non-carriers. A total of 245 Miniature horses were tested for these four ACAN alleles and also were measured for withers height. Of these horses, 98 were carriers and 147 were non-carriers. A statistically significant difference of 1.43 inches was observed with the carriers being shorter (P = 1.72E - 11). The range of heights for the two groups overlapped, indicating that other factors, including genes, have an impact on withers height. However, the high carrier rate of these dwarfism-causing variants may be due to selection for decreased height.


Assuntos
Agrecanas/genética , Nanismo/veterinária , Doenças dos Cavalos/genética , Agrecanas/metabolismo , Alelos , Animais , Nanismo/genética , Heterozigoto , Cavalos
13.
Biochem Biophys Res Commun ; 523(4): 841-846, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31954514

RESUMO

Metatropic dysplasia (MD) is a congenital skeletal dysplasia characterized by severe platyspondyly and dumbbell-like long-bone deformities. These skeletal phenotypes are predominantly caused by autosomal dominant gain-of-function (GOF) mutations in transient receptor potential vanilloid 4 (TRPV4), which encodes a nonselective Ca2+-permeable cation channel. Previous studies have shown that constitutive TRPV4 channel activation leads to irregular chondrogenic proliferation and differentiation, and thus to the disorganized endochondral ossification seen in MD. Therefore, the present study investigated the role of TRPV4 in osteoblast differentiation and MD pathogenesis. Specifically, the behavior of osteoblasts differentiated from patient-derived dental pulp stem cells carrying a heterozygous single base TRPV4 mutation, c.1855C > T (p.L619F) was compared to that of osteoblasts differentiated from isogenic control cells (in which the mutation was corrected using the CRISPR/Cas9 system). The mutant osteoblasts exhibited enhanced calcification (indicated by intense Alizarin Red S staining), increased intracellular Ca2+ levels, strongly upregulated runt-related transcription factor 2 and osteocalcin expression, and increased expression and nuclear translocation of nuclear factor-activated T cell c1 (NFATc1) compared to control cells. These results suggest that the analyzed TRPV4 GOF mutation disrupts osteoblastic differentiation and induces MD-associated disorganized endochondral ossification by increasing Ca2+/NFATc1 pathway activity. Thus, inhibiting the NFATc1 pathway may be a promising potential therapeutic strategy to attenuate skeletal deformities in MD.


Assuntos
Diferenciação Celular , Polpa Dentária/patologia , Nanismo/genética , Mutação com Ganho de Função/genética , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteocondrodisplasias/genética , Células-Tronco/metabolismo , Canais de Cátion TRPV/genética , Adolescente , Cálcio/metabolismo , Humanos , Espaço Intracelular/metabolismo , Fatores de Transcrição NFATC/metabolismo , Transdução de Sinais
14.
J Vet Diagn Invest ; 32(1): 99-102, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31906815

RESUMO

Four causative mutations (D1, D2, D3*, and D4) of chondrodysplastic dwarfism have been described in the equine aggrecan (ACAN) gene. Homozygotes for one of these mutations and heterozygotes for any combination of these mutations exhibit the disproportionate dwarfism phenotype. However, no case description of homozygotes for D4 (D4/D4) has been reported in the literature, to our knowledge. We report 2 Miniature horses with the genotype D4/D4 in the ACAN gene. Clinically, the 2 dwarfs had a domed head that was large compared to the rest of the body, mandibular prognathism, and short and bowed limbs, mainly in the proximal region of the metatarsal bones. Radiographic examination revealed contour irregularities of the subchondral bone in the long bones and confirmed mandibular prognathism; histopathology revealed irregular chondrocyte organization. To determine the genotypes of the horses, we performed DNA extraction from white blood cells, PCR, and Sanger sequencing. Genotyping demonstrated that these 2 animals had the D4/D4 genotype in the ACAN gene. The D4/D4 dwarfs were clinically similar to animals with the other ACAN genotypes reported for this disease. Identification of heterozygous animals makes mating selection possible and is the most important control measure to minimize economic losses and casualties.


