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1.
Nat Commun ; 12(1): 4680, 2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34344887

RESUMO

Craniofacial microsomia (CFM) is the second most common congenital facial anomaly, yet its genetic etiology remains unknown. We perform whole-exome or genome sequencing of 146 kindreds with sporadic (n = 138) or familial (n = 8) CFM, identifying a highly significant burden of loss of function variants in SF3B2 (P = 3.8 × 10-10), a component of the U2 small nuclear ribonucleoprotein complex, in probands. We describe twenty individuals from seven kindreds harboring de novo or transmitted haploinsufficient variants in SF3B2. Probands display mandibular hypoplasia, microtia, facial and preauricular tags, epibulbar dermoids, lateral oral clefts in addition to skeletal and cardiac abnormalities. Targeted morpholino knockdown of SF3B2 in Xenopus results in disruption of cranial neural crest precursor formation and subsequent craniofacial cartilage defects, supporting a link between spliceosome mutations and impaired neural crest development in congenital craniofacial disease. The results establish haploinsufficient variants in SF3B2 as the most prevalent genetic cause of CFM, explaining ~3% of sporadic and ~25% of familial cases.


Assuntos
Síndrome de Goldenhar/genética , Haploinsuficiência , Fatores de Processamento de RNA/genética , Adolescente , Adulto , Animais , Criança , Exoma/genética , Feminino , Estudos de Associação Genética , Síndrome de Goldenhar/patologia , Humanos , Lactente , Masculino , Mutação , Crista Neural/crescimento & desenvolvimento , Crista Neural/patologia , Linhagem , Spliceossomos/genética , Xenopus laevis
2.
Am J Med Genet A ; 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34291880

RESUMO

Robin sequence (RS) has many genetic and nongenetic causes, including isolated Robin sequence (iRS), Stickler syndrome (SS), and other syndromes (SyndRS). The purpose of this study was to determine if the presence and type of cleft palate varies between etiologic groups. A secondary endpoint was to determine the relationship of etiologic group, cleft type, and mortality. Retrospective chart review of patients with RS at two high-volume craniofacial centers. 295 patients with RS identified. CP was identified in 97% with iRS, 95% with SS, and 70% of those with SyndRS (p < .0001). U-shaped CP was seen in 86% of iRS, 82% with SS, but only 27% with SyndRS (p < .0001). At one institution, 12 children (6%) with RS died, all from the SyndRS group (p < .0001). All died due to medical comorbidities related to their syndrome. Only 25% of children who died had a U-shaped CP. The most common palatal morphology among those who died was an intact palate. U-shaped CP was most strongly associated with iRS and SS, and with a lower risk of mortality. RS with submucous CP, cleft lip and palate or intact palate was strongly suggestive of an underlying genetic syndrome and higher risk of mortality.

3.
Am J Hum Genet ; 108(8): 1436-1449, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34216551

RESUMO

Despite widespread clinical genetic testing, many individuals with suspected genetic conditions lack a precise diagnosis, limiting their opportunity to take advantage of state-of-the-art treatments. In some cases, testing reveals difficult-to-evaluate structural differences, candidate variants that do not fully explain the phenotype, single pathogenic variants in recessive disorders, or no variants in genes of interest. Thus, there is a need for better tools to identify a precise genetic diagnosis in individuals when conventional testing approaches have been exhausted. We performed targeted long-read sequencing (T-LRS) using adaptive sampling on the Oxford Nanopore platform on 40 individuals, 10 of whom lacked a complete molecular diagnosis. We computationally targeted up to 151 Mbp of sequence per individual and searched for pathogenic substitutions, structural variants, and methylation differences using a single data source. We detected all genomic aberrations-including single-nucleotide variants, copy number changes, repeat expansions, and methylation differences-identified by prior clinical testing. In 8/8 individuals with complex structural rearrangements, T-LRS enabled more precise resolution of the mutation, leading to changes in clinical management in one case. In ten individuals with suspected Mendelian conditions lacking a precise genetic diagnosis, T-LRS identified pathogenic or likely pathogenic variants in six and variants of uncertain significance in two others. T-LRS accurately identifies pathogenic structural variants, resolves complex rearrangements, and identifies Mendelian variants not detected by other technologies. T-LRS represents an efficient and cost-effective strategy to evaluate high-priority genes and regions or complex clinical testing results.


