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1.
J Matern Fetal Neonatal Med ; : 1-4, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31510824

RESUMO

Desbuquois dysplasia is a very severe and sometimes lethal form of osteochondrodysplasia characterized by prenatal onset of severe micromelic short stature, joint laxity with multiple joint dislocations, specific radiographic features, and facial dysmorphism. Here, we report a case for which whole exome sequencing allowed early prenatal diagnosis of Desbuquois dysplasia before the detection of characteristic ultrasound signs of the disease.

2.
Genes (Basel) ; 10(9)2019 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443423

RESUMO

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but high variable expressivity. NF1 is caused by loss-of-function mutations in the NF1 gene, a negative regulator of the RAS-MAPK pathway. The NF1 gene has one of the highest mutation rates in human disorders, which may explain the outbreak of independent de novo variants in the same family. Here, we report the co-occurrence of pathogenic variants in the NF1 and SPRED1 genes in six families with NF1 and Legius syndrome, using next-generation sequencing. In five of these families, we observed the co-occurrence of two independent NF1 variants. All NF1 variants were classified as pathogenic, according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines. In the sixth family, one sibling inherited a complete deletion of the NF1 gene from her mother and carried a variant of unknown significance in the SPRED1 gene. This variant was also present in her brother, who was diagnosed with Legius syndrome, a differential diagnosis of NF1. This work illustrates the complexity of molecular diagnosis in a not-so-rare genetic disease.

3.
J Med Genet ; 56(8): 526-535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30923172

RESUMO

BACKGROUND: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies. METHODS: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA. RESULTS: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (KANSL1, FOXP1, SPRED1, TLK2, MBD5, DMD, AUTS2, MEIS2, MEF2C, NRXN1, NFIX, SYNGAP1, GHR, ZMIZ1) and 7 by position effect (DLX5, MEF2C, BCL11B, SATB2, ZMIZ1). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation. CONCLUSION: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.

4.
Clin Genet ; 95(3): 420-426, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30633342

RESUMO

Rubinstein-Taybi syndrome (RSTS; OMIM 180849) is an autosomal dominant developmental disorder characterized by facial dysmorphism, broad thumbs and halluces associated with intellectual disability. RSTS is caused by alterations in CREBBP (about 60%) and EP300 genes (8%). RSTS is often diagnosed at birth or during early childhood but generally not suspected during antenatal period. We report nine cases of well-documented fetal RSTS. Two cases were examined after death in utero at 18 and 35 weeks of gestation and seven cases after identification of ultrasound abnormalities and termination of pregnancy. On prenatal sonography, a large gallbladder was detected in two cases, and brain malformations were noted in four cases, especially cerebellar hypoplasia. However, the diagnosis of RSTS has not been suggested during pregnancy. Fetal autopsy showed that all fetuses had large thumbs and/or suggestive facial dysmorphism. A CREBBP gene anomaly was identified in all cases. Alterations were similar to those found in typical RSTS children. This report will contribute to a better knowledge of the fetal phenotype to consider the hypothesis of RSTS during pregnancy. Genotyping allows reassuring genetic counseling.

5.
Genet Med ; 2018 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-30190612

RESUMO

PURPOSE: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants. METHODS: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants. RESULTS: The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes. CONCLUSION: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.

7.
Am J Med Genet C Semin Med Genet ; 175(4): 417-430, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29178447

RESUMO

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.


Assuntos
Síndrome CHARGE/diagnóstico , Síndrome CHARGE/genética , Estudos de Associação Genética , Genótipo , Fenótipo , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Adulto , Alelos , Substituição de Aminoácidos , Sistema Nervoso Central/anormalidades , Criança , Pré-Escolar , Estudos de Coortes , Nervos Cranianos/anormalidades , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Feminino , França , Testes Genéticos , Humanos , Lactente , Masculino , Técnicas de Diagnóstico Molecular , Adulto Jovem
8.
Prenat Diagn ; 36(13): 1270-1275, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27859469