Assuntos
Agrecanas/genética , Nanismo/veterinária , Genótipo , Cavalos/anormalidades , Cavalos/genética , Animais , Nanismo/genética , Masculino , Mutação
15.
J Clin Endocrinol Metab ; 105(3)2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31990356

RESUMO

CONTEXT: The C-type natriuretic peptide receptor encoded by the NPR2 gene is a paracrine regulator of the growth plate; heterozygous NPR2 variants cause short stature with possible presence of different signs of bone dysplasia. To date, the effect of growth hormone (GH) treatment has been described in a few individuals with NPR2 gene variants with inconsistent results. OBJECTIVES: To identify NPR2 gene variants among children with familial short stature (FSS) and to describe their phenotype, including GH treatment response. DESIGN, SETTINGS AND PATIENTS: Out of 747 patients with short stature treated with GH in a single center, 87 with FSS met the inclusion criteria (pretreatment height ≤ -2 standard deviation in both the patient and the shorter parent, unknown genetic etiology). Next-generation sequencing methods were performed to search for NPR2 gene variants. The results were evaluated using the American College of Medical Genetics and Genomics guidelines. The GH treatment response (growth velocity improvement and height standard deviation score development over the first 5 years of treatment) was evaluated. RESULTS: In 5/87 children (5.7%), a (likely) pathogenic variant in the NPR2 gene was identified (p.Ile558Thr [in 2], p.Arg205*, p.Arg557His, p.Ser603Thr). Two children had disproportionate short-limbed short stature, 1 a dysplastic 5th finger phalanx. The growth velocity in the first year of GH treatment accelerated by 3.6 to 4.2 cm/year; the height improved by 1.2 to 1.8 SD over 5 years of treatment. CONCLUSIONS: NPR2 gene variants cause FSS in a significant proportion of children. Their GH treatment response is promising. Studies including final height data are necessary to assess the long-term efficacy of this therapy.


Assuntos
Estatura/genética , Nanismo/tratamento farmacológico , Nanismo/genética , Hormônio do Crescimento Humano/administração & dosagem , Polimorfismo de Nucleotídeo Único , Receptores do Fator Natriurético Atrial/genética , Adolescente , Adulto , Biomarcadores/análise , Estatura/efeitos dos fármacos , Criança , Pré-Escolar , Estudos de Coortes , Nanismo/patologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Fenótipo , Prognóstico , Adulto Jovem
16.
Ann N Y Acad Sci ; 1462(1): 118-127, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31535723

RESUMO

Troyer syndrome is an autosomal recessive disease characterized by spastic paralysis, dysarthria, distal amyotrophy, and short stature. Recently, two siblings (an older brother and a younger sister) were admitted to our hospital for the chief complaints of "short stature and intellectual disability." Through whole exome sequencing of the sister, who is the proband, it was found that her SPG20 gene had compound heterozygous mutations: c.364_365delAT (p.Met122Valfs* 2) and c.892delA (p.Thr298Glnfs* 30). Target testing revealed that the brother had the same genotype as the sister, and the former mutation originated from the father, while the latter mutation originated from the mother. In summary, this is the first report of Troyer syndrome in a family caused by SPG20 compound heterozygous mutations. A novel SPG20 mutation was found, namely c.892delA (p.Thr298Glnfs* 30). In addition, we also summarize these Troyer syndrome patients' heights and their clinical characteristics, and provide a brief review of all known pathogenic mutations of SPG20.


Assuntos
Proteínas de Ciclo Celular/genética , Nanismo/genética , Mutação/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Pré-Escolar , Nanismo/complicações , Nanismo/diagnóstico por imagem , Feminino , Humanos , Masculino , Linhagem , Paraplegia Espástica Hereditária/complicações , Paraplegia Espástica Hereditária/diagnóstico por imagem
17.
Eur J Med Genet ; 63(2): 103643, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30922925

RESUMO

Majewski Osteodysplastic Primordial Dwarfism type II (MOPDII) is a form of dwarfism associated with severe microcephaly, characteristic skeletal findings, distinct dysmorphic features and increased risk for cerebral infarctions. The condition is caused by bi-allelic loss-of-function variants in the gene PCNT. Here we describe the identification of a novel founder pathogenic variant c.3465-1G > A observed in carriers from multiple Druze villages in Northern Israel. RNA studies show that the variant results in activation of a cryptic splice site causing a coding frameshift. The study was triggered by the diagnosis of a single child with MOPDII and emphasizes the advantages of applying next generation sequencing technologies in community genetics and the importance of establishing population-specific sequencing databases.


Assuntos
Antígenos/genética , Efeito Fundador , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Adolescente , Alelos , Linhagem Celular Tumoral , Análise Mutacional de DNA , Nanismo/diagnóstico , Nanismo/genética , Facies , Feminino , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/genética , Estudos de Associação Genética/métodos , Testes Genéticos , Humanos , Israel , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/genética , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
18.
Eur J Med Genet ; 63(2): 103659, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31048079