Assuntos
Aberrações Cromossômicas , Análise Citogenética/métodos , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genoma Humano , Mutação , Variações do Número de Cópias de DNA , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariotipagem , Masculino , Análise de Sequência de DNA
5.
Am J Hum Genet ; 102(6): 1143-1157, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29805042

RESUMO

Non-syndromic cleft lip with or without cleft palate (NS-CL/P) is one of the most common human birth defects and is generally considered a complex trait. Despite numerous loci identified by genome-wide association studies, the effect sizes of common variants are relatively small, with much of the presumed genetic contribution remaining elusive. We report exome-sequencing results in 209 people from 72 multi-affected families with pedigree structures consistent with autosomal-dominant inheritance and variable penetrance. Herein, pathogenic variants are described in four genes encoding components of the p120-catenin complex (CTNND1, PLEKHA7, PLEKHA5) and an epithelial splicing regulator (ESRP2), in addition to the known CL/P-associated gene, CDH1, which encodes E-cadherin. The findings were also validated in a second cohort of 497 people with NS-CL/P, comprising small families and singletons with pathogenic variants in these genes identified in 14% of multi-affected families and 2% of the replication cohort of smaller families. Enriched expression of each gene/protein in human and mouse embryonic oro-palatal epithelia, demonstration of functional impact of CTNND1 and ESRP2 variants, and recapitulation of the CL/P spectrum in Ctnnd1 knockout mice support a causative role in CL/P pathogenesis. These data show that primary defects in regulators of epithelial cell adhesion are the most significant contributors to NS-CL/P identified to date and that inherited and de novo single gene variants explain a substantial proportion of NS-CL/P.


Assuntos
Caderinas/genética , Cateninas/genética , Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Mutação/genética , Alelos , Sequência de Aminoácidos , Animais , Biotinilação , Epitélio/metabolismo , Epitélio/patologia , Feminino , Deleção de Genes , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Palato/patologia , Linhagem , Síndrome , Sequenciamento Completo do Exoma
6.
Am J Med Genet A ; 173(2): 414-420, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28102598

RESUMO

Relatively few patients with Cornelia de Lange syndrome (CdLS) due to SMC1A mutation have been reported, limiting understanding of the full extent of the phenotype. Compared to children with classic NIPBL-associated CdLS, patients with SMC1A-associated CdLS have a milder physical phenotype with prominent intellectual disability, high rate of cleft palate and absence of limb reductions. We present a patient with SMC1A-associated CdLS who had typical features including developmental delay, seizure disorder, feeding difficulties, hirsutism, and cleft palate. She also was found to have three novel features: (i) left ventricular non-compaction (LVNC) cardiomyopathy; (ii) microform cleft lip; and (iii) severe hyperopia and astigmatism. These features have implications regarding potential insight into the pathogenesis of the disorder, screening, and medical management. Hypertrophic cardiomyopathy has previously been reported in SMC1A-associated CdLS, but to our knowledge this is the first reported child with LVNC. Previous reports have included children with isolated clefts of the palate without involvement of the lip. When cleft palate alone is associated with a disorder, the underlying pathophysiology for clefting is sometimes secondary due to mechanical blocking of the fusion of the palatal shelves with the developing tongue. The presence of microform cleft lip in this patient suggests that the pathophysiology of clefting in SMC1A is primary rather than secondary. Few studies report ophthalmologic findings specific to SMC1A. Based on these findings, LVNC cardiomyopathy and cleft lip should be considered features of SMC1A-associated CdLS. All patients should receive echocardiogram and undergo thorough ophthalmologic evaluation as part of routine CdLS care. © 2016 Wiley Periodicals, Inc.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Fenda Labial/genética , Síndrome de Cornélia de Lange/diagnóstico , Síndrome de Cornélia de Lange/genética , Cardiopatias Congênitas/genética , Fenótipo , Transtornos da Visão/genética , Fenda Labial/diagnóstico , Ecocardiografia , Facies , Feminino , Estudos de Associação Genética , Cardiopatias Congênitas/diagnóstico , Humanos , Lactente , Transtornos da Visão/diagnóstico
7.
Birth Defects Res A Clin Mol Teratol ; 106(11): 915-926, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27891784

