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1.
Genet Med ; 21(11): 2644-2649, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31147633

RESUMO

PURPOSE: Beckwith-Wiedemann syndrome (BWS) is a human genomic imprinting disorder characterized by lateralized overgrowth, macroglossia, abdominal wall defects, congenital hyperinsulinism, and predisposition to embryonal tumors. One of the molecular etiologies underlying BWS is paternal uniparental isodisomy of chromosome 11p15.5 (pUPD11). About 8% of pUPD11 cases are due to genome-wide paternal uniparental isodisomy (GWpUPD). About 30 cases of live-born patients with GWpUPD have been described, most of whom were mosaic and female. We present male patients with BWS due to GWpUPD, elucidate the underlying mechanism, and make recommendations for management. METHODS: Three male patients with GWpUPD underwent clinical and molecular evaluation by single-nucleotide polymorphism (SNP) microarrays in different tissues. Previously published cases of GWpUPD were reviewed. RESULTS: SNP microarray demonstrated a GWpUPD cell population with sex chromosomes XX and biparental cell population with sex chromosomes XY, consistent with dispermic androgenetic chimerism. CONCLUSION: SNP microarray is necessary to distinguish GWpUPD cases and the underlying mechanisms. The percentage of GWpUPD cell population within a specific tissue type correlated with the amount of tissue dysplasia. Males with BWS due to GWpUPD are important to distinguish from other molecular etiologies because the mechanism indicates risk for germ cell tumors and autosomal recessive diseases in addition to other BWS features.

2.
Am J Med Genet A ; 179(8): 1543-1546, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31207089

RESUMO

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.

3.
Ann Neurol ; 86(2): 181-192, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31177578

RESUMO

OBJECTIVE: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. METHODS: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. RESULTS: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. INTERPRETATION: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.

4.
Am J Med Genet A ; 176(4): 925-935, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29436146

RESUMO

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

5.
Genet Med ; 20(2): 169-171, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29323668

RESUMO

Disclaimer: This Points to Consider document is designed as an educational resource to provide best practices for medical genetic clinicians, laboratories, and journals regarding the provision, publication, and dissemination of patient phenotypes in the context of genomic testing, clinical genetic practice, and research. While the goal of the document is the improvement of patient care, the considerations and practices described should not be considered inclusive of all proper considerations and practices or exclusive of others that are reasonably directed to obtaining the same goal. In determining the value of any practice, clinicians, laboratories, and journals should apply their own professional standards and judgment to the specific circumstances presented.The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the authors' affiliated institutions.


Assuntos
Testes Genéticos/normas , Genética Médica/normas , Genômica/normas , Disseminação de Informação , Papel Profissional , Publicações/normas , Testes Genéticos/métodos , Genética Médica/métodos , Genômica/métodos , Humanos
6.
Genome Med ; 9(1): 83, 2017 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-28934986

RESUMO

BACKGROUND: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery. METHODS: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association. RESULTS: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses. CONCLUSIONS: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.


Assuntos
Variações do Número de Cópias de DNA , Éxons , Doenças Genéticas Inatas , Estudos de Coortes , Genoma Humano , Proteínas de Homeodomínio/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Serina-Treonina Quinases/genética , Estudos Retrospectivos , Fatores de Transcrição/genética , Sequenciamento Completo do Genoma
7.
Medicine (Baltimore) ; 96(50): e9256, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29390364

