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1.
J Med Genet ; 60(6): 620-626, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36368868

RESUMO

BACKGROUND: Oculo-auriculo-vertebral spectrum (OAVS) is the second most common cause of head and neck malformations in children after orofacial clefts. OAVS is clinically heterogeneous and characterised by a broad range of clinical features including ear anomalies with or without hearing loss, hemifacial microsomia, orofacial clefts, ocular defects and vertebral abnormalities. Various genetic causes were associated with OAVS and copy number variations represent a recurrent cause of OAVS, but the responsible gene often remains elusive. METHODS: We described an international cohort of 17 patients, including 10 probands and 7 affected relatives, presenting with OAVS and carrying a 14q22.3 microduplication detected using chromosomal microarray analysis. For each patient, clinical data were collected using a detailed questionnaire addressed to the referring clinicians. We subsequently studied the effects of OTX2 overexpression in a zebrafish model. RESULTS: We defined a 272 kb minimal common region that only overlaps with the OTX2 gene. Head and face defects with a predominance of ear malformations were present in 100% of patients. The variability in expressivity was significant, ranging from simple chondromas to severe microtia, even between intrafamilial cases. Heterologous overexpression of OTX2 in zebrafish embryos showed significant effects on early development with alterations in craniofacial development. CONCLUSIONS: Our results indicate that proper OTX2 dosage seems to be critical for the normal development of the first and second branchial arches. Overall, we demonstrated that OTX2 genomic duplications are a recurrent cause of OAVS marked by auricular malformations of variable severity.


Assuntos
Fenda Labial , Fissura Palatina , Síndrome de Goldenhar , Humanos , Animais , Síndrome de Goldenhar/genética , Peixe-Zebra/genética , Variações do Número de Cópias de DNA/genética , Fatores de Transcrição Otx/genética
2.
BMC Ophthalmol ; 24(1): 81, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38388885

RESUMO

BACKGROUND: To report a case of a 4-year-old patient with Goldenhar syndrome. CASE PRESENTATION: The author presents a rare case report involving a 4-year-old boy with multiple malformations. A comprehensive examination showed that the patient primarily had a limbal dermoid. He also has bilateral microtia and ear canal deformities. The skull CT scan and spine X-ray showed Maxillofacial Abnormalities and scoliosis. Whole Exome Sequencing revealed potential gene variations related to microtia. Although certain circumstances prevented us from initiating follow-up treatment for the patient, we have provided a detailed account of the diagnostic methodologies used for this condition. CONCLUSIONS: Goldenhar syndrome is a congenital condition, predominantly presenting as sporadic cases. Its diagnosis and management typically necessitate the involvement of multiple disciplines, including otolaryngology and craniofacial surgery. The syndrome encompasses a variety of craniofacial features, which can facilitate early diagnosis and guide subsequent therapeutic interventions.


Assuntos
Anormalidades Múltiplas , Microtia Congênita , Neoplasias Oculares , Síndrome de Goldenhar , Masculino , Humanos , Pré-Escolar , Síndrome de Goldenhar/diagnóstico , Síndrome de Goldenhar/genética , Microtia Congênita/diagnóstico , Anormalidades Múltiplas/diagnóstico , Tomografia Computadorizada por Raios X
3.
Int J Mol Sci ; 25(9)2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38731925

RESUMO

Hemifacial microsomia (HFM) is a rare congenital genetic syndrome primarily affecting the first and second pharyngeal arches, leading to defects in the mandible, external ear, and middle ear. The pathogenic genes remain largely unidentified. Whole-exome sequencing (WES) was conducted on 12 HFM probands and their unaffected biological parents. Predictive structural analysis of the target gene was conducted using PSIPRED (v3.3) and SWISS-MODEL, while STRING facilitated protein-to-protein interaction predictions. CRISPR/Cas9 was applied for gene knockout in zebrafish. In situ hybridization (ISH) was employed to examine the spatiotemporal expression of the target gene and neural crest cell (NCC) markers. Immunofluorescence with PH3 and TUNEL assays were used to assess cell proliferation and apoptosis. RNA sequencing was performed on mutant and control embryos, with rescue experiments involving target mRNA injections and specific gene knockouts. CDC27 was identified as a novel candidate gene for HFM, with four nonsynonymous de novo variants detected in three unrelated probands. Structural predictions indicated significant alterations in the secondary and tertiary structures of CDC27. cdc27 knockout in zebrafish resulted in craniofacial malformation, spine deformity, and cardiac edema, mirroring typical HFM phenotypes. Abnormalities in somatic cell apoptosis, reduced NCC proliferation in pharyngeal arches, and chondrocyte differentiation issues were observed in cdc27-/- mutants. cdc27 mRNA injections and cdkn1a or tp53 knockout significantly rescued pharyngeal arch cartilage dysplasia, while sox9a mRNA administration partially restored the defective phenotypes. Our findings suggest a functional link between CDC27 and HFM, primarily through the inhibition of CNCC proliferation and disruption of pharyngeal chondrocyte differentiation.