RESUMO

BACKGROUND: Craniofacial microsomia (CFM) is a congenital condition with wide phenotypic variability, including hypoplasia of the mandible and external ear. We assembled a cohort of children with facial features within the CFM spectrum and children without known craniofacial anomalies. We sought to develop a standardized approach to assess and describe the facial characteristics of the study cohort, using multiple sources of information gathered over the course of this longitudinal study and to create case subgroups with shared phenotypic features. METHODS: Participants were enrolled between 1996 and 2002. We classified the facial phenotype from photographs, ratings using a modified version of the Orbital, Ear, Mandible, Nerve, Soft tissue (OMENS) pictorial system, data from medical record abstraction, and health history questionnaires. RESULTS: The participant sample included 142 cases and 290 controls. The average age was 13.5 years (standard deviation, 1.3 years; range, 11.1-17.1 years). Sixty-one percent of cases were male, 74% were white non-Hispanic. Among cases, the most common features were microtia (66%) and mandibular hypoplasia (50%). Case subgroups with meaningful group definitions included: (1) microtia without other CFM-related features (n = 24), (2) microtia with mandibular hypoplasia (n = 46), (3) other combinations of CFM- related facial features (n = 51), and (4) atypical features (n = 21). CONCLUSION: We developed a standardized approach for integrating multiple data sources to phenotype individuals with CFM, and created subgroups based on clinically-meaningful, shared characteristics. We hope that this system can be used to explore associations between phenotype and clinical outcomes of children with CFM and to identify the etiology of CFM. Birth Defects Research (Part A) 106:915-926, 2016.© 2016 Wiley Periodicals, Inc.


Assuntos
Face/anormalidades , Síndrome de Goldenhar/classificação , Síndrome de Goldenhar/patologia , Adolescente , Criança , Estudos de Coortes , Face/patologia , Feminino , Humanos , Masculino
8.
Am J Hum Genet ; 95(2): 235-40, 2014 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-25105228

RESUMO

Acromelic frontonasal dysostosis (AFND) is a rare disorder characterized by distinct craniofacial, brain, and limb malformations, including frontonasal dysplasia, interhemispheric lipoma, agenesis of the corpus callosum, tibial hemimelia, preaxial polydactyly of the feet, and intellectual disability. Exome sequencing of one trio and two unrelated probands revealed the same heterozygous variant (c.3487C>T [p. Arg1163Trp]) in a highly conserved protein domain of ZSWIM6; this variant has not been seen in the 1000 Genomes data, dbSNP, or the Exome Sequencing Project. Sanger validation of the three trios confirmed that the variant was de novo and was also present in a fourth isolated proband. In situ hybridization of early zebrafish embryos at 24 hr postfertilization (hpf) demonstrated telencephalic expression of zswim6 and onset of midbrain, hindbrain, and retinal expression at 48 hpf. Immunohistochemistry of later-stage mouse embryos demonstrated tissue-specific expression in the derivatives of all three germ layers. qRT-PCR expression analysis of osteoblast and fibroblast cell lines available from two probands was suggestive of Hedgehog pathway activation, indicating that the ZSWIM6 mutation associated with AFND may lead to the craniofacial, brain and limb malformations through the disruption of Hedgehog signaling.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas Hedgehog/genética , Disostose Mandibulofacial/genética , Anormalidades Múltiplas/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Anormalidades Craniofaciais , Análise Mutacional de DNA , Exoma/genética , Face/anormalidades , Humanos , Deficiência Intelectual , Deformidades Congênitas dos Membros/genética , Camundongos , Dados de Sequência Molecular , Mutação , Estrutura Terciária de Proteína/genética , Peixe-Zebra , Dedos de Zinco/genética
9.
Am J Med Genet A ; 161A(6): 1345-53, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23637006

