Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 87
Filtrar
Filtros adicionais











Intervalo de ano
1.
Am J Hum Genet ; 105(1): 132-150, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31230720

RESUMO

Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.

2.
J Hum Genet ; 64(7): 609-616, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31015584

RESUMO

Individuals affected with autosomal recessive cutis laxa type 2B and 3 usually show translucent skin with visible veins and abnormal elastic fibers, intrauterine and/or postnatal growth restriction and a typical triangular facial gestalt. Here we describe three unrelated individuals in whom such a cutis laxa syndrome was suspected, especially after electron microscopy revealed immature and less dense dermal elastic fibers in one of them. However, one of these children also displayed optic atrophy and two hypogammaglobulinemia. All had elevated liver enzymes and acute liver failure during febrile episodes leading to early demise in two of them. The only surviving patient had been treated with immunoglobulins. Through exome sequencing we identified mutations in NBAS, coding for a protein involved in Golgi-to-ER transport. NBAS deficiency causes several rare conditions ranging from isolated recurrent acute liver failure to a multisystem disorder mainly characterized by short stature, optic nerve atrophy and Pelger-Huët anomaly (SOPH). Since we subsequently verified Pelger-Huët anomaly in two of the patients the diagnosis SOPH syndrome was unequivocally proven. Our data show that SOPH syndrome can be regarded as a differential diagnosis for the progeroid forms of cutis laxa in early infancy and that possibly treatment of the hypogammaglobulinemia can be of high relevance for the prognosis.

3.
Gene ; 704: 59-67, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30980944

RESUMO

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by biallelic mutations in GALNS gene and characterized by progressive skeletal deformities with short stature. The aim of this study was to evaluate the genotype, longitudinal height measurement and clinical features of MPS IVA patients. Thirty-two patients from 22 families were enrolled. The ages of patients at diagnosis ranged from two months to 18 years of age, and followed up for three to twenty years. They were classified as severe and attenuated form (intermediate and mild) according to their height measurements. The mean height standard deviation scores (SDS) for Turkish standards at 0-3, 5 and 10 years of ages were found to be -1.1, -4.2 and -7.3 respectively in patients with severe phenotype, while they were +0.4, -1.5 and -3 for intermediate phenotype. Patients with severe form reached a mean final height of -8.5 SDS, and mild phenotype -3.6 SDS. The most common initial and current symptoms in the patients with the severe phenotype were pectus carinatus and/or kyphosis deformities which occurred between 5 months and 3 years of age, and genu valgum deformity which developed after 3 years of age. However, kyphoscoliosis was the most common initial and current findings in the attenuated phenotype. Although, initial symptoms appeared in early childhood in the intermediate phenotype, similar to the severe phenotype, the clinical findings progressed slowly and genu valgum deformity did not develop. In patients with mild phenotype, the onset of symptoms was after 5 years of age. In conclusion, this study provides significant insights into the initial and follow-up clinical features and height values that contribute to the differential diagnosis of the severe and intermediate phenotypes in early childhood. Eleven mutations in GALNS gene in which one of them is novel (c.416G>A) were associated with the severe phenotype and three mutations (c.1038C>A, c.850T>G, c.752G>A) lead to the attenuated phenotype.


Assuntos
Condroitina Sulfatases/genética , Estudos de Associação Genética , Testes Genéticos , Mucopolissacaridose IV/diagnóstico , Mucopolissacaridose IV/genética , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Seguimentos , Predisposição Genética para Doença , Testes Genéticos/métodos , Genótipo , Humanos , Lactente , Masculino , Técnicas de Diagnóstico Molecular/métodos , Mucopolissacaridose IV/classificação , Fenótipo , Índice de Gravidade de Doença
4.
Hum Mutat ; 40(7): 842-864, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30882951

