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Orphanet Journal of Rare Diseases Apr 2024Microtia is a congenital ear malformation that can occur as isolated microtia or as part of a syndrome. The etiology is currently poorly understood, although there is...
BACKGROUND
Microtia is a congenital ear malformation that can occur as isolated microtia or as part of a syndrome. The etiology is currently poorly understood, although there is strong evidence that genetics has a role in the occurrence of microtia. This systematic review aimed to determine the genes involved and the abnormalities in microtia patients' head and neck regions.
METHODS
We used seven search engines to search all known literature on the genetic and phenotypic variables associated with the development or outcome of microtia. The identified publications were screened and selected based on inclusion and exclusion criteria and assessed for methodological quality using the Joanna Briggs Institute (JBI) critical appraisal tools. We found 40 papers in this systematic review with phenotypic data in microtia involving 1459 patients and 30 articles containing genetic data involved in microtia.
RESULT
The most common accompanying phenotype of all microtia patients was external ear canal atresia, while the most common head and neck abnormalities were the auricular, mental, and oral regions. The most common syndrome found was craniofacial microsomia syndrome. In the syndromic microtia group, the most common genes were TCOF1 (43.75%), SIX2 (4.69%), and HSPA9 (4.69%), while in the non-syndromic microtia group, the most frequently found gene was GSC exon 2 (25%), FANCB (16.67%), HOXA2 (8.33%), GSC exon 3 (8.33%), MARS1 (8.33%), and CDT1 (8.33%).
CONCLUSIONS
Our systematic review shows some genes involved in the microtia development, including TCOF1, SIX2, HSPA9, GSC exon 2, FANCB, HOXA2, GSC exon 3, MARS1, and CDT1 genes. We also reveal a genotype-phenotype association in microtia. In addition, further studies with more complete and comprehensive data are needed, including patients with complete data on syndromes, phenotypes, and genotypes.
Topics: Humans; Congenital Microtia; Homeodomain Proteins; Ear; Phenotype; Syndrome; Genetic Association Studies
PubMed: 38594752
DOI: 10.1186/s13023-024-03142-9 -
Italian Journal of Pediatrics Nov 2023Congenital clubfoot is a fairly common and severe congenital malformation, most often of idiopathic origin. A smaller percentage of cases is related to chromosomal... (Review)
Review
BACKGROUND
Congenital clubfoot is a fairly common and severe congenital malformation, most often of idiopathic origin. A smaller percentage of cases is related to chromosomal abnormalities and genetic syndromes. It is estimated that 0.5/1000 newborns are affected worldwide, with a male to female ratio of 2:1 and greater distribution in developing countries (80%). The "European Surveillance of Congenital Anomalies (EUROCAT)" reported clubfoot prevalence in European newborns, but data regarding Italy are missing or poor. We aim to provide detailed data on clubfoot incidence according to the Apulian Regional Registry on Congenital Malformations and to report current knowledge on clubfoot genetic factors.
METHODS
We extrapolated data from the Regional Registry of Congenital Malformations to evaluate incidence and prevalence of congenital clubfoot in Apulia, Italy over a period of four years (2015-2018). We also performed a narrative review focusing on genetic mutations leading to congenital clubfoot.
RESULTS
Over the period from 2015 to 2018 in Apulia, Italy, 124,017 births were recorded and 209 cases of clubfoot were found, accounting for an incidence rate of 1.7/1,000 and a prevalence rate of 1.6/1,000. Six families of genes have been reported to have an etiopathogenetic role on congenital clubfoot.
CONCLUSIONS
Incidence and prevalence of congenital clubfoot in Apulia, Italy, are comparable with those reported in the other Italian regions but higher than those reported in previous studies from Europe. Genetic studies to better classify congenital clubfoot in either syndromic or isolated forms are desirable.