RESUMO

Frontonasal Dysplasia (FND) and Oculo-auriculo-vertebral spectrum (OAVS) are two well-recognized clinical entities. With features of both FND and OAVS, the term oculoauriculofrontonasal syndrome (OAFNS) was coined in 1981. The OAFNS phenotype combines elements of abnormal morphogenesis of the frontonasal and maxillary process (derived from forebrain neural crest) with abnormal development of the first and second branchial arches (derived from hindbrain neural crest). We present a case series of 33 children with OAFNS ascertained from a comprehensive review of the literature and report an additional retrospective series of eight patients displaying features consistent with OAFNS. Notably, in a subset of our cases, we have observed abnormalities in nasal ossification and bony structures of the maxilla that have not previously described in OAFNS and are not seen in either FND or OAVS. We present the phenotype and novel naso-maxillary findings and explore potential etiologic and developmental pathways for OAFNS. We highlight the differences in phenotypic characteristics of OAFNS compared to OAVS and FND. These observations support the classification of OAFNS as a discrete syndrome. Further phenotypic refinements of OAFNS are needed to understand pathogenesis of this syndrome and the newly described nasal malformation may help identify the etiology.


Assuntos
Anormalidades Múltiplas/classificação , Anormalidades Craniofaciais/classificação , Orelha Externa/anormalidades , Anormalidades do Olho/classificação , Face/anormalidades , Anormalidades do Sistema Respiratório/classificação , Coluna Vertebral/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/genética , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/genética , Orelha Externa/diagnóstico por imagem , Anormalidades do Olho/diagnóstico por imagem , Anormalidades do Olho/genética , Face/diagnóstico por imagem , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Maxila/anormalidades , Osso Nasal/anormalidades , Ossificação Heterotópica , Fenótipo , Radiografia , Anormalidades do Sistema Respiratório/diagnóstico por imagem , Anormalidades do Sistema Respiratório/genética , Estudos Retrospectivos , Coluna Vertebral/diagnóstico por imagem
10.
J Craniofac Surg ; 24(1): 178-85, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23348281

RESUMO

INTRODUCTION: The metopic suture is the only calvarial suture which normally closes during infancy. Upon closure, a palpable and visible ridge often forms which can be confused with metopic craniosynostosis. Metopic ridging (MR) is treated nonsurgically while metopic craniosynostosis (MCS) is treated surgically. Differentiating between the two is paramount; however, consensus is lacking about where a clear diagnostic threshold lies. The goal of this study is to describe the physical examination and CT scan characteristics which may help to differentiate between physiological closure of the metopic suture with ridging (MR) and MCS. METHODS: A retrospective chart review of all patients seen at Seattle Children's Hospital between 2004 and 2009 with the diagnosis of either MCS or MR (n = 282) was performed. Physical examination characteristics described by diagnosing practitioners were analyzed. Clinical photos were assessed by 3 expert raters to determine the importance of these characteristics. CT scan findings were abstracted and compared between the two diagnoses. RESULTS: The "classic" triad of narrow forehead, biparietal widening, and hypotelorism was present in only 14% of patients with MCS. Ninety-eight percent of patients in both groups had a palpable metopic ridge. The photographic finding of narrow forehead and pterional constriction was present in all patients with MCS, but only in 11.2% and 2.8% of patients with MR. On CT scan, the presence of 3 or more MCS findings was diagnostic of MCS in 96% of patients. Patients with MCS were more likely to present before 6 months of age (66% vs. 32%). CONCLUSIONS: Patients with MCS tend to present earlier than those with MR. Upon physical examination, the relationship between the lateral frontal bone and the lateral orbit is important in distinguishing between the two diagnoses. A CT scan can be helpful in making the diagnosis not to confirm a closed suture but to identify 3 or more MCS characteristics.