Assuntos
Síndrome de Goldenhar , Peixe-Zebra , Animais , Peixe-Zebra/genética , Humanos , Masculino , Feminino , Síndrome de Goldenhar/genética , Síndrome de Goldenhar/patologia , Apoptose/genética , Crista Neural/metabolismo , Sequenciamento do Exoma , Proliferação de Células/genética , Fenótipo , Mutação , Técnicas de Inativação de Genes
4.
Hum Mol Genet ; 30(11): 1045-1056, 2021 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-33615373

RESUMO

Craniofacial microsomia (CFM, OMIM%164 210) is one of the most common congenital facial abnormalities worldwide, but it's genetic risk factors and environmental threats are poorly investigated, as well as their interaction, making the diagnosis and prenatal screening of CFM impossible. We perform a comprehensive association study on the largest CFM cohort of 6074 samples. We identify 15 significant (P < 5 × 10-8) associated genomic loci (including eight previously reported) and decipher 107 candidates based on multi-omics data. Gene Ontology term enrichment found that these candidates are mainly enriched in neural crest cell (NCC) development and hypoxic environment. Single-cell RNA-seq data of mouse embryo demonstrate that nine of them show dramatic expression change during early cranial NCC development whose dysplasia is involved in pathogeny of CFM. Furthermore, we construct a well-performed CFM risk-predicting model based on polygenic risk score (PRS) method and estimate seven environmental risk factors that interacting with PRS. Single-nucleotide polymorphism-based PRS is significantly associated with CFM [P = 7.22 × 10-58, odds ratio = 3.15, 95% confidence interval (CI) 2.74-3.63], and the top fifth percentile has a 6.8-fold CFM risk comparing with the 10th percentile. Father's smoking increases CFM risk as evidenced by interaction parameter of -0.324 (95% CI -0.578 to -0.070, P = 0.011) with PRS. In conclusion, the newly identified risk loci will significantly improve our understandings of genetics contribution to CFM. The risk prediction model is promising for CFM prediction, and father's smoking is a key environmental risk factor for CFM through interacting with genetic factors.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença , Síndrome de Goldenhar/diagnóstico , Patologia Molecular , Adulto , Animais , Desenvolvimento Embrionário/genética , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Estudo de Associação Genômica Ampla , Síndrome de Goldenhar/genética , Síndrome de Goldenhar/patologia , Humanos , Masculino , Camundongos , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Diagnóstico Pré-Natal , RNA-Seq , Fatores de Risco , Análise de Célula Única
5.
Genet Med ; 25(1): 143-150, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36260083

RESUMO

PURPOSE: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. METHODS: We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro. RESULTS: We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3. CONCLUSION: Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.


Assuntos
Microtia Congênita , Síndrome de Goldenhar , Micrognatismo , Humanos , Síndrome de Goldenhar/genética , Microtia Congênita/genética , Orelha/anormalidades , Face
6.
J Med Genet ; 59(5): 417-427, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35110414

RESUMO

Oculo-auriculo-vertebral spectrum (OAVS) or Goldenhar syndrome is due to an abnormal development of first and second branchial arches derivatives during embryogenesis and is characterised by hemifacial microsomia associated with auricular, ocular and vertebral malformations. The clinical and genetic heterogeneity of this spectrum with incomplete penetrance and variable expressivity, render its molecular diagnosis difficult. Only a few recurrent CNVs and genes have been identified as causatives in this complex disorder so far. Prenatal environmental causal factors have also been hypothesised. However, most of the patients remain without aetiology. In this review, we aim at updating clinical diagnostic criteria and describing genetic and non-genetic aetiologies, animal models as well as novel diagnostic tools and surgical management, in order to help and improve clinical care and genetic counselling of these patients and their families.


