Haploinsufficiency of SF3B2 causes craniofacial microsomia.
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ABSTRACT:
SUBMITTER: Timberlake AT
PROVIDER: S-EPMC8333351 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundCraniofacial microsomia (CFM), also known as the oculo-auriculo-vertebral spectrum, comprises a variable phenotype with the most common features including microtia and mandibular hypoplasia on one or both sides, in addition to lateral oral clefts, epibulbar dermoids, cardiac, vertebral, and renal abnormalities. The etiology of CFM is largely unknown. The MYT1 gene has been reported as a candidate based in mutations found in three unrelated individuals. Additional patients with mutations in this gene are required to establish its causality. We present two individuals with CFM that have rare variants in MYT1 contributing to better understand the genotype and phenotype associated with mutations in this gene.Methods/resultsWe conducted genetic analysis using whole-exome and -genome sequencing in 128 trios with CFM. Two novel MYT1 mutations were identified in two participants. Sanger sequencing was used to confirm these mutations.ConclusionWe identified two additional individuals with CFM who carry rare variants in MYT1, further supporting the presumptive role of this gene in the CFM spectrum.
| S-EPMC7549594 | biostudies-literature
Project description:Craniofacial microsomia encapsulates congenital anomalies of the external and middle ear, maxilla, mandible, facial and trigeminal nerves, and surrounding soft tissues on the affected side. The recruitment of craniofacial microsomia samples is a huge problem to bind the investigation of its genetic basis because of the lower prevalence rate (ranging between 1 and 4 per 10,000 births) and consultation rate. Here, we performed the first genome-wide associations study on craniofacial microsomia and identified many significant loci associated with craniofacial microsomia.
2016-02-03 | GSE69664 | GEO
Project description: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.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.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.These findings suggest the need for a specific CFM code to facilitate CFM surveillance and research.
| S-EPMC3522759 | biostudies-literature
Project description:Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3. Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance.
| S-EPMC10090152 | biostudies-literature
Project description:PurposeCraniofacial 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.MethodsWe 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.ResultsWe 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.ConclusionDamaging 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.
| S-EPMC9885525 | biostudies-literature
Project description:BackgroundThe authors compared the IQ and academic achievement of adolescents with craniofacial microsomia (cases) and unaffected children (controls). Among cases, the authors analyzed cognitive functioning by facial phenotype.MethodsThe authors administered standardized tests of intelligence, reading, spelling, writing, and mathematics to 142 cases and 316 controls recruited from 26 cities across the United States and Canada. Phenotypic classification was based on integrated data from photographic images, health history, and medical chart reviews. Hearing screens were conducted for all participants.ResultsAfter adjustment for demographics, cases' average scores were lower than those of controls on all measures, but the magnitude of differences was small (standardized effect sizes, -0.01 to -0.3). There was little evidence that hearing status modified case-control group differences (Wald p > 0.05 for all measures). Twenty-five percent of controls and 38 percent of cases were classified as having learning problems (adjusted OR, 1.5; 95 percent CI, 0.9 to 2.4). Comparison of cases with and without learning problems indicated that those with learning problems were more likely to be male, Hispanic, and to come from lower income, bilingual families. Analyses by facial phenotype showed that case-control group differences were largest for cases with both microtia and mandibular hypoplasia (effect sizes, -0.02 to -0.6).ConclusionsThe highest risk of cognitive-academic problems was observed in patients with combined microtia and mandibular hypoplasia. Developmental surveillance of this subgroup is recommended, especially in the context of high socioeconomic risk and bilingual families. Given the early stage of research on craniofacial microsomia and neurodevelopment, replication of these findings is needed.Clinical question/level of evidenceRisk, II.
| S-EPMC5657387 | biostudies-literature
Project description:ImportanceKnowledge of unmet school participation needs for students with craniofacial microsomia (CFM) can inform decisions regarding intervention support.ObjectiveTo compare students with and without CFM on school participation (i.e., frequency, involvement, desire for participation to change) and caregivers' perceptions of environmental support for participation in occupations.DesignCross-sectional design using secondary analyses of a subset of data.SettingMultisite cohort study.ParticipantsCaregivers of students with CFM (n = 120) and of students without CFM (n = 315), stratified by history of education- and health-related service use.Outcomes and measuresSchool participation and environmental support, obtained with the Participation and Environment Measure-Children and Youth.ResultsSignificant group differences were found in frequency of school participation (effect size [ES] = -0.38, 95% confidence interval [-0.64, -0.12], p = .005), level of involvement (ES = -0.14, p = .029), and desired change (p = .001), with students with CFM exhibiting greater participation restriction than students without CFM and no history of service use. No statistically significant group differences were found in environmental support for participation in the school setting. Item-level findings showed statistically significant higher desire for participation to change in three of five school occupations (odds ratio = 1.77-2.39, p = .003-.045) for students with CFM compared with students without CFM and no history of service use.Conclusions and relevanceThe results suggest that students with CFM experience restriction in participation at school.What this article addsStudents with CFM may benefit from targeted school-based interventions to optimize their inclusion.
| S-EPMC7929606 | biostudies-literature
Project description:Craniofacial microsomia (CFM) is a rare congenital anomaly that involves immature derivatives from the first and second pharyngeal arches. The genetic pathogenesis of CFM is still unclear. Here we interrogate 0.9 million genetic variants in 939 CFM cases and 2,012 controls from China. After genotyping of an additional 443 cases and 1,669 controls, we identify 8 significantly associated loci with the most significant SNP rs13089920 (logistic regression P=2.15 × 10(-120)) and 5 suggestive loci. The above 13 associated loci, harboured by candidates of ROBO1, GATA3, GBX2, FGF3, NRP2, EDNRB, SHROOM3, SEMA7A, PLCD3, KLF12 and EPAS1, are found to be enriched for genes involved in neural crest cell (NCC) development and vasculogenesis. We then perform whole-genome sequencing on 21 samples from the case cohort, and identify several novel loss-of-function mutations within the associated loci. Our results provide new insights into genetic background of craniofacial microsomia.
| S-EPMC4748111 | biostudies-literature
Project description:Craniofacial microsomia (CFM) is characterized by underdevelopment of the structures derived from the first and second pharyngeal arches resulting in aesthetic, psychological, and functional problems including feeding and swallowing difficulties. The aim of this study is to gain more insight into swallowing difficulties in patients with CFM. A retrospective study was conducted in the population of patients diagnosed with CFM at three major craniofacial units. Patients with feeding difficulties and those who underwent video fluoroscopic swallow (VFS) studies were included for further analyses. The outcome of the VFS-studies was reviewed with regard to the four phases of swallowing. In our cohort, 13.5% of the 755 patients were diagnosed with swallowing difficulties. The outcome of the VFS-studies of 42 patients showed difficulties in the oral and pharyngeal phases with both thin and thick liquids. Patients with more severe mandibular hypoplasia showed more difficulties to form an appropriate bolus compared to patients who were less severely affected. This is the first study to document swallowing problems in patients with CFM. Difficulties were seen in both the oral and pharyngeal phases. We recommend routine screening for swallowing issues by a speech and language therapist in all patients with CFM and to obtain a VFS-study in patients with a type III mandible.
| S-EPMC5866261 | biostudies-literature
Project description:IntroductionAsymmetric mandibular hypoplasia, microtia, tongue and laryngeal anomalies, and soft palate and facial nerve dysfunction are clinical features observed in children with craniofacial microsomia (CFM). Despite involvement of all these structures in hearing and speech, there is limited evidence reporting speech outcomes in this population. Systematic reviews of clinical and surgical interventions related to CFM have been published, but no methodological review of speech outcomes exists. This scoping review will summarise what is known about speech production in individuals with CFM as well as illustrate gaps in the existing body of literature that will guide future research.Methods/analysisThis review will follow the methodological framework for scoping reviews first reported by Arksey & O'Malley and revised by Levac and others. Databases searched will include Ovid MEDLINE, EMBASE, CINAHL, PsycINFO and grey literature. Articles reporting any parameter of speech production in individuals with CFM will be considered for inclusion. Articles published in a language other than English will be excluded. Articles will be screened in three stages: (1) title review, (2) abstract review and (3) full text review. Ten per cent of articles will be rescreened by a second reviewer. Reference lists will be hand reviewed to identify additional relevant articles. Data charting will capture article metadata, study population and design, CFM diagnostic criteria, speech outcome measurement and key findings. The Preferred Reporting Systems for Systematic Reviews and Meta-Analyses Protocols-Extension for Scoping Reviews checklist will guide reporting of results. Descriptive analysis and data visualisation strategies will be used.Ethics and disseminationInstitutional review board approval is not required for a scoping review, as it does not directly involve human subjects. Results will be disseminated through peer-reviewed publication as well as conference presentation.
| S-EPMC9980328 | biostudies-literature