Assuntos
Suturas Cranianas/fisiologia , Criança , Pré-Escolar , Craniossinostoses/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Exame Físico , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
11.
Plast Reconstr Surg Glob Open ; 1(7): e62, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25289257

RESUMO

BACKGROUND: Metopic craniosynostosis can occur in isolation or in conjunction with other congenital anomalies. The surgical decision making and outcomes between these 2 groups are analyzed. METHODS: A retrospective review of all children evaluated in the craniofacial clinic at Seattle Children's Hospital for metopic craniosynostosis between 2004 and 2009 was performed. Physical examination and CT scan characteristics were analyzed as were the treatment decisions and surgical outcomes. RESULTS: From 2004 to 2009, 282 patients were evaluated and 100 were determined to have metopic craniosynostosis. Of these, 19 patients were found to have additional congenital anomalies. Review of these patients' CT scans revealed 13 with classic trigonencephaly, 3 with microcephaly, and 3 with narrow frontal bones, abnormal orbits, and small anterior fossa. Patients (90%) with isolated metopic craniosynostosis underwent cranial vault expansion, whereas only 63% of the complex group did so. The complex metopic group had a longer hospital stay (5 d vs 3.4 d), more intraoperative complications, and required more repeat surgery. CONCLUSION: Patients with metopic craniosynostosis and additional anomalies require special consideration when deciding upon surgical intervention and should be cared for by a multidisciplinary team to address their additional needs.

12.
Am J Med Genet A ; 161A(1): 108-13, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23239648

RESUMO

Heterozygous mutations in the EFTUD2 were identified in 12 individuals with a rare sporadic craniofacial condition termed Mandibulofacial dysostosis with microcephaly (MIM 610536). We present clinical and radiographic features of three additional patients with de novo heterozygous mutations in EFTUD2. Although clinical features overlap with findings of the original report (choanal atresia, cleft palate, maxillary and mandibular hypoplasia, and microtia), microcephaly was present in two of three patients and cognitive impairment was milder in those with head circumference proportional to height. Our cases expand the phenotypic spectrum to include epibulbar dermoids and zygomatic arch clefting. We suggest that craniofacial computed tomography studies to assess cleft of zygomatic arch may assist in making this diagnosis. We recommend consideration of EFTUD2 testing in individuals with features of oculo-auriculo-vertebral spectrum and bilateral microtia, or individuals with atypical CHARGE syndrome who do not have a CHD7 mutation, particularly those with a zygomatic arch cleft. The absence of microcephaly in one patient indicates that it is a highly variable phenotypic feature.


Assuntos
Disostose Mandibulofacial/genética , Microcefalia/genética , Mutação , Fator Tu de Elongação de Peptídeos/genética , Síndrome CHARGE/genética , Pré-Escolar , Estudos de Coortes , DNA Helicases/genética , DNA Helicases/metabolismo , Análise Mutacional de DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Exoma , Genômica/métodos , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Masculino , Disostose Mandibulofacial/diagnóstico , Microcefalia/diagnóstico , Fenótipo
13.
Cleft Palate Craniofac J ; 50(1): 104-8, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21970727

RESUMO

Bathrocephaly, a deformity of the posterior skull with bulging of the midportion of the occipital bone, is often associated with a benign variant of the mendosal suture ( Mulliken and Le, 2008 ). The endochondral and membranous portions of the occipital bone converge at the mendosal suture, which normally closes during fetal life or early infancy. When it persists, it is associated with a characteristic head shape that requires no intervention. We review the clinical findings associated with postnatal persistence of the mendosal suture and discuss other factors that may be associated with bathrocephaly.