RESUMO

OBJECTIVE: Fraser syndrome (FS) is a rare malformation recessive disorder. Major criteria are cryptophtalmos, syndactyly, respiratory, genital and urinary tract anomalies. Few prenatal presentations have been reported. METHOD: We analyzed the prenatal and postnatal fetal phenotype in 38 cases of FS, including 25 pregnancy termination cases, 8 intra-uterine death cases and 4 cases that died after birth. RESULTS: Including both prenatal and postnatal fetal phenotypic evaluation, all cases presented dysmorphic features with nose and ear dysplasia. Renal anomalies and syndactyly were present in 37/38 cases, cryptophtalmos in 36/38, airways anomalies in 30/37 and genital anomalies in 30/35 cases. Anomalies of the abdominal wall such as low set umbilicus and omphalocele were found in 31 cases. Among the 26 cases for which ultrasound data were available, detectable anomalies included oligohydramnios (22), ascites/hydrops (9), renal anomalies (20), evidence for high airways obstruction (11), ophthalmologic anomalies (4), ear dysplasia (2) and syndactyly (2). CONCLUSION: This study shows that the postnatal phenotype of FS is very specific, whereas oligohydramnios hampers the prenatal recognition of the cardinal FS diagnosis criteria. Association of oligohydramnios, kidney agenesis and CHAOS should lead to consider this diagnosis. © 2016 John Wiley & Sons, Ltd.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/embriologia , Síndrome de Fraser/diagnóstico , Síndrome de Fraser/embriologia , Diagnóstico Pré-Natal/métodos , Obstrução das Vias Respiratórias/diagnóstico por imagem , Obstrução das Vias Respiratórias/embriologia , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/embriologia , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/embriologia , Orelha/anormalidades , Orelha/diagnóstico por imagem , Orelha/embriologia , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/embriologia , Feminino , Síndrome de Fraser/diagnóstico por imagem , Idade Gestacional , Humanos , Hidropisia Fetal/diagnóstico por imagem , Recém-Nascido , Rim/anormalidades , Rim/diagnóstico por imagem , Rim/embriologia , Oligo-Hidrâmnio/diagnóstico por imagem , Fenótipo , Gravidez , Sindactilia/diagnóstico por imagem , Ultrassonografia Pré-Natal , Anormalidades Urogenitais/diagnóstico
9.
Prenat Diagn ; 36(8): 744-51, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27297286

RESUMO

OBJECTIVES: To describe macroscopic and microscopic anomalies present in fetuses carrying hepatocyte nuclear factor-1 ß mutation, their frequency, and genotype/phenotype correlations. METHODS: Clinical data, ultrasound findings, genetic studies, and autopsy reports of 20 fetal autopsies were analyzed. Histology was reviewed by two pathologists. RESULTS: Macroscopic findings were typically unilateral or bilateral renal enlargement and cortical cysts. Renal lesions were associated with congenital anomalies of the kidney and urinary tract in 25% of cases. Microscopic renal anomalies were dominated by glomerulocystic kidney and renal dysplasia. Extra-renal manifestations such as pancreatic hypoplasia (75%) and genital anomalies (68%) were only detected at autopsy. In 40% of cases, there was heterozygous deletion of the whole gene. There were de novo mutations in 40%. CONCLUSION: This study underlines the importance of considering hepatocyte nuclear factor-1 ß mutations in fetuses with congenital anomalies of the kidney and urinary tract, especially when associated with pancreatic hypoplasia. No correlation between phenotype and genotype was found, highlighting high intra-familial variability in cases with inherited mutations. © 2016 John Wiley & Sons, Ltd.


Assuntos
Fator 1-beta Nuclear de Hepatócito/genética , Rim/anormalidades , Pâncreas/anormalidades , Pancreatopatias/congênito , Anormalidades Urogenitais/genética , Autopsia , Anormalidades Congênitas/diagnóstico por imagem , Anormalidades Congênitas/genética , Anormalidades Congênitas/patologia , Feminino , Genótipo , Humanos , Rim/diagnóstico por imagem , Rim/patologia , Masculino , Mutação , Pâncreas/diagnóstico por imagem , Pancreatopatias/diagnóstico por imagem , Pancreatopatias/genética , Fenótipo , Gravidez , Ultrassonografia Pré-Natal , Anormalidades Urogenitais/diagnóstico por imagem , Anormalidades Urogenitais/patologia
10.
Hum Mutat ; 36(9): 894-902, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26077438

RESUMO

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder associating macroglossia, abdominal wall defects, visceromegaly, and a high risk of childhood tumor. Molecular anomalies are mostly epigenetic; however, mutations of CDKN1C are implicated in 8% of cases, including both sporadic and familial forms. We aimed to describe the phenotype of BWS patients with CDKN1C mutations and develop a functional test for CDKN1C mutations. For each propositus, we sequenced the three exons and intron-exon boundaries of CDKN1C in patients presenting a BWS phenotype, including abdominal wall defects, without 11p15 methylation defects. We developed a functional test based on flow cytometry. We identified 37 mutations in 38 pedigrees (50 patients and seven fetuses). Analysis of parental samples when available showed that all mutations tested but one was inherited from the mother. The four missense mutations led to a less severe phenotype (lower frequency of exomphalos) than the other 33 mutations. The following four tumors occurred: one neuroblastoma, one ganglioneuroblastoma, one melanoma, and one acute lymphoid leukemia. Cases of BWS caused by CDKN1C mutations are not rare. CDKN1C sequencing should be performed for BWS patients presenting with abdominal wall defects or cleft palate without 11p15 methylation defects or body asymmetry, or in familial cases of BWS.