RESUMO

Feeding intolerance in Prader-Willi syndrome (PWS) infants is well-recognized, but their swallow physiology is not well understood. Swallow dysfunction increases risks of respiratory compromise and choking, which have a high incidence in PWS. To investigate swallow pathology in PWS infants we undertook a retrospective review of videofluoroscopic swallow studies (VFSS) in infants with PWS seen at our institution. We hypothesize that VFSS will characterize swallow pathology suspected by clinical observation during a feeding evaluation and may help determine feeding safety in these infants.Retrospective review of 23 VFSS on 10 PWS infants (average age 9.7 ±â€Š8.4 months; range 3 weeks-29 months). Logistic regression models evaluated associations between gender, genetic subtype, and growth hormone (GH) use on aspiration incidence. Polysomnographic (PSG) studies conducted on the same participant ±1 year from VFSS were examined to characterize respiratory abnormalities.There was a high rate of swallowing dysfunction (pharyngeal residue 71%, aspiration events 87%) and disordered sleep. All aspiration events were silent. There were no differences in rates of aspiration for gender, genetic subtype, or GH use.A high incidence of aspiration was identified indicating swallow dysfunction may frequently be present in infants with PWS. Comprehensive evaluation of feeding and swallowing is essential and requires a multidisciplinary approach. Providers should recognize risk factors for swallow dysfunction and consider a multidisciplinary approach to guide decision making and optimize feeding safety in PWS.


Assuntos
Transtornos de Deglutição/fisiopatologia , Síndrome de Prader-Willi/fisiopatologia , Aspiração Respiratória/diagnóstico por imagem , Aspiração Respiratória/fisiopatologia , Pré-Escolar , Feminino , Fluoroscopia , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos , Fatores de Risco , Gravação em Vídeo
8.
J Physiol ; 594(2): 437-52, 2016 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-26460603

RESUMO

KEY POINTS: The contractile properties of human fetal cardiac muscle have not been previously studied. Small-scale approaches such as isolated myofibril and isolated contractile protein biomechanical assays allow study of activation and relaxation kinetics of human fetal cardiac muscle under well-controlled conditions. We have examined the contractile properties of human fetal cardiac myofibrils and myosin across gestational age 59-134 days. Human fetal cardiac myofibrils have low force and slow kinetics of activation and relaxation that increase during the time period studied, and kinetic changes may result from structural maturation and changes in protein isoform expression. Understanding the time course of human fetal cardiac muscle structure and contractile maturation can provide a framework to study development of contractile dysfunction with disease and evaluate the maturation state of cultured stem cell-derived cardiomyocytes. ABSTRACT: Little is known about the contractile properties of human fetal cardiac muscle during development. Understanding these contractile properties, and how they change throughout development, can provide valuable insight into human heart development, and provide a framework to study the early stages of cardiac diseases that develop in utero. We characterized the contractile properties of isolated human fetal cardiac myofibrils across 8-19 weeks of gestation. Mechanical measurements revealed that in early stages of gestation there is low specific force and slow rates of force development and relaxation, with increases in force and the rates of activation and relaxation as gestation progresses. The duration and slope of the initial, slow phase of relaxation, related to myosin detachment and thin filament deactivation rates, decreased with gestation age. F-actin sliding on human fetal cardiac myosin-coated surfaces slowed significantly from 108 to 130 days of gestation. Electron micrographs showed human fetal muscle myofibrils elongate and widen with age, but features such as the M-line and Z-band are apparent even as early as day 52. Protein isoform analysis revealed that ß-myosin is predominantly expressed even at the earliest time point studied, but there is a progressive increase in expression of cardiac troponin I (TnI), with a concurrent decrease in slow skeletal TnI. Together, our results suggest that cardiac myofibril force production and kinetics of activation and relaxation change significantly with gestation age and are influenced by the structural maturation of the sarcomere and changes in contractile filament protein isoforms.


Assuntos
Coração Fetal/fisiologia , Contração Miocárdica , Miofibrilas/fisiologia , Actinas/genética , Actinas/metabolismo , Adulto , Feminino , Coração Fetal/embriologia , Humanos , Masculino , Miofibrilas/metabolismo , Miofibrilas/ultraestrutura , Miosinas/genética , Miosinas/metabolismo , Troponina I/genética , Troponina I/metabolismo
9.
Pediatr Endocrinol Rev ; 12(3): 297-307, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25962207

RESUMO

Prader-Willi Syndrome (PWS) is one of the most common genetic causes of obesity. The phenotype of obesity in PWS is unique and characterized by hyperphagia, earlier meal initiation, delayed meal termination, reduced energy expenditure, abnormal gut hormone profiles, as well as irregular responses to food in areas of the brain associated with satiety and reward. Management of obesity is necessary to avoid major morbidity. The relentless food-seeking behavior associated with PWS such as stealing, hoarding food, eating inedibles, and lying about eating, can cause turmoil both inside and outside of the home. Management is challenging for both patients and caretakers, but at this time there are limited medical therapies available besides dietary restriction and behavior management. However, current research shows promise for discovery of additional treatment options for hyperphagia and obesity management in PWS.