Assuntos
Suturas Cranianas , Osso Occipital , Suturas Cranianas/cirurgia , Craniossinostoses , Cabeça , Humanos , Lactente , Anormalidades Maxilomandibulares , Crânio , Suturas
14.
Birth Defects Res A Clin Mol Teratol ; 94(12): 990-5, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22903955

RESUMO

BACKGROUND: Craniofacial microsomia (CFM) is a congenital condition characterized by microtia and mandibular underdevelopment. Healthcare databases and birth defects surveillance programs could be used to improve knowledge of CFM. However, no specific International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code exists for this condition, which makes standardized data collection challenging. Our aim was to evaluate the validity of existing ICD-9-CM codes to identify individuals with CFM. METHODS: Study sample eligibility criteria were developed by an expert panel and matched to 11 ICD-9-CM codes. We queried hospital discharge data from two craniofacial centers and identified a total of 12,254 individuals who had ≥1 potentially CFM-related code(s). We reviewed all (n = 799) medical records identified at the University of North Carolina (UNC) and 500 randomly selected records at Seattle Children's Hospital (SCH). Individuals were classified as a CFM case or non-case. RESULTS: Thirty-two individuals (6%) at SCH and 93 (12%) at UNC met the CFM eligibility criteria. At both centers, 59% of cases and 95% of non-cases had only one code assigned. At both centers, the most frequent codes were 744.23 (microtia), 754.0 and 756.0 (nonspecific codes), and the code 744.23 had a positive predictive value (PPV) >80% and sensitivity >70%. The code 754.0 had a sensitivity of 3% (PPV <1%) at SCH and 36% (PPV = 5%) at UNC, whereas 756.0 had a sensitivity of 38% (PPV = 5%) at SCH and 18% (PPV = 26%) at UNC. CONCLUSIONS: These findings suggest the need for a specific CFM code to facilitate CFM surveillance and research.


Assuntos
Codificação Clínica/métodos , Anormalidades Craniofaciais , Classificação Internacional de Doenças/normas , Coleta de Dados , Bases de Dados Factuais , Feminino , Humanos , Masculino , Estados Unidos
15.
Am J Hum Genet ; 90(5): 907-14, 2012 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-22560091

RESUMO

Auriculocondylar syndrome (ACS) is a rare, autosomal-dominant craniofacial malformation syndrome characterized by variable micrognathia, temporomandibular joint ankylosis, cleft palate, and a characteristic "question-mark" ear malformation. Careful phenotypic characterization of severely affected probands in our cohort suggested the presence of a mandibular patterning defect resulting in a maxillary phenotype (i.e., homeotic transformation). We used exome sequencing of five probands and identified two novel (exclusive to the patient and/or family studied) missense mutations in PLCB4 and a shared mutation in GNAI3 in two unrelated probands. In confirmatory studies, three additional novel PLCB4 mutations were found in multigenerational ACS pedigrees. All mutations were confirmed by Sanger sequencing, were not present in more than 10,000 control chromosomes, and resulted in amino-acid substitutions located in highly conserved protein domains. Additionally, protein-structure modeling demonstrated that all ACS substitutions disrupt the catalytic sites of PLCB4 and GNAI3. We suggest that PLCB4 and GNAI3 are core signaling molecules of the endothelin-1-distal-less homeobox 5 and 6 (EDN1-DLX5/DLX6) pathway. Functional studies demonstrated a significant reduction in downstream DLX5 and DLX6 expression in ACS cases in assays using cultured osteoblasts from probands and controls. These results support the role of the previously implicated EDN1-DLX5/6 pathway in regulating mandibular specification in other species, which, when disrupted, results in a maxillary phenotype. This work defines the molecular basis of ACS as a homeotic transformation (mandible to maxilla) in humans.