Assuntos
Síndrome de Goldenhar , Animais , Região Branquial , Variações do Número de Cópias de DNA , Síndrome de Goldenhar/diagnóstico , Síndrome de Goldenhar/genética , Humanos
7.
Oral Dis ; 29(8): 3472-3480, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36070195

RESUMO

OBJECTIVES: Hemifacial microsomia (HFM) is a common birth defect involving the first and second branchial arch derivatives. Although several chromosomal abnormalities and causal gene variants have been identified, genetic etiologies in a majority of cases with HFM remain unknown. This study aimed to identify genetic mutations in affected individuals with HFM. METHODS: Whole-exome sequencing and bioinformatics analysis were performed for 16 affected individuals and their family members. Sanger sequencing was applied for confirmation of selected mutations. Zebrafish embryos were used for in situ hybridization of candidate gene, microinjection with antisense morpholino, and cartilage staining. RESULTS: A homozygous missense mutation (c.484G > A; p.V162I) in the FRK gene was identified in an 18-year-old girl with HFM and dental abnormalities. Heterozygous mutation of this mutation was identified in her parents, who are first cousins in a consanguineous family. FRK is highly expressed in the Meckel's cartilage during embryonic development in mouse and zebrafish. Knockdown of frk in zebrafish showed a lower length and width ratio of Meckel's cartilage, abnormal mandibular jaw joint, and disorganized ceratobranchial cartilage and bone. CONCLUSIONS: We identified a recessive variant in the FRK gene as a novel candidate gene for a patient with HFM and mandibular hypoplasia and revealed its effects on craniofacial and embryonic development in zebrafish.


Assuntos
Síndrome de Goldenhar , Humanos , Feminino , Camundongos , Animais , Adolescente , Síndrome de Goldenhar/genética , Peixe-Zebra/genética , Mandíbula/anormalidades , Articulação Temporomandibular , Cartilagem , Proteínas de Neoplasias , Proteínas Tirosina Quinases
8.
Am J Med Genet A ; 188(5): 1515-1525, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35119197

RESUMO

A diagnosis of oculo-auriculo-vertebral spectrum (OAVS) is established when microtia is present in association with hemifacial hypoplasia (HH) and/or ocular, vertebral, and/or renal malformations. There is no consensus on which imaging studies should be used to rule out variable expressivity and distinguish "sporadic" from "familial" patients. This observational and descriptive study was performed in a Mexican population of 51 patients (32 males, 19 females, 0-18 years old) with microtia/OAVS, and their available parents. A clinical history, genealogy, and physical examination were obtained from all included patients, as were a computed tomography (CT) scan of the ear, audiological evaluation, orthopantomography, complete spine radiography, and renal ultrasound. The same approach was completed in their available parents (51 mothers and 40 fathers), excluding the CT scan and audiological evaluation. By genealogy, 53% of patients were classified as "sporadic"; of the "familial" patients, at least 79.1% had suggestion of a multifactorial inheritance. In the available parents, orthopantomography, complete spine X-ray, and renal ultrasound identified the following OAVS-related manifestations: HH (16.2%, n = 14/86), vertebral alterations (10.9%, n = 10/91), and renal anomalies (2.2%, n = 2/90). Our evaluation of the parents allowed three patients to be reclassified from "sporadic" to "familial" (5.8%, n = 3/51). Our proposed clinical and imaging approach allowed the identification of variable expressivity that more clearly distinguished between "sporadic" and "familial" OAVS patients, which is of utmost importance in providing proper genetic counseling to these families.


Assuntos
Microtia Congênita , Síndrome de Goldenhar , Adolescente , Criança , Pré-Escolar , Feminino , Síndrome de Goldenhar/diagnóstico por imagem , Síndrome de Goldenhar/genética , Humanos , Lactente , Recém-Nascido , Masculino , México , Coluna Vertebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X
9.
Int J Mol Sci ; 24(1)2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36613479

RESUMO

The etiology of oculo-auriculo-vertebral spectrum (OAVS) is not well established. About half of patients show a positive family history. The etiology of familiar cases is unclear but appears genetically heterogeneous. This motivated us to report a case of OAVS with microtia, ptosis, facial microsomy, and fusion of vertebral bodies associated with a novel genetic etiology, including a deletion at 1p36.12-13. This case report expands on the genetic etiology of OAVS. Furthermore, it also expands the clinical manifestations of patients with interstitial deletions of the de 1p36.12-13 region.