Assuntos
Obesidade/terapia , Síndrome de Prader-Willi/terapia , Animais , Humanos , Hiperfagia/complicações , Hiperfagia/terapia , Obesidade/etiologia , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/genética , Programas de Redução de Peso/métodos
10.
Am J Hum Genet ; 96(5): 841-9, 2015 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-25957469

RESUMO

Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.


Assuntos
Artrogripose/genética , Proteínas do Citoesqueleto/genética , Miosinas/biossíntese , Artrogripose/fisiopatologia , Proteínas do Citoesqueleto/biossíntese , Exoma/genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Miosinas/genética , Osteogênese/genética
11.
Hum Mol Genet ; 24(12): 3348-58, 2015 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-25740846

RESUMO

Distal arthrogryposis is the most common known heritable cause of congenital contractures (e.g. clubfoot) and results from mutations in genes that encode proteins of the contractile complex of skeletal muscle cells. Mutations are most frequently found in MYH3 and are predicted to impair the function of embryonic myosin. We measured the contractile properties of individual skeletal muscle cells and the activation and relaxation kinetics of isolated myofibrils from two adult individuals with an R672C substitution in embryonic myosin and distal arthrogryposis syndrome 2A (DA2A) or Freeman-Sheldon syndrome. In R672C-containing muscle cells, we observed reduced specific force, a prolonged time to relaxation and incomplete relaxation (elevated residual force). In R672C-containing muscle myofibrils, the initial, slower phase of relaxation had a longer duration and slower rate, and time to complete relaxation was greatly prolonged. These observations can be collectively explained by a small subpopulation of myosin cross-bridges with greatly reduced detachment kinetics, resulting in a slower and less complete deactivation of thin filaments at the end of contractions. These findings have important implications for selecting and testing directed therapeutic options for persons with DA2A and perhaps congenital contractures in general.


Assuntos
Disostose Craniofacial/genética , Disostose Craniofacial/fisiopatologia , Contração Muscular/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Mutação , Miosinas/genética , Adolescente , Adulto , Cálcio/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Disostose Craniofacial/patologia , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Feminino , Expressão Gênica , Humanos , Masculino , Músculo Esquelético/patologia , Miofibrilas/genética , Miofibrilas/metabolismo , Miosinas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto Jovem
12.
Pediatrics ; 135(3): e736-9, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25687148

RESUMO

Single-nucleotide polymorphism arrays and other types of genetic tests have the potential to detect first-degree consanguinity and uncover parental rape in cases of minor teenage pregnancy. We present 2 cases in which genetic testing identified parental rape of a minor teenager. In case 1, single-nucleotide polymorphism array in a patient with multiple developmental abnormalities demonstrated multiple long stretches of homozygosity, revealing parental rape of a teenage mother. In case 2, a vague maternal sexual assault history and diagnosis of Pompe disease by direct gene sequencing identified parental rape of a minor. Given the medical, legal, and ethical implications of such revelations, a protocol was developed at our institution to manage consanguinity identified via genetic testing.