Assuntos
Otopatias/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Mutação , Fosfolipase C beta/genética , Sequência de Aminoácidos , Estudos de Coortes , Orelha/anormalidades , Orelha/fisiopatologia , Otopatias/fisiopatologia , Endotelina-1/genética , Endotelina-1/metabolismo , Exoma , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Dados de Sequência Molecular , Linhagem , Fenótipo , Fosfolipase C beta/metabolismo , Conformação Proteica , Análise de Sequência de RNA
16.
J Craniofac Surg ; 23(1): 212-6, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22337411

RESUMO

Craniofacial anomalies comprise a frequent cause of birth defects requiring surgical treatment. A subset of children with craniofacial anomalies will have additional birth defects, developmental delays, or recognizable genetic syndromes. Genetic consultation should be offered to the families of children in this subgroup. The overall goal of a genetic consultation is the identification of a unifying diagnosis to direct medical management and provide families with information regarding prognosis and recurrence risk. Current clinical genetic testing options for children with recognizable craniofacial syndromes include single-gene-targeted mutation analysis, complete gene sequencing, and gene duplication/deletion analysis. Testing options for children who have multiple birth defects without a recognizable genetic syndrome include karyotype analysis and array comparative genomic hybridization. Future testing may include exome or whole-genome sequencing. In this article, we will discuss indications for genetic consultation and review current and future gene testing options for craniofacial conditions.


Assuntos
Anormalidades Craniofaciais/genética , Anormalidades Múltiplas/genética , Criança , Hibridização Genômica Comparativa , Anormalidades Craniofaciais/cirurgia , Exoma/genética , Deleção de Genes , Duplicação Gênica/genética , Serviços em Genética , Testes Genéticos/métodos , Genoma Humano/genética , Humanos , Cariotipagem , Mutação/genética , Planejamento de Assistência ao Paciente , Encaminhamento e Consulta , Análise de Sequência de DNA , Cirurgia Plástica , Síndrome
17.
Am J Med Genet A ; 158A(1): 124-39, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22106030

RESUMO

Microtia is a congenital anomaly of the ear that ranges in severity from mild structural abnormalities to complete absence of the ear, and can occur as an isolated birth defect or as part of a spectrum of anomalies or a syndrome. Microtia is often associated with hearing loss and patients typically require treatment for hearing impairment and surgical ear reconstruction. The reported prevalence varies among regions, from 0.83 to 17.4 per 10,000 births, and the prevalence is considered to be higher in Hispanics, Asians, Native Americans, and Andeans. The etiology of microtia and the cause of this wide variability in prevalence are poorly understood. Strong evidence supports the role of environmental and genetic causes for microtia. Although some studies have identified candidate genetic variants for microtia, no causal genetic mutation has been confirmed. The application of novel strategies in developmental biology and genetics has facilitated elucidation of mechanisms controlling craniofacial development. In this paper we review current knowledge of the epidemiology and genetics of microtia, including potential candidate genes supported by evidence from human syndromes and animal models. We also discuss the possible etiopathogenesis in light of the hypotheses formulated to date: Neural crest cells disturbance, vascular disruption, and altitude.


Assuntos
Anormalidades Congênitas/diagnóstico , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/genética , Surdez/epidemiologia , Animais , Anormalidades Congênitas/classificação , Microtia Congênita , Surdez/complicações , Modelos Animais de Doenças , Orelha/anormalidades , Humanos , Camundongos , Prevalência , Fatores de Risco
18.
Pediatrics ; 127(5): 936-48, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21464188

RESUMO

The triad of micrognathia, glossoptosis, and resultant airway obstruction is known as Robin sequence (RS). Although RS is a well-recognized clinical entity, there is wide variability in the diagnosis and care of children born with RS. Systematic evaluations of treatments and clinical outcomes for children with RS are lacking despite the advances in clinical care over the past 20 years. We explore the pathogenesis, developmental and genetic models, morphology, and syndromes and malformations associated with RS. Current classification systems for RS do not account for the heterogeneity among infants with RS, and they do not allow for prediction of the optimal management course for an individual child. Although upper airway obstruction for some infants with RS can be treated adequately with positioning, other children may require a tracheostomy. Care must be customized for each patient with RS, and health care providers must understand the anatomy and mechanism of airway obstruction to develop an individualized treatment plan to improve breathing and achieve optimal growth and development. In this article we provide a comprehensive overview of evaluation strategies and therapeutic options for children born with RS. We also propose a conceptual treatment protocol to guide the provider who is caring for a child with RS.