RESUMO

Achondroplasia (ACH) and hypochondroplasia (HCH) are genetic bone disorders known to be caused by gain-of-function mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Both conditions share radiographic and phenotypical features. HCH is a milder form of ACH. Most individuals with ACH have the recurrent mutation (p.Gly380Arg) in the transmembrane (TM) domain of the receptor and individuals with HCH show the common mutation (p.Asn540Lys) in the tyrosine kinase 1 (TK1) region. Other rare mutations have been reported, however no additional hot-spot has been identified. We report an 8-month-old infant, with the heterozygous mutation, c.1043C > G, leading to an amino acid change from serine at 348 to cysteine (p.Ser348Cys). Clinical diagnosis of the patient is intertwined with "mild ACH" or "severe HCH". He did not demonstrate acanthosis nigricans (AN). This mutation has been reported in two different patients and it is located in the Ig-III domain of the FGFR3 region near other mutations associated with ACH. Among the two the 8-year old one also demonstrated AN without evindece of hyperinsulinem. This report emphasizes the benefit of whole gene sequencing for FGFR3 in individuals with suspected "mild ACH/severe HCH". This child will be monitored for future occurrence of AN.


Assuntos
Acondroplasia/diagnóstico , Acondroplasia/genética , Osso e Ossos/anormalidades , Nanismo/diagnóstico , Nanismo/genética , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , Lordose/diagnóstico , Lordose/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acantose Nigricans , Acondroplasia/diagnóstico por imagem , Sequência de Aminoácidos , Osso e Ossos/diagnóstico por imagem , Nanismo/diagnóstico por imagem , Heterozigoto , Humanos , Hiperinsulinismo , Lactente , Deformidades Congênitas dos Membros/diagnóstico por imagem , Lordose/congênito , Lordose/diagnóstico por imagem , Masculino , Fenótipo , Mutação Puntual , Domínios Proteicos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/sangue , Análise de Sequência de DNA
19.
J Hum Genet ; 65(2): 133-141, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31656314

RESUMO

Alazami syndrome (MIM#615071) is a rare developmental disorder caused by biallelic variants in the LARP7 gene. Hallmark features include short stature, global developmental delay, and distinctive facial features. To date, 23 patients from 11 families have been reported in the literature. Here we describe a 19-year-old man who, in association with the typical features of Alazami syndrome, was diagnosed at the age of 14 years with papillary thyroid carcinoma, harboring the somatic BRAF V600E mutation. Whole exome sequencing revealed two novel LARP7 variants in compound heterozygosity, whereas only common variants were detected in genes associated with familial nonmedullary thyroid cancer (MIM#188550). LARP7 acts as a tumor suppressor in breast and gastric cancer, and possibly, according to recent studies, in thyroid tumors. Since thyroid cancer is rare among children and adolescents, we hypothesize that the LARP7 variants identified in our patient are responsible for both Alazami syndrome and tumor susceptibility. We also provide an overview of the clinical findings in all Alazami syndrome patients reported to date and discuss the possible pathogenetic mechanism that may underlie this condition, including the role of LARP7 in tumor susceptibility.


Assuntos
Deficiências do Desenvolvimento/genética , Nanismo/genética , Deficiência Intelectual/genética , Proteínas Proto-Oncogênicas B-raf/genética , Ribonucleoproteínas/genética , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Mutação da Fase de Leitura , Predisposição Genética para Doença , Heterozigoto , Humanos , Itália , Masculino , Fenótipo , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Neoplasias da Glândula Tireoide/patologia , Sequenciamento Completo do Exoma , Adulto Jovem
20.
J Hum Genet ; 65(2): 193-197, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31767933

RESUMO

Biallelic pathogenic variants in POC1A are ultra rare. They have been reported in 13 families as causing either Short stature, Onychodysplasia, Facial dysmorphism, and hypoTrichosis (SOFT) syndrome, or a milder partially overlapping phenotype, variant POC1A-related syndrome. This pleiotropic effect is likely precipitated by the variant's location and respective affected protein domain. Here, we describe seven patients from two consanguineous Omani families with classic SOFT syndrome and a novel homozygous POC1A variant (c.64G>T; p.(Val22Phe)), which is the first one described for the alternative exon 2. This result refines the POC1A mutational spectrum relevant for exertion of the described pleiotropic effect. Furthermore, six of our patients experienced recurrent mild to severe respiratory difficulties that have not been previously reported for SOFT syndrome and may be an underdiagnosed or a genotype-specific complication that warrants attention in future studies. Thus, our study unravels new aspects of the genotype-phenotype correlation suggested by previous reports.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Anormalidades Craniofaciais/genética , Proteínas do Citoesqueleto/genética , Nanismo/genética , Estudos de Associação Genética , Hipotricose/genética , Atrofia Muscular/genética , Processamento Alternativo , Criança , Pré-Escolar , Consanguinidade , Éxons/genética , Feminino , Genótipo , Humanos , Masculino , Mutação , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA