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1.
J Vasc Surg ; 71(1): 149-157, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353273

RESUMO

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare disorder and 1 of 13 types of EDS. The syndrome results in aortic and arterial aneurysms and dissections at a young age. Diagnosis is confirmed with molecular testing via skin biopsy or genetic testing for COL3A1 pathogenic variants. We describe a multi-institutional experience in the diagnosis of vEDS from 2000 to 2015. METHODS: This is a multi-institutional cross-sectional retrospective study of individuals with vEDS. The institutions were recruited through the Vascular Low Frequency Disease Consortium. Individuals were identified using the International Classification of Diseases-9 and 10-CM codes for EDS (756.83 and Q79.6). A review of records was then performed to select individuals with vEDS. Data abstraction included demographics, family history, clinical features, major and minor diagnostic criteria, and molecular testing results. Individuals were classified into two cohorts and then compared: those with pathogenic COL3A1 variants and those diagnosed by clinical criteria alone without molecular confirmation. RESULTS: Eleven institutions identified 173 individuals (35.3% male, 56.6% Caucasian) with vEDS. Of those, 11 (9.8%) had nonpathogenic alterations in COL3A1 and were excluded from the analysis. Among the remaining individuals, 86 (47.7% male, 68% Caucasian, 48.8% positive family history) had pathogenic COL3A1 variants and 76 (19.7% male, 19.7% Caucasian, 43.4% positive family history) were diagnosed by clinical criteria alone without molecular confirmation. Compared with the cohort with pathogenic COL3A1 variants, the clinical diagnosis only cohort had a higher number of females (80.3% vs 52.3%; P < .001), mitral valve prolapse (10.5% vs 1.2%; P = .009), and joint hypermobility (68.4% vs 40.7%; P < .001). Additionally, they had a lower frequency of easy bruising (23.7% vs 64%; P < .001), thin translucent skin (17.1% vs 48.8%; P < .001), intestinal perforation (3.9% vs 16.3%; P = .01), spontaneous pneumothorax/hemothorax (3.9% vs 14%, P.03), and arterial rupture (9.2% vs 17.4%; P = .13). There were no differences in mortality or age of mortality between the two cohorts. CONCLUSIONS: This study highlights the importance of confirming vEDS diagnosis by testing for pathogenic COL3A1 variants rather than relying on clinical diagnostic criteria alone given the high degree of overlap with other forms genetically triggered arteriopathies. Because not all COL3A1 variants are pathogenic, the interpretation of the genetic testing results by an individual trained in variant assessment is essential to confirm the diagnosis. An accurate diagnosis is critical and has serious implications for lifelong screening and treatment strategies for the affected individual and family members.


Assuntos
Colágeno Tipo III/genética , Análise Mutacional de DNA , Síndrome de Ehlers-Danlos/diagnóstico , Mutação , Adolescente , Adulto , Estudos Transversais , Diagnóstico Diferencial , Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/genética , Feminino , Predisposição Genética para Doença , Alemanha , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Estados Unidos , Adulto Jovem
2.
Am J Hum Genet ; 99(5): 1005-1014, 2016 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-27745832

RESUMO

Periodontal Ehlers-Danlos syndrome (pEDS) is an autosomal-dominant disorder characterized by early-onset periodontitis leading to premature loss of teeth, joint hypermobility, and mild skin findings. A locus was mapped to an approximately 5.8 Mb region at 12p13.1 but no candidate gene was identified. In an international consortium we recruited 19 independent families comprising 107 individuals with pEDS to identify the locus, characterize the clinical details in those with defined genetic causes, and try to understand the physiological basis of the condition. In 17 of these families, we identified heterozygous missense or in-frame insertion/deletion mutations in C1R (15 families) or C1S (2 families), contiguous genes in the mapped locus that encode subunits C1r and C1s of the first component of the classical complement pathway. These two proteins form a heterotetramer that then combines with six C1q subunits. Pathogenic variants involve the subunit interfaces or inter-domain hinges of C1r and C1s and are associated with intracellular retention and mild endoplasmic reticulum enlargement. Clinical features of affected individuals in these families include rapidly progressing periodontitis with onset in the teens or childhood, a previously unrecognized lack of attached gingiva, pretibial hyperpigmentation, skin and vascular fragility, easy bruising, and variable musculoskeletal symptoms. Our findings open a connection between the inflammatory classical complement pathway and connective tissue homeostasis.


Assuntos
Complemento C1r/genética , Complemento C1s/genética , Síndrome de Ehlers-Danlos/genética , Deleção de Genes , Mutação de Sentido Incorreto , Periodontite/genética , Adolescente , Adulto , Criança , Pré-Escolar , Mapeamento Cromossômico , Cromossomos Humanos Par 12/genética , Síndrome de Ehlers-Danlos/diagnóstico , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Exoma , Feminino , Loci Gênicos , Humanos , Masculino , Linhagem , Periodontite/diagnóstico , Conformação Proteica , Adulto Jovem
3.
Genet Med ; 21(2): 275-283, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29970925

RESUMO

PURPOSE: Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI. METHODS: Using data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves. RESULTS: In children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05). CONCLUSION: From the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.


Assuntos
Estatura/fisiologia , Peso Corporal/fisiologia , Osteogênese Imperfeita/epidemiologia , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Difosfonatos/uso terapêutico , Feminino , Humanos , Masculino , América do Norte , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/uso terapêutico , Adulto Jovem
4.
J Vasc Surg ; 70(5): 1543-1554, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31126764

RESUMO

OBJECTIVE: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder owing to pathogenic variants in COL3A1 that lead to impaired type III collagen production. We aim to describe the contemporary multi-institutional experience of aortic and arterial pathology in individuals with vEDS, to evaluate disease patterns and refine management recommendations. METHODS: This cross-sectional, retrospective study of individuals with genetically confirmed vEDS was conducted between 2000 and 2015 at multiple institutions participating in the Vascular Low Frequency Disease Consortium. Aortic and arterial events including aneurysms, pseudoaneurysms, dissections, fistulae, or ruptures were studied. Demographics, COL3A1 variants, management, and outcomes data were collected and analyzed. Individuals with and without arterial events were compared. RESULTS: Eleven institutions identified 86 individuals with pathogenic variants in COL3A1 (47.7% male, 86% Caucasian; median age, 41 years; interquartile range [IQR], 31.0-49.5 years; 65.1% missense COL3A1 variants). The median follow-up from the time of vEDS diagnosis was 7.5 years (IQR, 3.5-12.0 years). A total of 139 aortic/arterial pathologies were diagnosed in 53 individuals (61.6%; 50.9% male; 88.5% Caucasian; median age, 33 years; IQR, 25.0-42.3 years). The aortic/arterial events presented as an emergency in 52 cases (37.4%). The most commonly affected arteries were the mesenteric arteries (31.7%), followed by cerebrovascular (16.5%), iliac (16.5%), and renal arteries (12.2%). The most common management was medical management. When undertaken, the predominant endovascular interventions were arterial embolization of medium sized arteries (13.4%), followed by stenting (2.5%). Aortic pathology was noted in 17 individuals (32%; 58.8% male; 94.1% Caucasian; median age, 38.5 years; IQR, 30.8-44.7 years). Most notably, four individuals underwent successful abdominal aortic aneurysm repair with excellent results on follow-up. Individuals with missense mutations, in which glycine was substituted with a large amino acid, had an earlier onset of aortic/arterial pathology (median age, 30 years; IQR, 23.5-37 years) compared with the other pathogenic COL3A1 variants (median age, 36 years; IQR, 29.5-44.8 years; P = .065). There were 12 deaths (22.6%) at a median age of 36 years (IQR, 28-51 years). CONCLUSIONS: Most of the vEDS arterial manifestations were managed medically in this cohort. When intervention is required for an enlarging aneurysm or rupture, embolization, and less frequently stenting, seem to be well-tolerated. Open repair of abdominal aortic aneurysm seems to be as well-tolerated as in those without vEDS; vEDS should not be a deterrent to offering an operation. Future work to elucidate the role of surgical interventions and refine management recommendations in the context of patient centered outcomes is warranted.


Assuntos
Aneurisma/epidemiologia , Aorta/patologia , Artérias/patologia , Colágeno Tipo III/genética , Síndrome de Ehlers-Danlos/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneurisma/genética , Aneurisma/patologia , Aneurisma/terapia , Aorta/cirurgia , Artérias/cirurgia , Criança , Pré-Escolar , Colágeno Tipo III/metabolismo , Estudos Transversais , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/patologia , Embolização Terapêutica/estatística & dados numéricos , Procedimentos Endovasculares/métodos , Procedimentos Endovasculares/estatística & dados numéricos , Feminino , Seguimentos , Testes Genéticos/estatística & dados numéricos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Estudos Retrospectivos , Adulto Jovem
5.
Genet Med ; 20(4): 411-419, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28817112

RESUMO

PurposeOsteogenesis imperfecta (OI) is a heritable skeletal dysplasia. Dominant pathogenic variants in COL1A1 and COL1A2 explain the majority of OI cases. At least 15 additional genes have been identified, but those still do not account for all OI phenotypes that present. We sought the genetic cause of mild and lethal OI phenotypes in an unsolved family.MethodsWe performed exome sequencing on seven members of the family, both affected and unaffected.ResultsWe identified a variant in cyclic AMP responsive element binding protein 3-like 1 (CREB3L1) in a consanguineous family. The variant caused a prenatal/perinatal lethal OI in homozygotes, similar to that seen in OI type II as a result of mutations in type I collagen genes, and a mild phenotype (fractures, blue sclerae) in multiple heterozygous family members. CREB3L1 encodes old astrocyte specifically induced substance (OASIS), an endoplasmic reticulum stress transducer. The variant disrupts a DNA-binding site and prevents OASIS from acting on its transcriptional targets including SEC24D, which encodes a component of the coat protein II complex.ConclusionThis report confirms that CREB3L1 is an OI-related gene and suggests the pathogenic mechanism of CREB3L1-associated OI involves the altered regulation of proteins involved in cellular secretion.


Assuntos
Alelos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Proteínas do Tecido Nervoso/genética , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Sequência de Aminoácidos , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Análise Mutacional de DNA , Genótipo , Humanos , Mutação , Proteínas do Tecido Nervoso/metabolismo , Osteogênese Imperfeita/metabolismo , Linhagem , Fenótipo , Radiografia , Análise de Sequência de DNA , Índice de Gravidade de Doença , Ultrassonografia Pré-Natal
6.
J Vasc Surg ; 68(3): 701-711, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29510914

RESUMO

OBJECTIVE: The contemporary practice of testing for genetically triggered aortic and arterial aneurysms and dissections is not well described. This study aimed to describe this practice at a tertiary care academic center and to ascertain the yield of testing in establishing the diagnosis in patients referred on the basis of clinical suspicion. METHODS: This is a retrospective cohort study of patients referred for vascular genetic testing at an academic medical center between 2010 and 2015. Patients were identified by Current Procedural Terminology diagnostic codes 81405, 81408, and 81479 for genetic testing (Marfan syndrome, Loeys-Dietz syndrome, aneurysms-osteoarthritis syndrome, COL3A1, and familial thoracic aortic aneurysm panel [ACTA2, COL3A1, TGFBR1, TGFBR2, SMAD3, TGFB2, MYLK, MYH11, and PRKG1 genes]) and by review of the collagen vascular laboratory database for genetic testing results. Data abstracted included demographics, clinical history, reason for referral, family history, referring provider type, and outcomes of genetic testing. RESULTS: Ninety-six patients (44.3% male; median age, 40.8 years) were referred for suspected genetic vascular disease. Genetic testing was performed in 75 cases thought to have heritable mutations related to aortic or arterial aneurysms and dissections. The most common reason for genetic testing was a personal history of aortic or arterial aneurysms and dissections (62.3%; mean age, 45.8 ± 11.1 years), followed by a family history of aortic or arterial aneurysms and dissections without a personal history (26.6%; age, 28.8 ± 17.9 years). The most common genetic testing performed was a familial thoracic aortic aneurysm gene panel (44%), followed by single gene testing for vascular Ehlers-Danlos syndrome (33.3%). Genetic testing identified a pathogenic mutation in 36% of the cases. The highest likelihood of identifying a pathogenic mutation was in those who had a family history with an already diagnosed mutation (57.1%), followed by patients with aortic root and ascending aortic aneurysm or dissection (42.3%). CONCLUSIONS: In patients with suspected genetically triggered vascular disease, the yield of clinical vascular genetic testing is reasonable when selective genetic testing is performed on the basis of personal or family history. These tests should be obtained with appropriate expertise in genetic counseling and interpretation of genetic testing results. Negative genetic test results in the setting of a positive family history demonstrate the limits of testing and known mutations leading to genetically triggered aortic and arterial aneurysms and dissections and support the need for novel gene discovery.


Assuntos
Aneurisma Aórtico/genética , Dissecção Aórtica/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Padrões de Prática Médica , Centros Médicos Acadêmicos , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos , Centros de Atenção Terciária , Adulto Jovem
7.
J Med Genet ; 54(6): 432-440, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28258187

RESUMO

BACKGROUND: Collagens are one of the major constituents of the pial membrane, which plays a crucial role in neuronal migration and cortical lamination during brain development. Type III procollagen, the chains of which are encoded by COL3A1, is the ligand of the G protein-coupled receptor 56 (GPR56), also known as adhesion G protein-coupled receptor G1. Bi-allelic mutations in GPR56 give rise to cobblestone-like malformation, white matter changes and cerebellar dysplasia. This report shows that bi-allelic mutations in COL3A1 are associated with a similar phenotype. METHODS: Exome analysis was performed in a family consisting of two affected and two non-affected siblings. Brain imaging studies of this family and of two previously reported individuals with bi-allelic mutations in COL3A1 were reviewed. Functional assays were performed on dermal fibroblasts. RESULTS: Exome analysis revealed a novel homozygous variant c.145C>G (p.Pro49Ala) in exon 2 of COL3A1. Brain MRI in the affected siblings as well as in the two previously reported individuals with bi-allelic COL3A1 mutations showed a brain phenotype similar to that associated with mutations in GPR56. CONCLUSION: Homozygous or compound heterozygous mutations in COL3A1 are associated with cobblestone-like malformation in all three families reported to date. The variability of the phenotype across patients suggests that genetic alterations in distinct domains of type III procollagen can lead to different outcomes. The presence of cobblestone-like malformation in patients with bi-allelic COL3A1 mutations emphasises the critical role of the type III collagen-GPR56 axis and the pial membrane in the regulation of brain development and cortical lamination.


Assuntos
Colágeno Tipo III/genética , Cistos/genética , Malformações do Desenvolvimento Cortical/genética , Receptores Acoplados a Proteínas G/genética , Substância Branca/patologia , Adulto , Alelos , Células Cultivadas , Doenças Cerebelares/genética , Doenças Cerebelares/patologia , Criança , Pré-Escolar , Cistos/patologia , Exoma/genética , Éxons/genética , Feminino , Fibroblastos/patologia , Humanos , Ligantes , Imageamento por Ressonância Magnética/métodos , Masculino , Malformações do Desenvolvimento Cortical/patologia , Mutação/genética , Fenótipo , Adulto Jovem
8.
Am J Med Genet C Semin Med Genet ; 175(1): 40-47, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28306228

RESUMO

Vascular Ehlers Danlos syndrome (vEDS) is an uncommon genetic disorders characterized by arterial aneurysm, dissection and rupture, bowel rupture, and rupture of the gravid uterus. The frequency is estimated as 1/50,000-1/200,000 and results from pathogenic variants in COL3A1, which encodes the chains of type III procollagen, a major protein in vessel walls and hollow organs. Initial diagnosis depends on the recognitions of clinical features, including family history. Management is complex and requires multiple specialists who can respond to and manage the major complications. A summary of recommendations for management include: Identify causative variants in COL3A1 prior to application of diagnosis, modulate life style to minimize injury, risk of vessel/organ rupture, identify and create care team, provide individual plans for emergency care ("vascular EDS passport") with diagnosis and management plan for use when traveling, centralize management at centers of excellence (experience) when feasible, maintain blood pressure in the normal range and treat hypertension aggressively, surveillance of vascular tree by doppler ultrasound, CTA (low radiation alternatives) or MRA if feasible on an annual basis. These recommendations represent a consensus of an international group of specialists with a broad aggregate experience in the care of individuals with vascular EDS that will need to be assessed on a regular basis as new information develops. © 2017 Wiley Periodicals, Inc.


Assuntos
Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/terapia , Colágeno Tipo III/genética , Gerenciamento Clínico , Humanos , Guias de Prática Clínica como Assunto , Doenças Vasculares
9.
Am J Med Genet C Semin Med Genet ; 175(1): 8-26, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28306229

RESUMO

The Ehlers-Danlos syndromes (EDS) are a clinically and genetically heterogeneous group of heritable connective tissue disorders (HCTDs) characterized by joint hypermobility, skin hyperextensibility, and tissue fragility. Over the past two decades, the Villefranche Nosology, which delineated six subtypes, has been widely used as the standard for clinical diagnosis of EDS. For most of these subtypes, mutations had been identified in collagen-encoding genes, or in genes encoding collagen-modifying enzymes. Since its publication in 1998, a whole spectrum of novel EDS subtypes has been described, and mutations have been identified in an array of novel genes. The International EDS Consortium proposes a revised EDS classification, which recognizes 13 subtypes. For each of the subtypes, we propose a set of clinical criteria that are suggestive for the diagnosis. However, in view of the vast genetic heterogeneity and phenotypic variability of the EDS subtypes, and the clinical overlap between EDS subtypes, but also with other HCTDs, the definite diagnosis of all EDS subtypes, except for the hypermobile type, relies on molecular confirmation with identification of (a) causative genetic variant(s). We also revised the clinical criteria for hypermobile EDS in order to allow for a better distinction from other joint hypermobility disorders. To satisfy research needs, we also propose a pathogenetic scheme, that regroups EDS subtypes for which the causative proteins function within the same pathway. We hope that the revised International EDS Classification will serve as a new standard for the diagnosis of EDS and will provide a framework for future research purposes. © 2017 Wiley Periodicals, Inc.


Assuntos
Síndrome de Ehlers-Danlos/classificação , Guias de Prática Clínica como Assunto , Colágeno/genética , Doenças do Tecido Conjuntivo/genética , Síndrome de Ehlers-Danlos/diagnóstico , Síndrome de Ehlers-Danlos/genética , Heterogeneidade Genética , Humanos , Mutação
10.
Am J Hum Genet ; 92(4): 590-7, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23499310

RESUMO

Osteogenesis imperfecta (OI) is a heritable disorder that ranges in severity from death in the perinatal period to an increased lifetime risk of fracture. Mutations in COL1A1 and COL1A2, which encode the chains of type I procollagen, result in dominant forms of OI, and mutations in several other genes result in recessive forms of OI. Here, we describe four recessive-OI-affected families in which we identified causative mutations in wingless-type MMTV integration site family 1 (WNT1). In family 1, we identified a homozygous missense mutation by exome sequencing. In family 2, we identified a homozygous nonsense mutation predicted to produce truncated WNT1. In family 3, we found a nonsense mutation and a single-nucleotide duplication on different alleles, and in family 4, we found a homozygous 14 bp deletion. The mutations in families 3 and 4 are predicted to result in nonsense-mediated mRNA decay and the absence of WNT1. WNT1 is a secreted signaling protein that binds the frizzled receptor (FZD) and the coreceptor low-density lipoprotein-receptor-related protein 5 (LRP5). Biallelic loss-of-function mutations in LRP5 result in recessive osteoporosis-pseudoglioma syndrome with low bone mass, whereas heterozygous gain-of-function mutations result in van Buchem disease with elevated bone density. Biallelic loss-of-function mutations in WNT1 result in a recessive clinical picture that includes bone fragility with a moderately severe and progressive presentation that is not easily distinguished from dominant OI type III.


Assuntos
Genes Recessivos/genética , Mutação/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Adulto , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Lactente , Masculino , Osteogênese Imperfeita/patologia , Linhagem , Adulto Jovem
11.
Genet Med ; 18(1): 20-4, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25834947

RESUMO

PURPOSE: Genetic testing has shifted from academic laboratories with expertise in specific genes to commercial laboratories that offer tests of a diverse array of genes. The purpose of this comparative study was to determine whether one academic laboratory's model of variant interpretation is similar to that of several commercial laboratories. METHODS: The Collagen Diagnostic Laboratory (CDL) received, over a 14-month period, 38 requests to interpret variants originally identified by an outside laboratory (OL). The interpretations by the OL and CDL were compared and discrepancies were assessed. RESULTS: Interpretations from the OL and CDL were concordant in 11 inquiries (29%); discrepancies were moderate in 11 instances (29%) and significant in 16 (42%). Factors that caused discrepancies included the following: (i) private data were not shared in a public database (n = 9); (ii) publicly available allele frequency data were not referenced and used as evidence (n = 5); and (iii) important aspects of protein structure and function were not taken into account (n = 13). CONCLUSION: Comprehensive interpretation of sequence variants depends on good functional tests and well-curated variant databases. Provision of clinical information to the clinical laboratory, mandatory submission of identified variants with phenotype data to common resources, and collaboration between clinical laboratories and recognized experts is likely to improve consistency in variant interpretation among clinical laboratories.Genet Med 18 1, 20-24.


Assuntos
Análise de Sequência de DNA/métodos , Interpretação Estatística de Dados , Frequência do Gene , Estudos de Associação Genética , Testes Genéticos/métodos , Variação Genética , Humanos , Reprodutibilidade dos Testes
12.
Am J Med Genet C Semin Med Genet ; 169(4): 307-13, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26566591

RESUMO

Non-accidental injury (NAI) is a major medical concern in the United States. One of the challenges in evaluation of children with unexplained fractures is that genetic forms of bone fragility are one of the differential diagnoses. Infants who present with fractures with mild forms of osteogenesis imperfecta (OI) (OI type I or OI type IV), the most common genetic form of bone disease leading to fractures might be missed if clinical evaluation alone is used to make the diagnosis. Diagnostic clinical features (blue sclera, dentinogenesis imperfecta, Wormian bones on X-rays or positive family history) may not be present or apparent at the age of evaluation. The evaluating clinician faces the decision about whether genetic testing is necessary in certain NAI cases. In this review, we outline clinical presentations of mild OI and review the history of genetic testing for OI in the NAI versus OI setting. We summarize our data of molecular testing in the Collagen Diagnostic Laboratory (CDL) from 2008 to 2014 where NAI was noted on the request for DNA sequencing of COL1A1 and COL1A2. We provide recommendations for molecular testing in the NAI versus OI setting. First, DNA sequencing of COL1A1, COL1A2, and IFITM5 simultaneously and duplication/deletion testing is recommended. If a causative variant is not identified, in the absence of a pathologic clinical phenotype, no additional gene testing is indicated. If a VUS is found, parental segregation studies are recommended.


Assuntos
Maus-Tratos Infantis/diagnóstico , Fraturas Ósseas/etiologia , Osteogênese Imperfeita/diagnóstico , Pré-Escolar , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Diagnóstico Diferencial , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/diagnóstico por imagem , Testes Genéticos , Humanos , Lactente , Proteínas de Membrana/genética , Osteogênese Imperfeita/genética , Radiografia
13.
Genet Med ; 16(12): 874-80, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24922461

RESUMO

PURPOSE: The purpose of this study was to characterize the nature and magnitude of pregnancy risks in women with vascular Ehlers-Danlos syndrome. METHODS: Pregnancy-related death rate was determined by a review of pedigrees of families with vascular Ehlers-Danlos syndrome. Maternal morbidity was characterized through semistructured interviews with women with vascular Ehlers-Danlos syndrome or their next of kin. RESULTS: Pregnancy-related deaths occurred in 30 of 565 deliveries (5.3%). There was no difference in Kaplan-Meier survival curves between parous versus nulliparous women with vascular Ehlers-Danlos syndrome. Interviews with 39 women indicated that 46% of deliveries were uncomplicated. The most common pregnancy-related complications were third-/fourth-degree lacerations (20%) and preterm delivery (19%). Life-threatening complications occurred in 14.5% of deliveries and included arterial dissection/rupture (9.2%), uterine rupture (2.6%), and surgical complications (2.6%). There were 5 maternal deaths in 76 deliveries (6.5%). CONCLUSION: The risk of pregnancy-related complications is increased in women with vascular Ehlers-Danlos syndrome compared with the general population; however, survival data indicate that pregnancy does not appear to affect overall mortality compared with nulliparous women with vascular Ehlers-Danlos syndrome. The data were insufficient to determine whether mode or timing of delivery influenced risk of complications. Women with vascular Ehlers-Danlos syndrome should be engaged in a shared decision-making process when contemplating pregnancy and pregnancy management.


Assuntos
Síndrome de Ehlers-Danlos/complicações , Síndrome de Ehlers-Danlos/mortalidade , Complicações na Gravidez/mortalidade , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Dissecção Aórtica/complicações , Síndrome de Ehlers-Danlos/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Morte Materna , Pessoa de Meia-Idade , Mutação , Paridade , Linhagem , Gravidez , Estudos Retrospectivos , Fatores de Risco , Ruptura Espontânea , Resultado do Tratamento , Ruptura Uterina , Adulto Jovem
14.
Genet Med ; 16(12): 881-8, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24922459

RESUMO

PURPOSE: We sought to characterize the natural history of vascular Ehlers-Danlos syndrome in individuals with heterozygous COL3A1 mutations. METHODS: We reviewed clinical records for details of vascular, bowel, and organ complications in 1,231 individuals (630 index cases and 601 relatives). RESULTS: Missense and splice-site mutations accounted for more than 90% of the 572 alterations that we had identified in COL3A1. Median survival was 51 years but was influenced by gender (lower in men) and by the type of mutation. CONCLUSION: Although vascular Ehlers-Danlos syndrome appears to be genetically homogeneous, allelic heterogeneity is marked, and the natural history varies with gender and type of mutation in COL3A1. These findings indicate that when counseling families, confirmation of the presence of a COL3A1 mutation and its nature can help evaluate the risks of complications. These data are also important ingredients in both the selection and allocation of individuals to appropriate arms in clinical trials to assess the effects of interventions.


Assuntos
Colágeno Tipo III/genética , Análise Mutacional de DNA , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/mortalidade , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Splicing de RNA , Resultado do Tratamento , Adulto Jovem
15.
Hum Mol Genet ; 20(8): 1595-609, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21282188

RESUMO

Recessive mutations in the cartilage-associated protein (CRTAP), leucine proline-enriched proteoglycan 1 (LEPRE1) and peptidyl prolyl cis-trans isomerase B (PPIB) genes result in phenotypes that range from lethal in the perinatal period to severe deforming osteogenesis imperfecta (OI). These genes encode CRTAP (encoded by CRTAP), prolyl 3-hydroxylase 1 (P3H1; encoded by LEPRE1) and cyclophilin B (CYPB; encoded by PPIB), which reside in the rough endoplasmic reticulum (RER) and can form a complex involved in prolyl 3-hydroxylation in type I procollagen. CYPB, a prolyl cis-trans isomerase, has been thought to drive the prolyl-containing peptide bonds to the trans configuration needed for triple helix formation. Here, we describe mutations in PPIB identified in cells from three individuals with OI. Cultured dermal fibroblasts from the most severely affected infant make some overmodified type I procollagen molecules. Proα1(I) chains are slow to assemble into trimers, and abnormal procollagen molecules concentrate in the RER, and bind to protein disulfide isomerase (PDI) and prolyl 4-hydroxylase 1 (P4H1). These findings suggest that although CYPB plays a role in helix formation another effect is on folding of the C-terminal propeptide and trimer formation. The extent of procollagen accumulation and PDI/P4H1 binding differs among cells with mutations in PPIB, CRTAP and LEPRE1 with the greatest amount in PPIB-deficient cells and the least in LEPRE1-deficient cells. These findings suggest that prolyl cis-trans isomerase may be required to effectively fold the proline-rich regions of the C-terminal propeptide to allow proα chain association and suggest an order of action for CRTAP, P3H1 and CYPB in procollagen biosynthesis and pathogenesis of OI.


Assuntos
Colágeno Tipo I/metabolismo , Ciclofilinas/genética , Osteogênese Imperfeita/genética , Pró-Colágeno/metabolismo , Adolescente , Sequência de Aminoácidos , Sequência de Bases , Células Cultivadas , Criança , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Fêmur/anormalidades , Fêmur/diagnóstico por imagem , Fibroblastos/metabolismo , Humanos , Hidroxilação , Lactente , Recém-Nascido , Glicoproteínas de Membrana/genética , Chaperonas Moleculares , Dados de Sequência Molecular , Osteogênese Imperfeita/mortalidade , Linhagem , Fenótipo , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Prolina/metabolismo , Domínios Proteicos Ricos em Prolina , Prolil Hidroxilases , Isomerases de Dissulfetos de Proteínas/metabolismo , Processamento de Proteína Pós-Traducional , Estabilidade Proteica , Proteoglicanas/genética , Radiografia , Costelas/anormalidades , Costelas/diagnóstico por imagem , Deleção de Sequência , Crânio/anormalidades , Crânio/diagnóstico por imagem
16.
Am J Hum Genet ; 86(3): 389-98, 2010 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-20188343

RESUMO

Osteogenesis imperfecta (OI) is characterized by bone fragility and fractures that may be accompanied by bone deformity, dentinogenesis imperfecta, short stature, and shortened life span. About 90% of individuals with OI have dominant mutations in the type I collagen genes COL1A1 and COL1A2. Recessive forms of OI resulting from mutations in collagen-modifying enzymes and chaperones CRTAP, LEPRE1, PPIB, and FKBP10 have recently been identified. We have identified an autosomal-recessive missense mutation (c.233T>C, p.Leu78Pro) in SERPINH1, which encodes the collagen chaperone-like protein HSP47, that leads to a severe OI phenotype. The mutation results in degradation of the endoplasmic reticulum resident HSP47 via the proteasome. Type I procollagen accumulates in the Golgi of fibroblasts from the affected individual and a population of the secreted type I procollagen is protease sensitive. These findings suggest that HSP47 monitors the integrity of the triple helix of type I procollagen at the ER/cis-Golgi boundary and, when absent, the rate of transit from the ER to the Golgi is increased and helical structure is compromised. The normal 3-hydroxylation of the prolyl residue at position 986 of the triple helical domain of proalpha1(I) chains places the role of HSP47 downstream from the CRTAP/P3H1/CyPB complex that is involved in prolyl 3-hydroxylation. Identification of this mutation in SERPINH1 gives further insight into critical steps of the collagen biosynthetic pathway and the molecular pathogenesis of OI.


Assuntos
Proteínas de Choque Térmico HSP47/genética , Mutação de Sentido Incorreto , Osteogênese Imperfeita/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , Pré-Escolar , Colágeno Tipo I/química , Colágeno Tipo I/metabolismo , Consanguinidade , Sequência Conservada , DNA/genética , Retículo Endoplasmático/metabolismo , Evolução Fatal , Feminino , Genes Recessivos , Proteínas de Choque Térmico HSP47/metabolismo , Homozigoto , Humanos , Masculino , Dados de Sequência Molecular , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/metabolismo , Linhagem , Fenótipo , Complexo de Endopeptidases do Proteassoma/metabolismo , Estabilidade Proteica , Radiografia , Homologia de Sequência de Aminoácidos
17.
Genet Med ; 13(8): 717-22, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21637106

RESUMO

PURPOSE: To characterize the clinical outcome of heterozygosity for COL3A1 null mutations in Ehlers-Danlos syndrome type IV, the vascular type. METHODS: We identified mutations that produced premature termination codons and resulted in nonsense-mediated messenger RNA decay in 19 families. We reviewed the clinical and family histories and medical complications in 54 individuals from these families with COL3A1 null mutations. RESULTS: Compared with individuals with missense or exon-skipping mutations, we found that life span was extended, the age of first complication was delayed by almost 15 years, and major complications were limited to vascular events. The families were ascertained after a complication in a single individual, but only 28% of relatives, some of whom had reached their seventies or eighties without incidents, had a complication and only 30% had minor clinical features of Ehlers-Danlos syndrome type IV CONCLUSION: Null mutations have reduced penetrance compared with missense and splicing mutations, and the phenotype seems to be limited almost entirely to vascular events.


Assuntos
Colágeno Tipo III/genética , Síndrome de Ehlers-Danlos/complicações , Haploinsuficiência , Expectativa de Vida , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aneurisma/etiologia , Aneurisma/genética , Criança , Pré-Escolar , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/mortalidade , Feminino , Estudos de Associação Genética , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Penetrância , Análise de Sequência de DNA , Adulto Jovem
18.
Genet Med ; 13(2): 125-30, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21239989