Assuntos
Administração de Caso/organização & administração , Equipe de Assistência ao Paciente , Síndrome de Pierre Robin/diagnóstico , Síndrome de Pierre Robin/terapia , Obstrução das Vias Respiratórias/diagnóstico , Obstrução das Vias Respiratórias/terapia , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Micrognatismo/diagnóstico , Micrognatismo/terapia , Procedimentos Cirúrgicos Bucais/métodos , Síndrome de Pierre Robin/cirurgia , Prognóstico , Medição de Risco , Doenças da Língua/diagnóstico , Doenças da Língua/terapia , Traqueotomia/métodos , Resultado do Tratamento
19.
Am J Med Genet A ; 155A(1): 91-7, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21204214

RESUMO

The genetic contribution to the pathogenesis of isolated single suture craniosynostosis is poorly understood. The role of mutations in genes known to be associated with syndromic synostosis appears to be limited. We present our findings of a candidate gene resequencing approach to identify rare variants associated with the most common forms of isolated craniosynostosis. Resequencing of the coding regions, splice junction sites, and 5' and 3' untranslated regions of 27 candidate genes in 186 cases of isolated non-syndromic single suture synostosis revealed three novel and two rare sequence variants (R406H, R595H, N857S, P190S, M446V) in insulin-like growth factor I receptor (IGF1R) that are enriched relative to control samples. Mapping the resultant amino acid changes to the modeled homodimer protein structure suggests a structural basis for segregation between these and other disease-associated mutations found in IGF1R. These data suggest that IGF1R mutations may contribute to the risk and in some cases cause single suture craniosynostosis.


Assuntos
Craniossinostoses/genética , Craniossinostoses/fisiopatologia , Predisposição Genética para Doença/genética , Modelos Moleculares , Conformação Proteica , Receptor IGF Tipo 1/genética , Sequência de Aminoácidos , Sequência de Bases , Análise Mutacional de DNA , Estudos de Associação Genética , Humanos , Dados de Sequência Molecular , Mutação de Sentido Incorreto/genética , Receptor IGF Tipo 1/química
20.
Genet Med ; 12(10): 641-7, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20808231

RESUMO

PURPOSE: The short arm of chromosome 16 is rich in segmental duplications, predisposing this region of the genome to a number of recurrent rearrangements. Genomic imbalances of an approximately 600-kb region in 16p11.2 (29.5-30.1 Mb) have been associated with autism, intellectual disability, congenital anomalies, and schizophrenia. However, a separate, distal 200-kb region in 16p11.2 (28.7-28.9 Mb) that includes the SH2B1 gene has been recently associated with isolated obesity. The purpose of this study was to better define the phenotype of this recurrent SH2B1-containing microdeletion in a cohort of phenotypically abnormal patients not selected for obesity. METHODS: Array comparative hybridization was performed on a total of 23,084 patients in a clinical setting for a variety of indications, most commonly developmental delay. RESULTS: Deletions of the SH2B1-containing region were identified in 31 patients. The deletion is enriched in the patient population when compared with controls (P = 0.003), with both inherited and de novo events. Detailed clinical information was available for six patients, who all had developmental delays of varying severity. Body mass index was ≥95th percentile in four of six patients, supporting the previously described association with obesity. The reciprocal duplication, found in 17 patients, does not seem to be significantly enriched in our patient population compared with controls. CONCLUSIONS: Deletions of the 16p11.2 SH2B1-containing region are pathogenic and are associated with developmental delay in addition to obesity.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cromossomos Humanos Par 16/genética , Deficiências do Desenvolvimento/genética , Obesidade/genética , Deleção de Sequência , Anormalidades Múltiplas/genética , Índice de Massa Corporal , Pré-Escolar , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Dosagem de Genes , Estudo de Associação Genômica Ampla , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Hibridização de Ácido Nucleico , Fenótipo , Duplicações Segmentares Genômicas
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