Topics: Humans; Male; Infant, Newborn; Female; Clubfoot; Incidence; Prevalence; Italy; Europe
PubMed: 37964341
DOI: 10.1186/s13052-023-01559-9 -
European Journal of Human Genetics :... Apr 2024Many human teratogens are associated with a spectrum of congenital anomalies rather than a single defect, and therefore the identification of congenital anomalies... (Review)
Review
Many human teratogens are associated with a spectrum of congenital anomalies rather than a single defect, and therefore the identification of congenital anomalies occurring together more frequently than expected may improve the detection of teratogens. Thirty-two EUROCAT congenital anomaly registries covering 6,599,765 births provided 123,566 cases with one or more major congenital anomalies (excluding chromosomal and genetic syndromes) for the birth years 2008-2016. The EUROCAT multiple congenital anomaly algorithm identified 8804 cases with two or more major congenital anomalies in different organ systems, that were not recognized as part of a syndrome or sequence. For each pair of anomalies, the odds of a case having both anomalies relative to having only one anomaly was calculated and the p value was estimated using a two-sided Fisher's exact test. The Benjamini-Hochberg procedure adjusted p values to control the false discovery rate and pairs of anomalies with adjusted p values < 0.05 were identified. A total of 1386 combinations of two anomalies were analyzed. Out of the 31 statistically significant positive associations identified, 20 were found to be known associations or sequences already described in the literature and 11 were considered "potential new associations" by the EUROCAT Coding and Classification Committee. After a review of the literature and a detailed examination of the individual cases with the anomaly pairs, six pairs remained classified as new associations. In summary, systematically searching for congenital anomalies occurring together more frequently than expected using the EUROCAT database is worthwhile and has identified six new associations that merit further investigation.
Topics: Humans; Teratogens; Abnormalities, Multiple; Registries; Syndrome; Databases, Factual; Congenital Abnormalities; Prevalence; Europe
PubMed: 38052905
DOI: 10.1038/s41431-023-01502-w -
Asian Journal of Surgery Apr 2024
Topics: Humans; Ectopia Lentis; Iris; Craniofacial Abnormalities
PubMed: 38199882
DOI: 10.1016/j.asjsur.2023.12.135 -
Aging and Disease Feb 2024Genetic studies have shown that Robinow syndrome (RS), a rare skeletal dysplasia, is caused by ROR2 mutation. However, the cell origin and molecular mechanisms...
Genetic studies have shown that Robinow syndrome (RS), a rare skeletal dysplasia, is caused by ROR2 mutation. However, the cell origin and molecular mechanisms underlying this disease remain elusive. We established a conditional knockout system by crossing Prx1cre and Osxcre with Ror2 mice. and conducted histological and immunofluorescence analyses to investigate the phenotypes during skeletal development. In the Prx1cre line, we observed RS-like skeletal abnormities, including short stature and an arched skull. Additionally, we found inhibition of chondrocyte differentiation and proliferation. In the Osxcre line, loss of ROR2 in osteoblast lineage cells led to reduced osteoblast differentiation during both embryonic and postnatal stages. Furthermore, ROR2 mutant mice exhibited increased adipogenesis in the bone marrow compared to their littermate controls. To further explore the underlying mechanisms, bulk RNA-seq analysis of Prx1cre; Ror2 embryos was performed, results revealed decreased BMP/TGF-β signaling. Immunofluorescence analysis further confirmed the decreased expression of p-smad1/5/8, accompanied by disrupted cell polarity in the developing growth plate. Pharmacological treatment using FK506 partially rescued the skeletal dysplasia and resulted in increased mineralization and osteoblast differentiation. By modeling the phenotype of RS in mice, our findings provide evidence for the involvement of mesenchymal progenitors as the cell origin and highlight the molecular mechanism of BMP/TGF-β signaling in skeletal dysplasia.
Topics: Mice; Animals; Chondrocytes; Cell Differentiation; Osteogenesis; Osteoblasts; Transforming Growth Factor beta; Dwarfism; Urogenital Abnormalities; Limb Deformities, Congenital; Craniofacial Abnormalities
PubMed: 37307827
DOI: 10.14336/AD.2023.0531 -
Cell and Tissue Research May 2024Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and...
Joubert syndrome (JS) is a recessively inherited congenital ataxia characterized by hypotonia, psychomotor delay, abnormal ocular movements, intellectual disability, and a peculiar cerebellar and brainstem malformation, the "molar tooth sign." Over 40 causative genes have been reported, all encoding for proteins implicated in the structure or functioning of the primary cilium, a subcellular organelle widely present in embryonic and adult tissues. In this paper, we developed an in vitro neuronal differentiation model using patient-derived induced pluripotent stem cells (iPSCs), to evaluate possible neurodevelopmental defects in JS. To this end, iPSCs from four JS patients harboring mutations in distinct JS genes (AHI1, CPLANE1, TMEM67, and CC2D2A) were differentiated alongside healthy control cells to obtain mid-hindbrain precursors and cerebellar granule cells. Differentiation was monitored over 31 days through the detection of lineage-specific marker expression by qRT-PCR, immunofluorescence, and transcriptomics analysis. All JS patient-derived iPSCs, regardless of the mutant gene, showed a similar impairment to differentiate into mid-hindbrain and cerebellar granule cells when compared to healthy controls. In addition, analysis of primary cilium count and morphology showed notable ciliary defects in all differentiating JS patient-derived iPSCs compared to controls. These results confirm that patient-derived iPSCs are an accessible and relevant in vitro model to analyze cellular phenotypes connected to the presence of JS gene mutations in a neuronal context.