Assuntos
Síndrome de Goldenhar , Humanos , Síndrome de Goldenhar/genética
10.
Cleft Palate Craniofac J ; 59(9): 1114-1124, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34410171

RESUMO

OBJECTIVE: Oculoauriculovertebral spectrum (OAVS) is a genetically and clinically heterogeneous disorder that occurs due to a developmental field defect of the first and second pharyngeal arches. Even though recent whole exome sequencing studies (WES) have led to identification of several genes associated with this spectrum in a subset of individuals, complete pathogenesis of OAVS remains unsolved. In this study, molecular genetic etiology of OAVS was systematically investigated. DESIGN/SETTING/PATIENTS: A cohort of 23 Turkish patients with OAVS, referred to Hacettepe University Hospital, Department of Pediatric Genetics from 2008 to 2018, was included in this study. Minimal diagnostic criteria for OAVS were considered as unilateral microtia or hemifacial microsomia with preauricular skin tag. The cohort was clinically reevaluated for craniofacial and extracranial findings. Molecular etiology was investigated using candidate gene sequencing following copy number variant (CNV) analysis. WES was also performed for 2 of the selected patients. RESULTS: Patients in the study cohort presented similar demographic and phenotypic characteristics to previously described patients in the literature except for a higher frequency of bilaterality, cardiac findings, and intellectual disability/developmental delay. CNV analysis revealed a possible genetic etiology for 3 patients (13%). Additional WES in 1 of the 2 patients uncovered a novel heterozygous nonsense variant in Elongation factor Tu GTP-binding domain-containing 2 (EFTUD2) causing mandibulofacial dysostosis with microcephaly (MFDM), which clinically overlaps with OAVS. CONCLUSION: Detailed clinical evaluation for any patient with OAVS is recommended due to a high rate of accompanying systemic findings. We further expand the existing genetic heterogeneity of OAVS by identifying several CNVs and a phenotypically overlapping disorder, MFDM.


Assuntos
Síndrome de Goldenhar , Disostose Mandibulofacial , Microcefalia , Criança , Estudos de Coortes , Deficiências do Desenvolvimento/genética , Síndrome de Goldenhar/genética , Humanos , Disostose Mandibulofacial/genética , Microcefalia/genética , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética
11.
Hum Genet ; 140(6): 933-944, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33475861

RESUMO

Goldenhar syndrome or oculo-auriculo-vertebral spectrum (OAVS) is a complex developmental disorder characterized by asymmetric ear anomalies, hemifacial microsomia, ocular and vertebral defects. We aimed at identifying and characterizing a new gene associated with OAVS. Two affected brothers with OAVS were analyzed by exome sequencing that revealed a missense variant (p.(Asn358Ser)) in the EYA3 gene. EYA3 screening was then performed in 122 OAVS patients that identified the same variant in one individual from an unrelated family. Segregation assessment in both families showed incomplete penetrance and variable expressivity. We investigated this variant in cellular models to determine its pathogenicity and demonstrated an increased half-life of the mutated protein without impact on its ability to dephosphorylate H2AFX following DNA repair pathway induction. Proteomics performed on this cellular model revealed four significantly predicted upstream regulators which are PPARGC1B, YAP1, NFE2L2 and MYC. Moreover, eya3 knocked-down zebrafish embryos developed specific craniofacial abnormalities corroborating previous animal models and supporting its involvement in the OAVS. Additionally, EYA3 gene expression was deregulated in vitro by retinoic acid exposure. EYA3 is the second recurrent gene identified to be associated with OAVS. Moreover, based on protein interactions and related diseases, we suggest the DNA repair as a key molecular pathway involved in craniofacial development.