Assuntos
Síndrome de Beckwith-Wiedemann/diagnóstico , Síndrome de Beckwith-Wiedemann/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Estudos de Associação Genética , Impressão Genômica , Fenótipo , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Feminino , Genótipo , Humanos , Masculino , Dados de Sequência Molecular , Mutação , Linhagem , Alinhamento de Sequência
11.
Prenat Diagn ; 35(7): 675-84, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25754886

RESUMO

OBJECTIVES: Conradi-Hünermann-Happle [X-linked dominant chondrodysplasia punctata 2 (CDPX2)] syndrome is a rare X-linked dominant skeletal dysplasia usually lethal in men while affected women show wide clinical heterogeneity. Different EBP mutations have been reported. Severe female cases have rarely been reported, with only six antenatal presentations. METHODS: To better characterize the phenotype in female fetuses, we included nine antenatally diagnosed cases of women with EBP mutations. All cases were de novo except for two fetuses with an affected mother and one case of germinal mosaicism. RESULTS: The mean age at diagnosis was 22 weeks of gestation. The ultrasound features mainly included bone abnormalities: shortening (8/9 cases) and bowing of the long bones (5/9), punctuate epiphysis (7/9) and an irregular aspect of the spine (5/9). Postnatal X-rays and examination showed ichthyosis (8/9) and epiphyseal stippling (9/9), with frequent asymmetric short and bowed long bones. The X-inactivation pattern of the familial case revealed skewed X-inactivation in the mildly symptomatic mother and random X-inactivation in the severe fetal case. Differently affected skin samples of the same fetus revealed different patterns of X-inactivation. CONCLUSION: Prenatal detection of asymmetric shortening and bowing of the long bones and cartilage stippling should raise the possibility of CPDX2 in female fetuses, especially because the majority of such cases involve de novo mutations.


Assuntos
Condrodisplasia Punctata/diagnóstico por imagem , Fenótipo , Índice de Gravidade de Doença , Ultrassonografia Pré-Natal , Condrodisplasia Punctata/genética , Feminino , Marcadores Genéticos , Testes Genéticos , Humanos , Recém-Nascido , Mutação , Gravidez , Segundo Trimestre da Gravidez , Radiografia , Estudos Retrospectivos , Esteroide Isomerases/genética , Inativação do Cromossomo X
12.
J Am Acad Dermatol ; 72(2): 333-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25484267

RESUMO

BACKGROUND: Primary lymphedema in children, especially generalized disease with facial involvement, is rare. OBJECTIVE: We sought to report 3 childhood cases of lymphedema with associated neurologic findings and to provide a pathophysiologic explanation for this association. METHODS: Clinical observations, electroencephalography, and neuroimaging studies were evaluated. Microcomparative genomic hybridization was performed in 1 case. RESULTS: The 3 children had primary lymphedema of all 4 limbs and the face. This was confirmed by lymphoscintigraphy, which showed hypoplasia of vessels and hypofixation of lymph nodes. They had nonspecific neurologic disorders and electroencephalography abnormalities, without intellectual deficit. Neuroimaging revealed normal findings. Microcomparative genomic hybridization in 1 patient revealed no cytogenetic anomaly. The outcome was fatal in 1 case with development of visceral lymphedema and coma. LIMITATIONS: Genetic studies were performed in only 1 case. CONCLUSION: These observations suggest that neurologic assessment and electroencephalography are indicated for patients with lymphedema of the limbs and face to identify this syndrome.


Assuntos
Epilepsia/diagnóstico , Linfedema/diagnóstico , Transtornos do Sono-Vigília/diagnóstico , Adolescente , Adulto , Criança , Eletroencefalografia , Extremidades , Face , Evolução Fatal , Feminino , Humanos , Linfedema/congênito , Linfedema/terapia , Masculino , Doenças do Sistema Nervoso/diagnóstico , Neuroimagem , Tomografia Computadorizada por Raios X
13.
Acta Neuropathol ; 126(3): 427-42, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23820807

RESUMO

L1 syndrome results from mutations in the L1CAM gene located at Xq28. It encompasses a wide spectrum of diseases, X-linked hydrocephalus being the most severe phenotype detected in utero, and whose pathophysiology is incompletely understood. The aim of this study was to report detailed neuropathological data from patients with mutations, to delineate the neuropathological criteria required for L1CAM gene screening in foetuses by characterizing the sensitivity, specificity and positive predictive value of the cardinal signs, and to discuss the main differential diagnoses in non-mutated foetuses in order to delineate closely related conditions without L1CAM mutations. Neuropathological data from 138 cases referred to our genetic laboratory for screening of the L1CAM gene were retrospectively reviewed. Fifty-seven cases had deleterious L1CAM mutations. Of these, 100 % had hydrocephalus, 88 % adducted thumbs, 98 % pyramidal tract agenesis/hypoplasia, 90 % stenosis of the aqueduct of Sylvius and 68 % agenesis/hypoplasia of the corpus callosum. Two foetuses had L1CAM mutations of unknown significance. Seventy-nine cases had no L1CAM mutations; these were subdivided into four groups: (1) hydrocephalus sometimes associated with corpus callosum agenesis (44 %); (2) atresia/forking of the aqueduct of Sylvius/rhombencephalosynapsis spectrum (27 %); (3) syndromic hydrocephalus (9 %), and (4) phenocopies with no mutations in the L1CAM gene (20 %) and in whom family history strongly suggested an autosomal recessive mode of transmission. These data underline the existence of closely related clinical entities whose molecular bases are currently unknown. The identification of the causative genes would greatly improve our knowledge of the defective pathways involved in these cerebral malformations.


Assuntos
Aqueduto do Mesencéfalo/anormalidades , Aqueduto do Mesencéfalo/patologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Hidrocefalia/patologia , Doenças do Sistema Nervoso/patologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Feminino , Humanos , Recém-Nascido , Mutação/genética , Doenças do Sistema Nervoso/genética , Molécula L1 de Adesão de Célula Nervosa/genética , Linhagem , Fenótipo , Gravidez
14.
Hum Mutat ; 33(2): 316-26, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22095942

RESUMO

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.


Assuntos
Genes Recessivos , Mutação , Sistema Renina-Angiotensina/genética , Anormalidades Urogenitais/genética , Angiotensinogênio/genética , Animais , Modelos Animais de Doenças , Estudos de Associação Genética , Humanos , Túbulos Renais Proximais/anormalidades , Peptidil Dipeptidase A/genética , Receptor Tipo 1 de Angiotensina/genética , Renina/genética , Anormalidades Urogenitais/diagnóstico
15.
Am J Med Genet A ; 123A(2): 129-39, 2003 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-14598336

RESUMO

Non-syndromic X-linked mental retardation (MRX) is a frequent cause of inherited mental retardation. It is a heterogeneous condition in which the first 12 genes discovered to date explain no more than 15% of the MRX situations ascertained by recurrence in multiplex families. In Rett syndrome (RTT), an X-linked dominant condition mostly sporadic and usually lethal in males, most affected females have been shown to be mutated in the Methyl-CpG binding protein 2 gene (MECP2) that maps at Xq28. Some mentally retarded males related to RTT females carry the same mutation. Several MRX families mapping to Xq28 were subsequently tested for MECP2 and a causative mutation was discovered in three families, suggesting that it could be one of the main genes involved in MRX. We report here the corresponding phenotypes in these three families of increasing severity. In family 1, an in-frame deletion DeltaP387-M466 was found in the 3' region. The patients had severe to mild non-progressive MR, with better motor skills than verbal abilities. In family 2, an Arg to Trp substitution (R167W) was found between the transcription repression domain (TRD) and the methyl binding domain (MBD). The patients had brisk reflexes and essential tremor with mild and non-progressive MR, poor motor co-ordination and written language difficulties. In the third family (MRX16), a Glu to Gly substitution (E137G) was found in the MBD. The patients had manifestations similar to those of family 2, but MR was mild to moderate, speech articulation was poor and some had verbal stereotypies. Regression of language skills was suspected in three patients. Phenotype-genotype correlation could thus be suspected and is discussed in these three families.


Assuntos
Proteínas Cromossômicas não Histona , Proteínas de Ligação a DNA/genética , Retardo Mental Ligado ao Cromossomo X/genética , Mutação/genética , Proteínas Repressoras , Adulto , Feminino , Componentes do Gene , Genótipo , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG , Pessoa de Meia-Idade , Linhagem , Fenótipo , Síndrome de Rett/genética , Distúrbios da Fala/genética
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