RESUMO

Mutations in the GNPTAB and GNPTG genes cause mucolipidosis (ML) type II, type III alpha/beta, and type III gamma, which are autosomal recessively inherited lysosomal storage disorders. GNPTAB and GNPTG encode the α/ß-precursor and the γ-subunit of N-acetylglucosamine (GlcNAc)-1-phosphotransferase, respectively, the key enzyme for the generation of mannose 6-phosphate targeting signals on lysosomal enzymes. Defective GlcNAc-1-phosphotransferase results in missorting of lysosomal enzymes and accumulation of non-degradable macromolecules in lysosomes, strongly impairing cellular function. MLII-affected patients have coarse facial features, cessation of statural growth and neuromotor development, severe skeletal abnormalities, organomegaly, and cardiorespiratory insufficiency leading to death in early childhood. MLIII alpha/beta and MLIII gamma are attenuated forms of the disease. Since the identification of the GNPTAB and GNPTG genes, 564 individuals affected by MLII or MLIII have been described in the literature. In this report, we provide an overview on 258 and 50 mutations in GNPTAB and GNPTG, respectively, including 58 novel GNPTAB and seven novel GNPTG variants. Comprehensive functional studies of GNPTAB missense mutations did not only gain insights into the composition and function of the GlcNAc-1-phosphotransferase, but also helped to define genotype-phenotype correlations to predict the clinical outcome in patients.

5.
Nat Commun ; 9(1): 3087, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30082715

RESUMO

Skeletal dysplasia with multiple dislocations are severe disorders characterized by dislocations of large joints and short stature. The majority of them have been linked to pathogenic variants in genes encoding glycosyltransferases, sulfotransferases or epimerases required for glycosaminoglycan synthesis. Using exome sequencing, we identify homozygous mutations in SLC10A7 in six individuals with skeletal dysplasia with multiple dislocations and amelogenesis imperfecta. SLC10A7 encodes a 10-transmembrane-domain transporter located at the plasma membrane. Functional studies in vitro demonstrate that SLC10A7 mutations reduce SLC10A7 protein expression. We generate a Slc10a7-/- mouse model, which displays shortened long bones, growth plate disorganization and tooth enamel anomalies, recapitulating the human phenotype. Furthermore, we identify decreased heparan sulfate levels in Slc10a7-/- mouse cartilage and patient fibroblasts. Finally, we find an abnormal N-glycoprotein electrophoretic profile in patient blood samples. Together, our findings support the involvement of SLC10A7 in glycosaminoglycan synthesis and specifically in skeletal development.

6.
Epileptic Disord ; 20(3): 219-224, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29905153

RESUMO

Proximal duplication of chromosome 14q, including the FOXG1 gene located on 14q12, is a rare condition characterised by developmental delay, dysmorphic craniofacial features, epilepsy, and severe speech delay. Here, we report a patient with West syndrome whose chromosome analysis revealed 14q11.2-21.1 duplication. The patient was admitted due to infantile epileptic spasms at eight months of age, motor developmental delay, and dysmorphic features. Chromosome and array-CGH analysis revealed de novo 14q11.2-21.1 duplication, spanning ∼20 Mb (minimal interval chr14:20203610_40396835). The patient was followed up to 13 years of age, and at the last examination was shown to have severe speech delay, seizures, and continuous spike-and-wave activity on EEG. The possibility of this chromosomal abnormality should be kept in mind in patients with developmental delay, epilepsy, and hypsarrtyhmia, in the absence of any structural brain lesion or metabolic aetiology.


Assuntos
Espasmos Infantis/diagnóstico , Adolescente , Criança , Pré-Escolar , Duplicação Cromossômica , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia
7.
Am J Hum Genet ; 103(1): 115-124, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29887215

RESUMO

MYF5 is member of the Myc-like basic helix-loop-helix transcription factor family and, in cooperation with other myogenic regulatory factors MYOD and MYF5, is a key regulator of early stages of myogenesis. Here, we report three consanguineous families with biallelic homozygous loss-of-function mutations in MYF5 who define a clinical disorder characterized by congenital ophthalmoplegia with scoliosis and vertebral and rib anomalies. The clinical phenotype overlaps strikingly with that reported in several Myf5 knockout mouse models. Affected members of two families share a haploidentical region that contains a homozygous 10 bp frameshift mutation in exon 1 of MYF5 (c.23_32delAGTTCTCACC [p.Gln8Leufs∗86]) predicted to undergo nonsense-mediated decay. Affected members of the third family harbor a homozygous missense change in exon 1 of MYF5 (c.283C>T [p.Arg95Cys]). Using in vitro assays, we show that this missense mutation acts as a loss-of-function allele by impairing MYF5 DNA binding and nuclear localization. We performed whole-genome sequencing in one affected individual with the frameshift mutation and did not identify additional rare variants in the haploidentical region that might account for differences in severity among the families. These data support the direct role of MYF5 in rib, spine, and extraocular muscle formation in humans.