Assuntos
Reparo do DNA , Proteínas de Ligação a DNA/genética , Síndrome de Goldenhar/genética , Mutação de Sentido Incorreto , Proteínas Tirosina Fosfatases/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Animais , Criança , Pré-Escolar , Proteínas de Ligação a DNA/deficiência , Embrião não Mamífero , Feminino , Regulação da Expressão Gênica , Síndrome de Goldenhar/metabolismo , Síndrome de Goldenhar/patologia , Histonas/genética , Histonas/metabolismo , Humanos , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Linhagem , Penetrância , Proteínas Tirosina Fosfatases/deficiência , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Irmãos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Sequenciamento do Exoma , Proteínas de Sinalização YAP , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo
12.
Clin Genet ; 100(3): 268-279, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33988253

RESUMO

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder of craniofacial morphogenesis. Its etiology is unclear, but assumed to be complex and heterogeneous, with contribution of both genetic and environmental factors. We assessed the occurrence of copy number variants (CNVs) in a cohort of 19 unrelated OAVS individuals with congenital heart defect. Chromosomal microarray analysis identified pathogenic CNVs in 2/19 (10.5%) individuals, and CNVs classified as variants of uncertain significance in 7/19 (36.9%) individuals. Remarkably, two subjects had small intragenic CNVs involving DACH1 and DACH2, two paralogs coding for key components of the PAX-SIX-EYA-DACH network, a transcriptional regulatory pathway controlling developmental processes relevant to OAVS and causally associated with syndromes characterized by craniofacial involvement. Moreover, a third patient showed a large duplication encompassing DMBX1/OTX3, encoding a transcriptional repressor of OTX2, another transcription factor functionally connected to the DACH-EYA-PAX network. Among the other relevant CNVs, a deletion encompassing HSD17B6, a gene connected with the retinoic acid signaling pathway, whose dysregulation has been implicated in craniofacial malformations, was also identified. Our findings suggest that CNVs affecting gene dosage likely contribute to the genetic heterogeneity of OAVS, and implicate the PAX-SIX-EYA-DACH network as novel pathway involved in the etiology of this developmental trait.


Assuntos
Variações do Número de Cópias de DNA , Síndrome de Goldenhar/genética , Cardiopatias Congênitas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Síndrome de Goldenhar/fisiopatologia , Humanos , Lactente , Recém-Nascido , Masculino , Análise em Microsséries , Polimorfismo de Nucleotídeo Único , Adulto Jovem
13.
Am J Med Genet A ; 185(7): 2056-2064, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33880880

RESUMO

Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder characterized by anomalies mainly involving the structures derived from the first and second pharyngeal arches. The spectrum presents with heterogeneous clinical features and complex etiology with genetic factors not yet completely understood. To date, MYT1 is the most important gene unambiguously associated with the spectrum and with functional data confirmation. In this work, we aimed to identify new single nucleotide variants (SNVs) affecting MYT1 in a cohort of 73 Brazilian patients diagnosed with OAVS. In addition, we investigated copy number variations (CNVs) encompassing this gene or its cis-regulatory elements and compared the frequency of these events in patients versus a cohort of 455 Brazilian control individuals. A new SNV, predicted as likely deleterious, was identified in five unrelated patients with OAVS. All five patients presented hearing impairment and orbital asymmetry suggesting an association with the variant. CNVs near MYT1, located in its neighboring topologically associating domain (TAD), were found to be enriched in patients when compared to controls, indicating a possible involvement of this region with OAVS pathogenicity. Our findings highlight the genetic complexity of the spectrum that seems to involve more than one variant type and inheritance patterns.


Assuntos
Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Síndrome de Goldenhar/genética , Fatores de Transcrição/genética , Região Branquial/patologia , Brasil/epidemiologia , Variações do Número de Cópias de DNA/genética , Feminino , Síndrome de Goldenhar/epidemiologia , Síndrome de Goldenhar/patologia , Humanos , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
14.
Int J Mol Sci ; 22(3)2021 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-33530447

RESUMO

Oculo-auriculo-vertebral-spectrum (OAVS; OMIM 164210) is a rare disorder originating from abnormal development of the first and second branchial arch. The clinical phenotype is extremely heterogeneous with ear anomalies, hemifacial microsomia, ocular defects, and vertebral malformations being the main features. MYT1, AMIGO2, and ZYG11B gene variants were reported in a few OAVS patients, but the etiology remains largely unknown. A multifactorial origin has been proposed, including the involvement of environmental and epigenetic mechanisms. To identify the epigenetic mechanisms contributing to OAVS, we evaluated the DNA-methylation profiles of 41 OAVS unrelated affected individuals by using a genome-wide microarray-based methylation approach. The analysis was first carried out comparing OAVS patients with controls at the group level. It revealed a moderate epigenetic variation in a large number of genes implicated in basic chromatin dynamics such as DNA packaging and protein-DNA organization. The alternative analysis in individual profiles based on the searching for Stochastic Epigenetic Variants (SEV) identified an increased number of SEVs in OAVS patients compared to controls. Although no recurrent deregulated enriched regions were found, isolated patients harboring suggestive epigenetic deregulations were identified. The recognition of a different DNA methylation pattern in the OAVS cohort and the identification of isolated patients with suggestive epigenetic variations provide consistent evidence for the contribution of epigenetic mechanisms to the etiology of this complex and heterogeneous disorder.


Assuntos
Metilação de DNA , Epigênese Genética , Estudo de Associação Genômica Ampla , Síndrome de Goldenhar/diagnóstico , Síndrome de Goldenhar/genética , Biologia Computacional/métodos , Ilhas de CpG , Feminino , Perfilação da Expressão Gênica , Estudos de Associação Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Anotação de Sequência Molecular , Fenótipo
15.
Am J Med Genet C Semin Med Genet ; 184(4): 970-985, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33215817

RESUMO

The aim of this study was to perform 22q11.2 deletion screening and chromosomal microarray analysis (CMA) in individuals clinically diagnosed with craniofacial microsomia (CFM) and review previously published cases of CFM with genomic imbalances. It included 54 individuals who were evaluated by a clinical geneticist. Copy number variants (CNVs) in the 22q11.2 region were investigated by multiplex ligation-dependent probe amplification (MLPA) for all individuals. The CMA was performed only for individuals with additional major features. MLPA revealed pathogenic CNVs at the 22q11 region in 3/54 (5.6%) individuals. CMA revealed pathogenic CNVs in 4/17 (23.5%) individuals, including the three CNVs at the 22q11 region also detected by MLPA, and CNVs classified as variants of unknown significance (VOUS) in 4/17 (23.5%) individuals. Pathogenic alterations were found at the 2p12, 5p15, 13q13, and 22q11 regions. VOUS were found at 3q29, 5q22.2, 5q22.1, and 9p22 regions. All individuals with pathogenic alterations presented additional major features, including congenital heart disease (CHD). The literature review revealed pathogenic CNVs in 17/193 (8.8%) individuals and most of them also presented additional major features, such as CHD, renal anomalies, or developmental delay. In conclusion, CNVs should be investigated in patients with CFM and additional major features.


Assuntos
Síndrome de Goldenhar , Cardiopatias Congênitas , Variações do Número de Cópias de DNA , Genômica , Síndrome de Goldenhar/genética , Humanos , Análise em Microsséries
16.
Clin Genet ; 98(4): 384-389, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32639022

RESUMO

Oculo-auriculo-vertebral spectrum (OAVS) [MIM:164210], or Goldenhar syndrome, is a developmental disorder associating defects of structures derived from the first and second branchial arches. The genetic origin of OAVS is supported by the description of rare deleterious variants in a few causative genes, and several chromosomal copy number variations. We describe here a large family with eight male members affected by a mild form of the spectrum, mostly auricular defects, harboring a hemizygous ZIC3 variant detected by familial exome sequencing: c.159_161dup p.(Ala55dup), resulting in an expansion of the normal 10 consecutive alanine residues to 11 alanines. Segregation analysis shows its presence in all the affected individuals, with a recessive X-linked transmission. Whole-genome sequencing performed in another affected male allowed to exclude linkage disequilibrium between this ZIC3 variant and another potential pathogenic variant in this family. Furthermore, by screening of a cohort of 274 OAVS patients, we found 1 male patient carrying an expansion of 10 to 12 alanines, a variant previously reported in patient presenting with VACTERL. Loss-of-function variants of ZIC3 are causing heterotaxy or cardiac malformations. These alanine expansion variants could have a different impact on the protein and thereby resulting in a different phenotype within the OAVS/VACTERL.


Assuntos
Canal Anal/anormalidades , Esôfago/anormalidades , Doenças Genéticas Ligadas ao Cromossomo X/genética , Predisposição Genética para Doença , Síndrome de Goldenhar/genética , Cardiopatias Congênitas/genética , Proteínas de Homeodomínio/genética , Rim/anormalidades , Deformidades Congênitas dos Membros/genética , Coluna Vertebral/anormalidades , Traqueia/anormalidades , Fatores de Transcrição/genética , Adolescente , Adulto , Alanina/genética , Canal Anal/patologia , Região Branquial/diagnóstico por imagem , Região Branquial/patologia , Criança , Pré-Escolar , Variações do Número de Cópias de DNA/genética , Esôfago/patologia , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Síndrome de Goldenhar/patologia , Cardiopatias Congênitas/patologia , Humanos , Lactente , Rim/patologia , Deformidades Congênitas dos Membros/patologia , Mutação com Perda de Função/genética , Masculino , Sequências Repetitivas de Aminoácidos/genética , Coluna Vertebral/patologia , Traqueia/patologia , Sequenciamento Completo do Genoma , Adulto Jovem
17.
Am J Med Genet A ; 182(11): 2624-2631, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32893956

RESUMO

Oculo-auriculo-vertebral spectrum (hemifacial microsomia/OAVS, OMIM #164210) is a heterogenous and congenital condition caused by a morphogenesis defect of the first and second pharyngeal arches. Etiology includes unknown genetic, environmental factors and chromosomal alterations, which 22q11.2 region is the most frequently reported. Several candidate genes for OAVS have been proposed; however, none has been confirmed as causative of the phenotype. This review aims to sum up all clinical and molecular findings in 22q region of individuals diagnosed with OAVS and to investigate genes that may be involved in the development of the spectrum. A search was performed in PubMed using all entry terms to OAVS and Chromosome 22q11. After screening, 11 papers were eligible for review. Deletions and duplications in the q11.2 region were the most frequent (18/22) alterations reported and a total of 68 genes were described. Our systematic review reinforces the hypothesis that 22q11 region is a candidate locus for OAVS as well as CLTCL1, GSC2, HIRA, MAPK1, TBX1, and YPEL1 as potential candidates genes for genotype-phenotype correlation. Complementary studies regarding genes interaction involved in the 22q11 region are still necessary in the search for a genotype-phenotype association, since the diagnosis of OAVS is a constant medical challenge.


Assuntos
Cromossomos Humanos Par 22 , Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome de Goldenhar/diagnóstico , Síndrome de Goldenhar/genética , Adolescente , Criança , Pré-Escolar , Aberrações Cromossômicas , Feminino , Deleção de Genes , Duplicação Gênica , Humanos , Lactente , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único
18.
Am J Med Genet A ; 176(3): 638-648, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29368383

RESUMO

The oculoauriculovertebral spectrum (OAVS) is characterized by anomalies involving the development of the first and second pharyngeal arches during the embryonic period. The phenotype is highly heterogeneous, involving ears, eyes, face, neck, and other systems and organs. There is no agreement in the literature for the minimum phenotypic inclusion criteria, but the primary phenotype involves hemifacial microsomia with facial asymmetry and microtia. Most cases are sporadic and the etiology of this syndrome is not well known. Environmental factors, family cases that demonstrate Mendelian inheritance, such as preauricular appendages, microtia, mandibular hypoplasia, and facial asymmetry; chromosomal abnormalities and some candidate genes suggest a multifactorial inheritance model. We evaluated clinical, cytogenomic and molecularly 72 patients with OAVS, and compared our findings with patients from the literature. We found 15 CNVs (copy number variations) considered pathogenic or possibly pathogenic in 13 out of 72 patients. Our results did not indicated a single candidate genomic region, but recurrent chromosomal imbalances were observed in chromosome 4 and 22, in regions containing genes relevant to the OAVS phenotype or related to known OMIM diseases suggesting different pathogenic mechanisms involved in this genetically and phenotypic heterogeneous spectrum.


Assuntos
Aberrações Cromossômicas , Estudos de Associação Genética , Síndrome de Goldenhar/diagnóstico , Síndrome de Goldenhar/genética , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Análise Citogenética , Variações do Número de Cópias de DNA , Feminino , Síndrome de Goldenhar/epidemiologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto Jovem
19.
Am J Med Genet A ; 173(2): 309-314, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27774762

RESUMO

Oculoauriculovertebral spectrum (OAVS), also known as Goldenhar syndrome, is considered a condition associated to failing of embryogenesis involving the first and second branchial arches, leading to structural abnormalities arising from it. The aim of this study is to verify the hearing features presented by patients with OAVS and provide additional information that may contribute to improvement of speech therapy. The sample consisted of 10 individuals diagnosed with OAVS and cared for by the Clinical Genetics Service. All patients underwent objective assessment of auditory function through tonal and vocal audiometry. This evaluation was completed using TOAE and BERA. The patient's age ranged from 1 year and 9 months to 27 years and 4 months. At physical examination it was found that 10 had microtia, 7 preauricular tags, 6 low-set ears, 6 ear canal atresia, and 2 preauricular pits. Among the patients, five presented with abnormal hearing. Three patients had conductive hearing loss ranging from mild to moderate, and two patients had sensorineural hearing loss from mild to profound. Three patients had hearing loss in both ears. Speech-language disorders are common in children with OAVS. Thus, the referral to the audiologist and speech pathologist is indicated as soon as possible. Early recognition and detailed understanding of aspects related to the etiology, clinical features, and outcome of patients with OAVS are essential for their proper management. © 2016 Wiley Periodicals, Inc.


Assuntos
Síndrome de Goldenhar/diagnóstico , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Síndrome de Goldenhar/genética , Perda Auditiva/diagnóstico , Perda Auditiva/genética , Testes Auditivos , Humanos , Lactente , Masculino , Exame Físico , Estudos Prospectivos , Adulto Jovem
20.
Am J Med Genet A ; 173(5): 1208-1218, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28319315

RESUMO

Hemifacial microsomia (HFM) is a rare, multisystemic congenital disease with estimated frequency of 1/26370 births in Europe. Most cases are sporadic and caused by unilateral abnormal morphogenesis of the first and second pharyngeal arches. The aim of this study is to define the types and frequency of maxillofacial and systemic malformations in HFM patients. This is a case series study of patients with HFM evaluated at a single institution. Data were acquired through history, physical examination, photographs, diagnostic radiology, and laboratory and analyzed by the FileMakerPro database on 95 patients (54F; 41M) of which 89 met the inclusion criteria. Mandibular hypoplasia was observed in 86 patients with right-side preponderance (50). One patient had bilateral mandibular hypoplasia. Seventy-four had external ear anomalies (anotia or microtia). Eleven had bilateral malformed ears. Hearing impairment, associated with stenosis or atresia of the external ear canal, was found in 69 patients (eight with bilateral canal defects). Ocular anomalies were seen in 41 (23 with dermoid cysts) and 39 had orbital malformations. Facial nerve paralysis was observed in 38 patients. Cleft lip/palate (10), preauricular tags (55), and macrostomia (41) were also described. A total of 73/86 had systemic malformations, mainly vertebral (40), genitourinary (25), and cardiovascular (28). Sixteen had cerebral anomalies (four with intellectual disability). All patients suspected of HFM should undergo a complete systematic clinical and imaging investigation to define the full scope of anomalies. Since the disease is rare and complex, affected patients should be monitored by specialized multidisciplinary team centers.


Assuntos
Fenda Labial/genética , Assimetria Facial/genética , Síndrome de Goldenhar/genética , Anormalidades Maxilofaciais/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Fenda Labial/diagnóstico , Fenda Labial/fisiopatologia , Fissura Palatina/diagnóstico , Fissura Palatina/genética , Fissura Palatina/fisiopatologia , Orelha Externa/anormalidades , Assimetria Facial/diagnóstico , Assimetria Facial/fisiopatologia , Feminino , Síndrome de Goldenhar/diagnóstico , Síndrome de Goldenhar/fisiopatologia , Humanos , Lactente , Masculino , Mandíbula/anormalidades , Anormalidades Maxilofaciais/diagnóstico , Anormalidades Maxilofaciais/fisiopatologia , Pessoa de Meia-Idade , Adulto Jovem
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