Topics: Induced Pluripotent Stem Cells; Humans; Cell Differentiation; Eye Abnormalities; Cerebellum; Neurons; Abnormalities, Multiple; Retina; Kidney Diseases, Cystic; Male; Female; Mutation; Cilia
PubMed: 38502237
DOI: 10.1007/s00441-024-03876-9 -
Human Molecular Genetics Aug 2023Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis...
Orofacial clefts, including cleft lip and palate (CL/P) and neural tube defects (NTDs) are among the most common congenital anomalies, but knowledge of the genetic basis of these conditions remains incomplete. The extent to which genetic risk factors are shared between CL/P, NTDs and related anomalies is also unclear. While identification of causative genes has largely focused on coding and loss of function mutations, it is hypothesized that regulatory mutations account for a portion of the unidentified heritability. We found that excess expression of Grainyhead-like 2 (Grhl2) causes not only spinal NTDs in Axial defects (Axd) mice but also multiple additional defects affecting the cranial region. These include orofacial clefts comprising midline cleft lip and palate and abnormalities of the craniofacial bones and frontal and/or basal encephalocele, in which brain tissue herniates through the cranium or into the nasal cavity. To investigate the causative mutation in the Grhl2Axd strain, whole genome sequencing identified an approximately 4 kb LTR retrotransposon insertion that disrupts the non-coding regulatory region, lying approximately 300 base pairs upstream of the 5' UTR. This insertion also lies within a predicted long non-coding RNA, oriented on the reverse strand, which like Grhl2 is over-expressed in Axd (Grhl2Axd) homozygous mutant embryos. Initial analysis of the GRHL2 upstream region in individuals with NTDs or cleft palate revealed rare or novel variants in a small number of cases. We hypothesize that mutations affecting the regulation of GRHL2 may contribute to craniofacial anomalies and NTDs in humans.
Topics: Animals; Humans; Mice; Abnormalities, Multiple; Cleft Lip; Cleft Palate; Encephalocele; Mutation; Neural Tube Defects; Spinal Dysraphism
PubMed: 37364051
DOI: 10.1093/hmg/ddad094 -
Journal of Vascular Surgery. Venous and... Sep 2023In recent years, genotypic characterization of congenital vascular malformations (CVMs) has gained attention; however, the spectrum of clinical phenotype remains...
OBJECTIVE
In recent years, genotypic characterization of congenital vascular malformations (CVMs) has gained attention; however, the spectrum of clinical phenotype remains difficult to attribute to a genetic cause and is rarely described in the adult population. The aim of this study is to describe a consecutive series of adolescent and adult patients in a tertiary center, where a multimodal phenotypic approach was used for diagnosis.
METHODS
We analyzed clinical findings, imaging, and laboratory results at initial presentation, and set a diagnosis according to the International Society for the Study of Vascular Anomalies (ISSVA) classification for all consecutively registered patients older than 14 years of age who were referred to the Center for Vascular Malformations at the University Hospital of Bern between 2008 and 2021.
RESULTS
A total of 457 patients were included for analysis (mean age, 35 years; females, 56%). Simple CVMs were the most common (n = 361; 79%), followed by CVMs associated with other anomalies (n = 70; 15%), and combined CVMs (n = 26; 6%). Venous malformations (n = 238) were the most common CVMs overall (52%), and the most common simple CVMs (66%). Pain was the most frequently reported symptom in all patients (simple, combined, and vascular malformation with other anomalies). Pain intensity was more pronounced in simple venous and arteriovenous malformations. Clinical problems were related to the type of CVM diagnosed, with bleeding and skin ulceration in arteriovenous malformations, localized intravascular coagulopathy in venous malformations, and infectious complications in lymphatic malformations. Limb length difference occurred more often in patients with CVMs associated with other anomalies as compared with simple or combined CVM (22.9 vs 2.3%; P < .001). Soft tissue overgrowth was seen in one-quarter of all patients independent of the ISSVA group.
CONCLUSIONS
In our adult and adolescent population with peripheral vascular malformations, simple venous malformations predominated, with pain as the most common clinical symptom. In one-quarter of cases, patients with vascular malformations presented with associated anomalies on tissue growth. The differentiation of clinical presentation with or without accompanying growth abnormalities need to be added to the ISSVA classification. Phenotypic characterization considering vascular and non-vascular features remains the cornerstone of diagnosis in adult as well as pediatric patients.
Topics: Female; Humans; Vascular Malformations; Arteriovenous Malformations; Veins; Pain; Phenotype
PubMed: 37030445
DOI: 10.1016/j.jvsv.2023.03.012 -
Proceedings of the National Academy of... Aug 2023Mutations in signal transduction pathways lead to various diseases including cancers. MEK1 kinase, encoded by the human gene, is one of the central components of the...
Mutations in signal transduction pathways lead to various diseases including cancers. MEK1 kinase, encoded by the human gene, is one of the central components of the MAPK pathway and more than a hundred somatic mutations in the gene were identified in various tumors. Germline mutations deregulating MEK1 also lead to congenital abnormalities, such as the cardiofaciocutaneous syndrome and arteriovenous malformation. Evaluating variants associated with a disease is a challenge, and computational genomic approaches aid in this process. Establishing evolutionary history of a gene improves computational prediction of disease-causing mutations; however, the evolutionary history of MEK1 is not well understood. Here, by revealing a precise evolutionary history of MEK1, we construct a well-defined dataset of MEK1 metazoan orthologs, which provides sufficient depth to distinguish between conserved and variable amino acid positions. We matched known and predicted disease-causing and benign mutations to evolutionary changes observed in corresponding amino acid positions and found that all known and many suspected disease-causing mutations are evolutionarily intolerable. We selected several variants that cannot be unambiguously assessed by automated prediction tools but that are confidently identified as "damaging" by our approach, for experimental validation in . In all cases, evolutionary intolerant variants caused increased mortality and severe defects in fruit fly embryos confirming their damaging nature. We anticipate that our analysis will serve as a blueprint to help evaluate known and novel missense variants in MEK1 and that our approach will contribute to improving automated tools for disease-associated variant interpretation.
Topics: Humans; Animals; Mutation; Ectodermal Dysplasia; Mutation, Missense; Heart Defects, Congenital; Amino Acids; MAP Kinase Kinase 1
PubMed: 37579140
DOI: 10.1073/pnas.2304184120 -
Transcatheter closure of atrial septal defect in the elderly: a systematic review and meta-analysis.Heart (British Cardiac Society) Nov 2023Despite the establishment of transcatheter closure as the treatment of choice in adults with secundum atrial septal defects (ASDs), the effectiveness of this approach in... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Despite the establishment of transcatheter closure as the treatment of choice in adults with secundum atrial septal defects (ASDs), the effectiveness of this approach in the elderly is disputed. This systematic review and meta-analysis aims to explore the impact of transcatheter ASD closure in patients ≥60 years old.
METHODS
We systematically searched four major electronic databases (PubMed, CENTRAL (Cochrane Central Register of Controlled Trials), Scopus and Web of Science), ClinicalTrials.gov, article references and grey literature. Primary outcomes were the right ventricular end-diastolic diameter (RVEDD) and the New York Heart Association functional class change, whereas secondary outcomes included systolic pulmonary arterial pressure (sPAP), left ventricular end-diastolic diameter (LVEDD), brain natriuretic peptide (BNP), tricuspid valve regurgitation (TR) change, as well as the rate of atrial arrhythmias and all-cause mortality.
RESULTS
In total, 18 single-arm cohorts comprising 1184 patients were included. RVEDD was reduced after ASD closure (standardised mean difference (SMD) -0.9, 95% CI -1.2 to -0.7). Elderly patients had 9.5 times higher odds of being asymptomatic after ASD closure (95% CI 5.06 to 17.79). Furthermore, ASD closure improved sPAP (mean difference (MD) -10.8, 95% CI -14.6 to -7), LVEDD (SMD 0.8, 95% CI 0.7 to 1.0), TR severity (OR 0.39, 95% CI 0.25 to 0.60) and BNP (MD -68.3, 95% CI -114.4 to -22.1). There was a neutral effect of ASD closure on atrial arrhythmias.
CONCLUSIONS
Transcatheter ASD closure is beneficial for the elderly population since it improves functional capacity, biventricular dimensions, pulmonary pressures, TR severity and BNP. However, the incidence of atrial arrhythmias did not change significantly after the intervention.
PROSPERO REGISTRATION NUMBER
CRD42022378574.
Topics: Adult; Humans; Aged; Middle Aged; Atrial Fibrillation; Tricuspid Valve Insufficiency; Heart Septal Defects, Atrial; Cardiac Catheterization; Treatment Outcome
PubMed: 37380331
DOI: 10.1136/heartjnl-2023-322529