RESUMO

PURPOSE: Recurrence of lethal osteogenesis imperfecta in families results from either dominant (parental mosaicism) or recessive inheritance. The proportion of these two mechanisms is not known, and determination of the contribution of each is important to structure genetic counseling for these families. METHODS: We measured the recurrence rate of lethal osteogenesis imperfecta after the birth of an affected infant. We determined the rate of parental mosaicism in a subset of families in which we had identified dominant mutations. In 37 families in which two or more affected infants were born, we identified mutations and determined the proportion that resulted from recessive inheritance. RESULTS: The recurrence rate after the first affected pregnancy was 1.3%. The rate of parental mosaicism in families in which a dominant mutation was identified in a first affected child was 16%. In 37 families with two affected infants, 26 had dominant mutations, seven had recessive mutations, and we failed to find mutations in four. The overall recurrence rate for couples after two or more affected infants was 32%; 27% for families with parental mosaicism, 31% for recessive mutations, and 50% for families with no identified mutation. CONCLUSIONS: In most populations, recurrence of lethal osteogenesis imperfecta usually results from parental mosaicism for dominant mutations, but the carrier frequency of recessive forms of osteogenesis imperfecta will alter that proportion. Mutation identification is an important tool to assess risk and facilitate prenatal or preimplantation diagnosis.


Assuntos
Genes Dominantes , Genes Recessivos , Mosaicismo , Osteogênese Imperfeita/diagnóstico , Osteogênese Imperfeita/genética , Diagnóstico Pré-Natal , Células Cultivadas , Colágeno/genética , Colágeno Tipo I , Ciclofilinas/genética , Proteínas da Matriz Extracelular/genética , Feminino , Aconselhamento Genético , Mutação em Linhagem Germinativa , Humanos , Lactente , Glicoproteínas de Membrana/genética , Chaperonas Moleculares , Linhagem , Gravidez , Prolil Hidroxilases , Proteoglicanas/genética , Recidiva , Medição de Risco
19.
HGG Adv ; 2(4): 100051, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-35047842

RESUMO

The bone disorder osteogenesis imperfecta (OI) is genetically heterogeneous. Most affected individuals have an autosomal dominant disorder caused by heterozygous variants in either of the type I collagen genes (COL1A1 or COL1A2). To date, two reports have linked Mesoderm Development LRP Chaperone (MESD) to autosomal recessive OI type XX. Four different biallelic pathogenic variants in MESD were shown to cause a progressively deforming phenotype, associated with recurrent fractures and oligodontia in five individuals in five families. Recently, compound heterozygosity for a frameshift predicted to lead to a premature termination codon in exon 2 of the 3-exon gene and a second frameshift in the terminal exon in MESD were detected in three stillbirths in one family with severe OI consistent with the neonatal lethal phenotype. We have identified four additional individuals from four independent families with biallelic variants in MESD: the earlier reported c.632dupA (p.Lys212Glufs∗19) and c.676C>T (p.Arg226∗)-which are associated with a severe form of OI-and one new pathogenic variant, c.603-606delTAAA (p.Asn201Lysfs∗15), which causes a neonatal lethal form of OI. MESD acts in the WNT signaling pathway, where it is thought to play a role in the folding of the WNT co-receptors low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/LRP6) and in chaperoning their transit to the cell surface. Our report broadens the phenotypic and genetic spectrum of MESD-related OI, provides additional insight into the pathogenic pathways, and underscores the necessity of MESD for normal WNT signaling in bone formation.

20.
JBMR Plus ; 3(5): e10118, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31131341

RESUMO

Osteogenesis imperfecta (OI) is characterized by low bone mass and bone fragility. Using data from a large cohort of individuals with OI from the Osteogenesis Imperfecta Foundation's linked clinical research centers, we examined the association between exposure to bisphosphonate (BPN) treatment (past or present) and lumbar spine (LS) areal bone mineral density (aBMD), fractures, scoliosis, and mobility. From 466 individuals, we obtained 1394 participant-age LS aBMD data points. Though all OI subtypes were examined, primary analyses were restricted to type I OI (OI-1). Using linear regression, we constructed expected OI-1 LS aBMD-for-age curves from the data from individuals who had never received BPN. LS aBMD in those who had been exposed to BPN was then compared with the computed expected aBMD. BPN exposure in preadolescent years (age <14 years) was associated with a LS aBMD that was 9% more than the expected computed values in BPN-naïve individuals (p < 0.01); however, such association was not observed across all ages. Exposure to i.v. BPN and treatment duration >2 years correlated with LS aBMD in preadolescent individuals. BPN exposure also had a significant association with non-aBMD clinical outcome variables. Logistic regression modeling predicted that with BPN exposure, a 1-year increase in age would be associated with an 8.2% decrease in fracture probability for preadolescent individuals with OI-1, compared with no decrease in individuals who had never received any BPN (p < 0.05). In preadolescent individuals with OI-1, a 0.1 g/cm2 increase in LS aBMD was associated with a 10.6% decrease in scoliosis probability, compared with a 46.8% increase in the BPN-naïve group (p < 0.01). For the same changes in age and LS aBMD in preadolescent individuals, BPN exposure was also associated with higher mobility scores (p < 0.01), demonstrating that BPN treatment may be associated with daily function. © 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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