Assuntos
Anormalidades Múltiplas/diagnóstico , Consanguinidade , Testes Genéticos/métodos , Anormalidades Múltiplas/genética , Adolescente , Criança , Feminino , Humanos , Recém-Nascido , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez
13.
Am J Hum Genet ; 96(3): 462-73, 2015 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-25683120

RESUMO

Freeman-Sheldon syndrome, or distal arthrogryposis type 2A (DA2A), is an autosomal-dominant condition caused by mutations in MYH3 and characterized by multiple congenital contractures of the face and limbs and normal cognitive development. We identified a subset of five individuals who had been putatively diagnosed with "DA2A with severe neurological abnormalities" and for whom congenital contractures of the limbs and face, hypotonia, and global developmental delay had resulted in early death in three cases; this is a unique condition that we now refer to as CLIFAHDD syndrome. Exome sequencing identified missense mutations in the sodium leak channel, non-selective (NALCN) in four families affected by CLIFAHDD syndrome. We used molecular-inversion probes to screen for NALCN in a cohort of 202 distal arthrogryposis (DA)-affected individuals as well as concurrent exome sequencing of six other DA-affected individuals, thus revealing NALCN mutations in ten additional families with "atypical" forms of DA. All 14 mutations were missense variants predicted to alter amino acid residues in or near the S5 and S6 pore-forming segments of NALCN, highlighting the functional importance of these segments. In vitro functional studies demonstrated that NALCN alterations nearly abolished the expression of wild-type NALCN, suggesting that alterations that cause CLIFAHDD syndrome have a dominant-negative effect. In contrast, homozygosity for mutations in other regions of NALCN has been reported in three families affected by an autosomal-recessive condition characterized mainly by hypotonia and severe intellectual disability. Accordingly, mutations in NALCN can cause either a recessive or dominant condition characterized by varied though overlapping phenotypic features, perhaps based on the type of mutation and affected protein domain(s).


Assuntos
Contratura/genética , Extremidades/fisiopatologia , Face/anormalidades , Hipotonia Muscular/genética , Canais de Sódio/genética , Artrogripose/genética , Disostose Craniofacial/genética , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Exoma , Feminino , Frequência do Gene , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Canais de Sódio/metabolismo
14.
Genet Med ; 17(5): 400-4, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25232848

RESUMO

PURPOSE: The broad use of single-nucleotide polymorphism microarrays has increased identification of unexpected consanguinity. Therefore, guidelines to address reporting of consanguinity have been published for clinical laboratories. Because no such guidelines for clinicians exist, we describe a case and present recommendations for clinicians to disclose unexpected consanguinity to families. METHODS: In a boy with multiple endocrine abnormalities and structural birth defects, single-nucleotide polymorphism array analysis revealed ~23% autosomal homozygosity suggestive of a first-degree parental relationship. We assembled an interdisciplinary health-care team, planned the most appropriate way to discuss results of the single-nucleotide polymorphism array with the adult mother, including the possibility of multiple autosomal recessive disorders in her child, and finally met with her as a team. RESULTS: From these discussions, we developed four major considerations for clinicians returning results of unexpected consanguinity, all guided by the child's best interests: (i) ethical and legal obligations for reporting possible abuse, (ii) preservation of the clinical relationship, (iii) attention to justice and psychosocial challenges, and (iv) utilization of the single-nucleotide polymorphism array results to guide further testing. CONCLUSION: As single-nucleotide polymorphism arrays become a common clinical diagnostic tool, clinicians can use this framework to return results of unexpected consanguinity to families in a supportive and productive manner.


Assuntos
Consanguinidade , Achados Incidentais , Polimorfismo de Nucleotídeo Único , Mapeamento Cromossômico , Família , Homozigoto , Humanos , Lactente , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Médicos , Revelação da Verdade
15.
Am J Med Genet A ; 164A(11): 2808-13, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25256237

RESUMO

Distal arthrogryposis (DA) syndromes are a group of disorders characterized by multiple congenital contractures. DA type 2A (DA2A or Freeman-Sheldon syndrome), caused by mutations in MYH3, is typically considered the most severe of the DA syndromes. However, there is wide phenotypic variability among individuals with DA2A. We characterized genotype-phenotype relationships in 46 families with DA2A. MYH3 mutations were found in 43/46 (93%) kindreds, with three mutations (p.T178I, p.R672C, and p.R672H) explaining 39/43 (91%) of cases. Phenotypic severity varied significantly by genotype (P=0.0055). Individuals with p.T178I were the most severely affected with both facial contractures and congenital scoliosis. Classification of individuals with DA2A into phenotypic groups of varying severity should facilitate providing families with more accurate information about natural history and suggests that individuals might benefit from personalized medical management motivated by MYH3 genotype.


Assuntos
Disostose Craniofacial/diagnóstico , Disostose Craniofacial/genética , Estudos de Associação Genética , Genótipo , Fenótipo , Adolescente , Criança , Pré-Escolar , Proteínas do Citoesqueleto/genética , Análise Mutacional de DNA , Éxons , Facies , Feminino , Humanos , Lactente , Masculino , Mutação , Radiografia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/patologia
16.
Am J Hum Genet ; 94(5): 734-44, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24726473

RESUMO

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.


Assuntos
Anormalidades Múltiplas/genética , Aracnodactilia/genética , Artrogripose/genética , Blefarofimose/genética , Fissura Palatina/genética , Pé Torto Equinovaro/genética , Doenças do Tecido Conjuntivo/genética , Contratura/genética , Deformidades Congênitas da Mão/genética , Canais Iônicos/genética , Oftalmoplegia/genética , Doenças Retinianas/genética , Anormalidades Múltiplas/patologia , Aracnodactilia/patologia , Artrogripose/patologia , Blefarofimose/patologia , Criança , Pré-Escolar , Fissura Palatina/patologia , Pé Torto Equinovaro/patologia , Doenças do Tecido Conjuntivo/patologia , Contratura/patologia , Exoma/genética , Feminino , Deformidades Congênitas da Mão/patologia , Humanos , Masculino , Mutação , Oftalmoplegia/patologia , Linhagem , Doenças Retinianas/patologia
17.
J Physiol ; 591(12): 3049-61, 2013 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-23629510

RESUMO

Little is known about the contraction and relaxation properties of fetal skeletal muscle, and measurements thus far have been made with non-human mammalian muscle. Data on human fetal skeletal muscle contraction are lacking, and there are no published reports on the kinetics of either fetal or adult human skeletal muscle myofibrils. Understanding the contractile properties of human fetal muscle would be valuable in understanding muscle development and a variety of muscle diseases that are associated with mutations in fetal muscle sarcomere proteins. Therefore, we characterised the contractile properties of developing human fetal skeletal muscle and compared them to adult human skeletal muscle and rabbit psoas muscle. Electron micrographs showed human fetal muscle sarcomeres are not fully formed but myofibril formation is visible. Isolated myofibril mechanical measurements revealed much lower specific force, and slower rates of isometric force development, slow phase relaxation, and fast phase relaxation in human fetal when compared to human adult skeletal muscle. The duration of slow phase relaxation was also significantly longer compared to both adult groups, but was similarly affected by elevated ADP. F-actin sliding on human fetal skeletal myosin coated surfaces in in vitro motility (IVM) assays was much slower compared with adult rabbit skeletal myosin, though the Km(app) (apparent (fitted) Michaelis-Menten constant) of F-actin speed with ATP titration suggests a greater affinity of human fetal myosin for nucleotide binding. Replacing ATP with 2 deoxy-ATP (dATP) increased F-actin speed for both groups by a similar amount. Titrations of ADP into IVM assays produced a similar inhibitory affect for both groups, suggesting ADP binding may be similar, at least under low load. Together, our results suggest slower but similar mechanisms of myosin chemomechanical transduction for human fetal muscle that may also be limited by immature myofilament structure.


Assuntos
Feto/fisiologia , Contração Isométrica , Músculo Esquelético/embriologia , Músculo Esquelético/fisiologia , Actinas/metabolismo , Difosfato de Adenosina/metabolismo , Adulto , Animais , Proteínas do Citoesqueleto/metabolismo , Desenvolvimento Fetal , Feto/ultraestrutura , Humanos , Cinética , Relaxamento Muscular , Músculo Esquelético/ultraestrutura , Miosinas/metabolismo , Coelhos , Sarcômeros/metabolismo , Sarcômeros/fisiologia , Sarcômeros/ultraestrutura
18.
Am J Hum Genet ; 92(4): 621-6, 2013 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-23541344

RESUMO

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2α (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. The identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.


Assuntos
Anormalidades Múltiplas/etiologia , Síndrome Brânquio-Otorrenal/etiologia , Displasia Ectodérmica/etiologia , Exoma/genética , Hipospadia/etiologia , Hipotonia Muscular/etiologia , Mutação de Sentido Incorreto/genética , Proteínas Repressoras/genética , Anormalidades Múltiplas/patologia , Sequência de Aminoácidos , Síndrome Brânquio-Otorrenal/patologia , Orelha Externa/anormalidades , Orelha Externa/patologia , Displasia Ectodérmica/patologia , Feminino , Humanos , Hipospadia/patologia , Masculino , Dados de Sequência Molecular , Hipotonia Muscular/patologia , Mamilos/anormalidades , Mamilos/patologia , Linhagem , Fenótipo , Estrutura Terciária de Proteína , Couro Cabeludo/anormalidades , Couro Cabeludo/patologia , Homologia de Sequência de Aminoácidos
19.
Am J Med Genet A ; 161A(3): 550-5, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23401156

RESUMO

The distal arthrogryposis (DA) syndromes are a group of disorders characterized by non-progressive congenital contractures of the limbs. Mutations that cause distal arthrogryposis syndromes have been reported in six genes, each of which encodes a component of the contractile apparatus of skeletal myofibers. However, these reports have usually emanated from gene discovery efforts and thus potentially bias estimates of the frequency of pathogenic mutations at each locus. We characterized the spectrum of pathogenic variants in a cohort of 153 cases of DA1 (n = 48) and DA2B (n = 105). Disease-causing mutations in 56/153 (37%) kindreds including 14/48 (29%) with DA1 and 42/105 (40%) with DA2B were distributed nearly equally across TNNI2, TNNT3, TPM2, and MYH3. In TNNI2, TNNT3, and TPM2 the same mutation caused DA1 in some families and DA2B in others. We found no significant differences among the clinical characteristics of DA by locus or between each locus and DA1 or DA2B. Collectively, the substantial overlap between phenotypic characteristics and spectrum of mutations suggests that DA1 and DA2B should be considered phenotypic extremes of the same disorder.


Assuntos
Artrogripose/genética , Adolescente , Criança , Proteínas do Citoesqueleto/genética , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , Mutação de Sentido Incorreto , Deleção de Sequência , Tropomiosina/genética , Troponina I/genética , Troponina T/genética
20.
Am J Hum Genet ; 92(1): 150-6, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23261301

RESUMO

Distal arthrogryposis (DA) syndromes are the most common of the heritable congenital-contracture disorders, and ~50% of cases are caused by mutations in genes that encode contractile proteins of skeletal myofibers. DA type 5D (DA5D) is a rare, autosomal-recessive DA previously defined by us and is characterized by congenital contractures of the hands and feet, along with distinctive facial features, including ptosis. We used linkage analysis and whole-genome sequencing of a multiplex consanguineous family to identify in endothelin-converting enzyme-like 1 (ECEL1) mutations that result in DA5D. Evaluation of a total of seven families affected by DA5D revealed in five families ECEL1 mutations that explain ~70% of cases overall. ECEL1 encodes a neuronal endopeptidase and is expressed in the brain and peripheral nerves. Mice deficient in Ecel1 exhibit perturbed terminal branching of motor neurons to the endplate of skeletal muscles, resulting in poor formation of the neuromuscular junction. Our results distinguish a second developmental pathway that causes congenital-contracture syndromes.


Assuntos
Artrogripose/genética , Metaloendopeptidases/genética , Consanguinidade , Feminino , Ligação Genética , Humanos , Masculino , Mutação , Análise de Sequência de DNA
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