8.
Mol Syndromol ; 9(3): 134-140, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29928178

RESUMO

Dysspondyloenchondromatosis (DSC) is a rare form of generalized enchondromatosis and characterized by short stature with unequal limb length, multiple enchondromas in metaphyseal and diaphyseal parts of the long tubular bones, and progressive kyphoscoliosis. Although the COL2A1 gene mutation was found to be responsible for DSC, a case of DSC with no pathogenic mutation in the COL2A1 gene has also been reported, suggesting that the condition is genetically heterogeneous. Here, we report 2 novel heterozygous mutations in COL2A1 in 2 patients with DSC. They had prenatal onset short stature with unequal limb length and generalized enchondroma-like lesions in metaphyseal and diaphyseal parts of the long tubular bones, and osteopenia. The first patient was diagnosed at 3 months of age and followed for 10.5 years. Severe lumbosacral scoliosis and recurrent fractures were observed. The second patient was diagnosed at the age of 4 years. Mild deterioration in scoliosis was observed during the 3-year-long follow-up period. However, skeletal radiography of both patients showed the improvement of enchondromatous lesions. In conclusion, we verified that the COL2A1 gene mutations are responsible for the DSC phenotype. We observed severe osteopenia and fractures which were not reported previously.

9.
Mol Genet Genomic Med ; 6(2): 230-248, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29397575

RESUMO

BACKGROUND: The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is a rare autosomal recessive condition characterized by camptodactyly, noninflammatory arthropathy, coxa vara, and pericarditis. CACP is caused by mutations in the proteoglycan 4 (PRG4) gene, which encodes a lubricating glycoprotein present in the synovial fluid and at the surface of articular cartilage. METHODS: In the present study, we compared the clinical and molecular findings of CACP syndrome in 35 patients from 11 unrelated families. In 28 patients, whole exome sequencing was used to investigate genomic variations. RESULTS: We found that camptodactyly of hands was the first symptom presented by most patients. Swelling of wrists, knees, and elbows began before 4 years of age, while the age of joint involvement was variable. Patients reported an increased pain level after the age of 10, and severe hip involvement developed after 20 years old. All patients presented developmental coxa vara and seven patients (~22%) had pleural effusion, pericarditis, and/or ascites. We identified nine novel genomic alterations, including the first case of homozygous complete deletion of exon 1 in the PRG4 gene. CONCLUSION: With this study, we contribute to the catalog of CACP causing variants. We confirm that the skeletal component of this disease worsens with age, and presents the potential mechanisms for interfamily variability, by discussing the influence of a modifier gene and escape from nonsense-mediated mRNA decay. We believe that this report will increase awareness of this familial arthropathic condition and the characteristic clinical and radiological findings will facilitate the differentiation from the common childhood rheumatic diseases such as juvenile idiopathic arthritis.


Assuntos
Artropatia Neurogênica/diagnóstico , Artropatia Neurogênica/genética , Coxa Vara/diagnóstico , Coxa Vara/genética , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Proteoglicanas/genética , Sinovite/diagnóstico , Sinovite/genética , Adolescente , Adulto , Criança , Pré-Escolar , Éxons/genética , Feminino , Estudos de Associação Genética/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteoglicanas/metabolismo , Estudos Retrospectivos , Deleção de Sequência , Sequenciamento Completo do Exoma/métodos
10.
Gene ; 642: 398-407, 2018 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-29170090

RESUMO

Mucolipidosis type III gamma (MLIII gamma) is a lysosomal storage disease characterized by joint stiffness, mild coarse face and corneal clouding, which becomes recognizable usually in childhood. Biallelic mutations in the GNPTG gene, which encode the γ subunit of the N-acetylglucosamine-1-phosphotransferase enzyme, are the underlying cause of MLIII gamma. The aim of this study is to evaluate the longitudinal findings and genotype of eleven patients from eight families with MLIII gamma and to establish a genotype-phenotype correlation. The most frequently observed initial finding was stiffness of finger joints, which detected in patients between 18month-olds and five year-olds. However, in four patients presented here, initial finding was knee pain or waddling gait, which started between six-16years of age. All patients also had variable degrees of stiffness on large joints. The longest follow up period was 16years while the shortest was three years and six months. We observed that the patients who had an early onset disease and severe joint stiffness had also rapidly progressive joint involvement mostly localized in hands, shoulders, and hip. However; the patients with late onset and/or mild joint stiffness experienced slowly progressive symptoms. Most patients dropped in their growth curve in time and the ones who were severely affected reached the final height below the third centile. Seven disease-causing mutations, three of them novel, were detected in GNPTG gene. According to our clinical observations c.493_494insC and c.283_284insC mutations lead to a severe phenotype and c.196C>T, c.347_349del, c.652_655delTACT and c.445delG/c.367A>G mutations seemed to generate a milder phenotype.


Assuntos
Mucolipidoses/genética , Mutação , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Estudos Longitudinais , Masculino , Fenótipo , Prognóstico , Adulto Jovem
11.
Mol Syndromol ; 8(6): 318-324, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29230162

RESUMO

We described a heterozygous de novo mutation (G434V) in the frizzled class receptor 2 (FZD2) gene in a patient with distinct facial features including hypertelorism, bilateral cleft lip/palate, short nose with a broad nasal bridge, microretrognathia, and bilateral shortness of the upper limbs, first metacarpal bones, and middle phalanges of the 5th digits. The findings of our patient were compared to an autosomal dominant omodysplasia (OMOD2) family with FZD2 mutation reported in the literature. OMOD2 is a rare skeletal dysplasia and characterized by facial dysmorphism and shortness of the upper extremities and first metacarpal bones. This is the second report which supports the findings of the first family described and points out that heterozygous FZD2 mutations may be disease-causing for OMOD2.

12.
Am J Med Genet A ; 173(12): 3195-3200, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28884924

RESUMO

We report on two new patients with spondyloocular syndrome. Both patients harbor novel homozygous mutations in the XYLT2 gene. The patients present severe generalized osteoporosis, multiple fractures, short stature, cataract, and mild hearing impairment. XYLT2 mutations have been identified in spondyloocular syndrome, however only five mutations have been reported previously. These two patients with novel mutations extend the phenotypic and genotypic spectrum of spondyloocular syndrome.


Assuntos
Catarata/genética , Anormalidades Craniofaciais/genética , Oftalmopatias Hereditárias/genética , Osteocondrodisplasias/genética , Pentosiltransferases/genética , Descolamento Retiniano/genética , Catarata/diagnóstico por imagem , Criança , Anormalidades Craniofaciais/diagnóstico por imagem , Oftalmopatias Hereditárias/diagnóstico por imagem , Feminino , Genótipo , Homozigoto , Humanos , Mutação , Osteocondrodisplasias/diagnóstico por imagem , Fenótipo , Descolamento Retiniano/diagnóstico por imagem
13.
Sci Rep ; 7: 43708, 2017 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-28272472

RESUMO

Recessive mutations in WD repeat domain 62 (WDR62) cause microcephaly and a wide spectrum of severe brain malformations. Disruption of the mouse ortholog results in microcephaly underlain by reduced proliferation of neocortical progenitors during late neurogenesis, abnormalities in asymmetric centrosome inheritance leading to neuronal migration delays, and altered neuronal differentiation. Spindle pole localization of WDR62 and mitotic progression are defective in patient-derived fibroblasts, which, similar to mouse neocortical progenitors, transiently arrest at prometaphase. Expression of WDR62 is closely correlated with components of the chromosome passenger complex (CPC), a key regulator of mitosis. Wild type WDR62, but not disease-associated mutant forms, interacts with the CPC core enzyme Aurora kinase B and staining of CPC components at centromeres is altered in patient-derived fibroblasts. Our findings demonstrate critical and diverse functions of WDR62 in neocortical development and provide insight into the mechanisms by which its disruption leads to a plethora of structural abnormalities.


Assuntos
Aurora Quinase B/genética , Centrossomo/metabolismo , Epistasia Genética , Padrões de Herança , Microcefalia/genética , Proteínas do Tecido Nervoso/genética , Animais , Encéfalo/anormalidades , Encéfalo/metabolismo , Encéfalo/patologia , Ciclo Celular/genética , Diferenciação Celular/genética , Proliferação de Células , Consanguinidade , Modelos Animais de Doenças , Imunofluorescência , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Knockout , Microcefalia/diagnóstico por imagem , Microcefalia/patologia , Mutação , Células-Tronco Neurais/metabolismo , Linhagem , Sequenciamento Completo do Genoma
15.
J Clin Res Pediatr Endocrinol ; 9(1): 74-79, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27425121

RESUMO

Pseudohypoparathyroidism type Ia (PHP-Ia) is characterized by multihormone resistance and an Albright hereditary osteodystrophy (AHO) phenotype. It is caused by heterozygous mutations in GNAS gene. Clinical and biochemical findings of a female PHP-Ia patient were evaluated from age of diagnosis (6.5 years) to 14.5 years of age. The patient had short stature, brachydactyly, and subcutaneous heterotopic ossifications. Serum calcium and phosphorus levels were normal, but parathyroid hormone levels were high. Based on the typical clinical findings of AHO phenotype and biochemical findings, she was diagnosed as having PHP-Ia. A novel heterozygous mutation (c.128T>C) was found in the GNAS gene. Follow-up examinations revealed resistance to thyroid-stimulating hormone and a bioinactive growth hormone. Clinicians should take into consideration PHP-Ia in patients referred with short stature, and patients with an AHO phenotype must be further evaluated for hormone resistance, GNAS gene mutation, Gsα activity. To our knowledge, this is the first case report describing bioinactive growth hormone in PHP-Ia.


Assuntos
Cromograninas/genética , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença/genética , Mutação , Pseudo-Hipoparatireoidismo/genética , Adolescente , Criança , Análise Mutacional de DNA , Feminino , Seguimentos , Heterozigoto , Humanos , Pseudo-Hipoparatireoidismo/classificação , Pseudo-Hipoparatireoidismo/diagnóstico , Turquia
16.
J Craniomaxillofac Surg ; 44(8): 919-24, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27325544

RESUMO

PURPOSE: The objective of this case series was to determine the oral, dental and craniofacial features of patients with EvC syndrome. MATERIAL AND METHODS: Eight patients with EvC syndrome were enrolled. A complete family history, pedigree analysis, detailed medical history were collected. Findings of clinical examination, including craniofacial and orodental manifestations, and radiological investigations were thoroughly studied. RESULTS: All eight patients had characteristic face, hypertrophic frenulum, conical and peg-shaped teeth, hypodontia of deciduous and/or permanent teeth and also skeletal dysplasia, small chest, short stature and hypoplastic nails. Additionally dysmorphic filtrum, serrated appearance of gingiva, diastema, enamel hypoplasia, microdontia, taurodontism, single rooted permanent molar, delayed eruption and high caries rate were observed with varying degrees. Cephalometric evaluation revealed skeletal Class III growth pattern in four subjects and Class II growth pattern in one subject. CONCLUSION: Evaluation of craniofacial and orodental anomalies of EvC syndrome is required for accurate differential diagnosis from other congenital syndromes.


Assuntos
Síndrome de Ellis-Van Creveld , Face/anormalidades , Anormalidades do Sistema Estomatognático , Adolescente , Criança , Cárie Dentária/complicações , Cavidade Pulpar/anormalidades , Síndrome de Ellis-Van Creveld/complicações , Feminino , Humanos , Masculino , Anormalidades Dentárias , Turquia , Adulto Jovem
17.
J Clin Endocrinol Metab ; 101(7): 2759-67, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27144933

RESUMO

CONTEXT: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near-total lack of body fat. OBJECTIVE: We aimed to study natural history and disease burden of various subtypes of CGL. DESIGN: We attempted to ascertain nearly all patients with CGL in Turkey. SETTING: This was a nationwide study. PATIENTS OR OTHER PARTICIPANTS: Participants included 33 patients (22 families) with CGL and 30 healthy controls. MAIN OUTCOME MEASURE(S): We wanted to ascertain genotypes by sequencing of the known genes. Whole-body magnetic resonance imaging was used to investigate the extent of fat loss. Metabolic abnormalities and end-organ complications were measured on prospective follow-up. RESULTS: Analysis of the AGPAT2 gene revealed four previously reported and four novel mutations (CGL1; c.144C>A, c.667_705delinsCTGCG, c.268delC, and c.316+1G>T). Analysis of the BSCL2 gene revealed four different homozygous and one compound heterozygous possible disease-causing mutations (CGL2), including four novel mutations (c.280C>T, c.631delG, c.62A>T, and c.465-468delGACT). Two homozygous PTRF mutations (c.481-482insGTGA and c.259C>T) were identified (CGL4). Patients with CGL1 had preservation of adipose tissue in the palms, soles, scalp, and orbital region, and had relatively lower serum adiponectin levels as compared to CGL2 patients. CGL4 patients had myopathy and other distinct clinical features. All patients developed various metabolic abnormalities associated with insulin resistance. Hepatic involvement was more severe in CGL2. End-organ complications were observed at young ages. Two patients died at age 62 years from cardiovascular events. CONCLUSIONS: CGL patients from Turkey had both previously reported and novel mutations of the AGPAT2, BSCL2, and PTRF genes. Our study highlights the early onset of severe metabolic abnormalities and increased risk of end-organ complications in patients with CGL.


Assuntos
Lipodistrofia Generalizada Congênita/patologia , Aciltransferases/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA , Progressão da Doença , Feminino , Subunidades gama da Proteína de Ligação ao GTP/genética , Humanos , Lactente , Resistência à Insulina , Lipodistrofia Generalizada Congênita/complicações , Lipodistrofia Generalizada Congênita/diagnóstico , Lipodistrofia Generalizada Congênita/genética , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Prognóstico , Turquia , Adulto Jovem
18.
J Bone Miner Res ; 31(8): 1577-85, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26987875

RESUMO

Spondyloocular syndrome is an autosomal-recessive disorder with spinal compression fractures, osteoporosis, and cataract. Mutations in XYLT2, encoding isoform of xylosyltransferase, were recently identified as the cause of the syndrome. We report on 4 patients, 2 unrelated patients and 2 siblings, with spondyloocular syndrome and novel mutations in XYLT2. Exome sequencing revealed a homozygous nonsense mutation, NM_022167.3(XYLT2): c.2188C>T, resulting in a premature stop codon (p.Arg730*) in a female patient. The patient presents visual impairment, generalized osteoporosis, short stature with short trunk, spinal compression fractures, and increased intervertebral disc space and hearing loss. We extended our XYLT2 analysis to a cohort of 22 patients with generalized osteoporosis, mostly from consanguineous families. In this cohort, we found by Sanger sequencing 2 siblings and 1 single patient who were homozygous for missense mutations in the XYLT2 gene (p.Arg563Gly and p.Leu605Pro). The patients had osteoporosis, compression fractures, cataracts, and hearing loss. Bisphosphonate treatment in 1 patient resulted in almost complete normalization of vertebral structures by adolescence, whereas treatment response in the others was variable. This report together with a previous study shows that mutations in the XYLT2 gene result in a variable phenotype dominated by spinal osteoporosis, cataract, and hearing loss. © 2016 American Society for Bone and Mineral Research.


Assuntos
Catarata/genética , Mutação/genética , Osteoporose/genética , Pentosiltransferases/genética , Fraturas da Coluna Vertebral/genética , Adolescente , Catarata/complicações , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Osteoporose/complicações , Linhagem , Fenótipo , Fraturas da Coluna Vertebral/complicações , Fraturas da Coluna Vertebral/diagnóstico por imagem , Síndrome , Sequenciamento Completo do Exoma
19.
Am J Med Genet A ; 170A(5): 1187-95, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26749367

RESUMO

Mucolipidosis IIIalpha/beta (MLIIIalpha/beta) is a rare lysosomal storage disorder characterized by childhood onset of flexion contractures of fingers, joint stiffness in the shoulders, hips, and knees, and mild short stature. Recessive mutations in the GNPTAB gene have been associated with MLIIIalpha/beta. We present five children aged 9-16 years from a large kindred family whose serum activities of several lysosomal enzymes were significantly elevated. Whole exome sequencing followed by confirmation by Sanger sequencing identified a novel homozygous missense mutation (c.22 A > G; p.R8G) in the GNPTAB gene in all affected subjects. The five patients initially presented with flexion contractures of fingers followed by stiffnes of large joints. Only two affected boys also had a nephrotic-range proteinuria. Renal biopsy showed focal segmental glomerulosclerosis and foamy appearance of glomerular visceral epithelial cells which were compatible with storage disease. No other known causes of proteinuria could be detected by both laboratory and biopsy findings. There was no known family history of hereditary kidney disease, and healthy siblings and parents had normal renal function and urinalysis. These findings suggest that the renal involvement probably due to MLIIIalpha/beta, although it can still be present by coincidence in the two affected patients.


Assuntos
Rim/fisiopatologia , Mucolipidoses/genética , Transferases (Outros Grupos de Fosfato Substituídos)/genética , Adolescente , Sequência de Bases/genética , Criança , Exoma , Feminino , Glomerulosclerose Segmentar e Focal , Homozigoto , Humanos , Rim/diagnóstico por imagem , Masculino , Mucolipidoses/diagnóstico por imagem , Mucolipidoses/fisiopatologia , Mutação de Sentido Incorreto , Linhagem
20.
J Clin Invest ; 126(2): 762-78, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26752647

RESUMO

BACKGROUND: Arthrogryposis, defined as congenital joint contractures in 2 or more body areas, is a clinical sign rather than a specific disease diagnosis. To date, more than 400 different disorders have been described that present with arthrogryposis, and variants of more than 220 genes have been associated with these disorders; however, the underlying molecular etiology remains unknown in the considerable majority of these cases. METHODS: We performed whole exome sequencing (WES) of 52 patients with clinical presentation of arthrogryposis from 48 different families. RESULTS: Affected individuals from 17 families (35.4%) had variants in known arthrogryposis-associated genes, including homozygous variants of cholinergic γ nicotinic receptor (CHRNG, 6 subjects) and endothelin converting enzyme-like 1 (ECEL1, 4 subjects). Deleterious variants in candidate arthrogryposis-causing genes (fibrillin 3 [FBN3], myosin IXA [MYO9A], and pleckstrin and Sec7 domain containing 3 [PSD3]) were identified in 3 families (6.2%). Moreover, in 8 families with a homozygous mutation in an arthrogryposis-associated gene, we identified a second locus with either a homozygous or compound heterozygous variant in a candidate gene (myosin binding protein C, fast type [MYBPC2] and vacuolar protein sorting 8 [VPS8], 2 families, 4.2%) or in another disease-associated genes (6 families, 12.5%), indicating a potential mutational burden contributing to disease expression. CONCLUSION: In 58.3% of families, the arthrogryposis manifestation could be explained by a molecular diagnosis; however, the molecular etiology in subjects from 20 families remained unsolved by WES. Only 5 of these 20 unrelated subjects had a clinical presentation consistent with amyoplasia; a phenotype not thought to be of genetic origin. Our results indicate that increased use of genome-wide technologies will provide opportunities to better understand genetic models for diseases and molecular mechanisms of genetically heterogeneous disorders, such as arthrogryposis. FUNDING: This work was supported in part by US National Human Genome Research Institute (NHGRI)/National Heart, Lung, and Blood Institute (NHLBI) grant U54HG006542 to the Baylor-Hopkins Center for Mendelian Genomics, and US National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS058529 to J.R. Lupski.


Assuntos
Artrogripose/genética , Exoma , Família , Artrogripose/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Turquia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA