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Hemifacial microsomia (HFM) is a rare congenital disease characterized by a spectrum of craniomaxillofacial malformations, including unilateral hypoplasia of the mandible and surrounding structures. Genetic predisposition for HFM is evident but the causative genes have not been fully understood. Thus, in the present study, we used whole-exome seque...
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... database mining identified a number of gene and chromosome regions that have been previously associated with HFM (Table 2). Next, rare, potentially causative mutations that were detected in the 52 patients in the present study were screened to identify novel mutations in the known HFM genes. ...Context 2
... date, the molecular mechanisms that underlie HFM pathogenesis remain unclear; however, strong evidence suggests that these include genetic factors, as evidenced by the fact that several chromosomal abnormalities and gene mutations have been previously reported in patients with HFM ( Table 2). The largest study conducted to date was a genome-wide association study (GWAS) that was performed in 2016 ( Zhang et al., 2016). ...Similar publications
Familial pancreatic cancer (FPC) is a rare hereditary tumor entity with broad phenotypic heterogeneity, including colorectal carcinoma (CRC) in some families. The underlying factors for this co-occurrence are still not well evaluated. FPC families in the National Case Collection of Familial Pancreatic Cancer with an additional occurrence of CRC wer...
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... With the development of sequencing technologies and the reduction of technology costs, whole-exome sequencing (WES) has been widely applied to reveal the genetic aetiology of congenital diseases, especially in rare diseases with extreme genotypic and phenotypic heterogeneity (Chen et al., 2021;Pan et al., 2022;Wang et al., 2022;Zhang et al., 2022). Here, we collected a pedigree of four siblings affected by MKS and identified two novel splice site variations of the TMEM231 gene (NM_001077418.2; ...
Background: Meckel Syndrome (MKS, OMIM #249000) is a rare and fatal autosomal recessive ciliopathy with high clinical and genetic heterogeneity. MKS shows complex allelism with other related ciliopathies such as Joubert Syndrome (JBTS, OMIM #213300). In MKS, the formation and function of the primary cilium is defective, resulting in a multisystem disorder including occipital encephalocele, polycystic kidneys, postaxial polydactyly, liver fibrosis, central nervous system malformations and genital anomalies. This study aimed to analyze the genotype of MKS patients and investigate the correlation between genotype and phenotype.
Methods: A nonconsanguineous couple who conceived four times with a fetus affected by multiorgan dysfunction and intrauterine fetal death was studied. Whole exome sequencing (WES) was performed in the proband to identify the potentially pathogenic variant. Sanger sequencing was performed in family members. In silico tools were used to analyse the pathogenicity of the identified variants. cDNA TA-cloning sequencing was performed to validate the effects of intronic variants on mRNA splicing. Quantitative real-time PCR was performed to investigate the effect of the variants on gene expression. Immunofluorescence was performed to observe pathological changes of the primary cilium in kidney tissue from the proband.
Results: Two splice site variants of TMEM231 (NM_001077418.2, c.583-1G>C and c.583-2_588delinsTCCTCCC) were identified in the proband, and the two variants have not been previously reported. The parents were confirmed as carriers. The two variants were predicted to be pathogenic by in silico tools and were classified as pathogenic/likely pathogenic variants according to the American College of Medical Genetics and Genomics guideline. cDNA TA cloning analysis showed that both splice site variants caused a deletion of exon 5. RT-PCR revealed that the expression of TMEM231 was significantly decreased and immunofluorescence showed that the primary cilium was almost absent in the proband’s kidney tissue.
Conclusion: We reported the clinical, genetic, molecular and histochemical characterisation of a family affected by MKS. Our findings not only extended the mutation spectrum of the TMEM231 gene, but also revealed for the first time the pathological aetiology of primary cilia in humans and provide a basis for genetic counselling of the parents to their offspring.
... Microtia is a congenital malformation of the external and middle ear caused by the abnormal development of the frst and second visceral arch and the frst sulcus [1,2]. Although it is believed that both genetic and environmental factors may play an important role in microtia, there is currently no consensus concerning the pathogenesis and etiology of microtia [3,4]. ...
Nonsyndromic microtia is a kind of congenital ear malformation with unclear pathogenic genes. Cadherin-11 (CDH11, OB-cadherin) is a member of the cadherin family, which has been demonstrated to play important roles in controlling morphogenesis and cell biological characteristics during multiple developmental processes. In the present study, we found low expression of CDH11 in microtia cartilage compared with the normal one for the first time. For a more comprehensive and in-depth understanding of CDH11 in microtia development, we performed both gain- and loss-of-function experiments to detect the effect of CDH11 on chondrocytes. CDH11 promoted chondrocyte proliferation by increasing S-phase cell numbers and increasing cell migration, which is important for tissue morphogenesis. Additionally, knockdown of CDH11 in chondrocytes reduced the quality of engineered cartilage by decreasing the key transcription factors of chondrogenesis, SOX9 expression, and cartilage ECM production, including collagen type II (COL2A) and elastin (ELN), compared to the control group. Furthermore, RNA-Seq on CDH11 knockdown chondrocytes showed that it was highly related to HOX family genes, which have been reported to be important regulatory genes patterning craniofacial tissue formation. This study identified CDH11 as a candidate pathogenic gene of microtia and supported the potential key role of CDH11 in craniofacial malformations.
... HFM can also be observed as part of other syndromes, such as Treacher Collins syndrome and Goldenhar syndrome, implying potentially genetic causes of HFM. Although several whole exome sequencing studies have identified candidate genes associated with HFM, the cellular and molecular basis of its pathogenesis remain to be elucidated (Chen, Liu, Mar Aung, Zhang, & Chai, 2021;G€ uleray et al., 2021;Liu et al., 2021;Lopez et al., 2016;Rengasamy Venugopalan et al., 2019;Timberlake et al., 2021). Currently there are two prevailing theories for the pathogenic mechanisms underlying HFM: vascular hemorrhage and disruption of cranial NCC development. ...
Craniofacial anomalies often exhibit phenotype variability and non-mendelian inheritance due to their multifactorial origin, involving both genetic and environmental factors. A combination of epidemiologic studies, genome-wide association, and analysis of animal models have provided insight into the effects of gene–environment interactions on craniofacial and brain development and the pathogenesis of congenital disorders. In this chapter, we briefly summarize the etiology and pathogenesis of common craniofacial anomalies, focusing on orofacial clefts, hemifacial microsomia, and microcephaly. We then discuss how environmental risk factors interact with genes to modulate the incidence and phenotype severity of craniofacial anomalies. Identifying environmental risk factors and dissecting their interaction with different genes and modifiers is central to improved strategies for preventing craniofacial anomalies.
... Some groups have previously analyzed genetic factors related to microtia/ OAVS [22][23][24][26][27][28][52][53][54][55][56], but no previous gene-gene interaction analysis has been per-formed in these patients. Given the genomic differences found across populations and the high prevalence of this disorder in Latin-American populations worldwide, it is important to obtain a more precise knowledge in patients with microtia/OAVS of this ethnic origin. ...
The clinical 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. Genetic and non-genetic factors have been associated with microtia/OAVS. Although the etiology remains unknown in most patients, some cases may have an autosomal dominant, autosomal recessive, or multifactorial inheritance. Among the possible genetic factors, gene–gene interactions may play important roles in the etiology of complex diseases, but the literature lacks related reports in OAVS patients. Therefore, we performed a gene–variant interaction analysis within five microtia/OAVS candidate genes (HOXA2, TCOF1, SALL1, EYA1 and TBX1) in 49 unrelated OAVS Mexican patients (25 familial and 24 sporadic cases). A statistically significant intergenic interaction (p-value < 0.001) was identified between variants p.(Pro1099Arg) TCOF1 (rs1136103) and p.(Leu858=) SALL1 (rs1965024). This intergenic interaction may suggest that the products of these genes could participate in pathways related to craniofacial alterations, such as the retinoic acid (RA) pathway. The absence of clearly pathogenic variants in any of the analyzed genes does not support a monogenic etiology for microtia/OAVS involving these genes in our patients. Our findings could suggest that in addition to high-throughput genomic approaches, future gene–gene interaction analyses could contribute to improving our understanding of the etiology of microtia/OAVS.
... Some groups have previously analyzed genetic factors related to microtia/ OAVS [22][23][24][26][27][28][52][53][54][55][56], but no previous gene-gene interaction analysis has been per-formed in these patients. Given the genomic differences found across populations and the high prevalence of this disorder in Latin-American populations worldwide, it is important to obtain a more precise knowledge in patients with microtia/OAVS of this ethnic origin. ...
The clinical 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. Genetic and non-genetic factors have been associated with microtia/OAVS. Although the etiology remains unknown in most patients, some cases may have an autosomal dominant, autosomal recessive, or multifactorial inheritance. Among the possible genetic factors, gene-gene interactions may play important roles in the etiology of complex diseases, but the literature lacks related reports in OAVS patients. Therefore, we performed a gene-variant interaction analysis within five microtia/OAVS candidate genes (HOXA2, TCOF1, SALL1, EYA1 and TBX1) in 49 unrelated OAVS Mexican patients (25 familial and 24 sporadic cases). A statistically significant intergenic interaction (p-value < 0.001) was identified between variants p.(Pro1099Arg) TCOF1 (rs1136103) and p.(Leu858=) SALL1 (rs1965024). This intergenic interaction may suggest that the products of these genes could participate in pathways related to craniofacial alterations, such as the retinoic acid (RA) pathway. The absence of clearly pathogenic variants in any of the analyzed genes does not support a monogenic etiology for microtia/OAVS involving these genes in our patients. Our findings could suggest that in addition to high-throughput genomic approaches, future gene-gene interaction analyses could contribute to improving our understanding of the etiology of microtia/OAVS.
The authors browsed through past genetic findings in hemifacial microsomia along with our previously identified mutations in ITGB4 and PDE4DIP from whole genome sequencing of hemifacial microsomia patients. Wondering whether these genes influence mandibular bone modeling by regulation on osteogenesis, the authors approached mechanisms of hemifacial microsomia through this investigation into gene knockdown effects in vitro. MC3T3E1 cells were divided into 5 groups: the negative control group without osteogenesis induction or siRNA, the positive control group with only osteogenesis induction, and 3 gene silenced groups with both osteogenesis induction and siRNA. Validation of transfection was through fluorescence microscopy and quantitative real-time Polymerase chain reaction on knockdown efficiency. Changes in expression levels of the 3 genes during osteogenesis and impact of Itgb4 and Pde4dip knockdown on osteogenesis were examined by quantitative real-time Polymerase chain reaction, alkaline phosphatase, and alizarin red staining. Elevation of osteogenic genes Alpl, Col1a1, Bglap, Spp1, and Runx2 verified successful osteogenesis. Both genes were upregulated under osteogenic induction, while they had different trends over time. Intracellular fluorophores under microscope validated successful transfection and si-m-Itgb4_003, si-m-Pde4dip_002 had satisfactory knockdown effects. During osteogenesis, Pde4dip knockdown enhanced Spp1 expression (1.95±0.13 folds, P=0.045). The authors speculated that these genes may have different involvements in osteogenesis. Stimulated expression of Spp1 by Pde4dip knockdown may suggest that Pde4dip inhibits osteogenesis.
The authors attempt to approach hemifacial microsomia with macroscopic techniques and look for a link between clinical manifestations with pathogenesis. In this study, for the first time mandibular medullary cavities as essential parts of the mandible were intravitally measured based on the 3-dimensional models. A total of 153 patients were included. The 3-dimensional models of patients' mandibles were reconstructed and medullary cavity volumes (mm3) were measured. The ratio of medullary cavity volume to mandible volume was calculated to determine the proportion of the marrow in the bone. Statistical significance was found in mandible volumes (P<0.001) and medullary cavity volumes (P<0.001) on different sides. Medullary cavity volumes were significantly related to mandible volumes on both sides (both P<0.001). Medullary cavity volumes on the nonaffected and affected side were both in correlation with age but in different degrees (r=0.214, P=0.008 versus r=0.170, P=0.036). The ratios of medullary cavity volume and the mandible were significantly different (P<0.001) on 2 sides. The volume ratio on the nonaffected side correlated to age while this correlation did not exist on the affected side (r=0.195, P=0.016 versus r=0.129, P=0.112). A smaller medullary cavity found on the affected side could lead to a reduced amount of bone marrow cells and consequently reduced osteogenic and hematopoietic potential. This could result in abnormal bone formation on the affected side of mandible. Proportions of marrow in bone on the affected side irrelevant to patients' ages signify a poorer potential of expansion. This may explain a higher reluctancy of growth in affected mandibular sides.
Les variations hétérozygotes pathogènes de MED13L provoquent un trouble du neurodéveloppement rare caractérisé par une déficience intellectuelle modérée à sévère. Le séquençage non ciblé chez des patients atteints de déficiences intellectuelles non-syndromiques a conduit à l'identification d'un nombre croissant de variations faux-sens candidates dans MED13L.Par une collaboration internationale entre des centres d'expertise pour les anomalies du développement, nous avons rapporté 36 patients présentant une variation pathogène de MED13L afin de préciser le phénotype. Cinq variantes faux-sens pathogènes provoquant soit un phénotype sévère (p.Pro866Leu, p.Pro869Ser, et p.Cys1131Tyr) soit un phénotype typique (p.Gly1899Arg et p.Thr2162Met) ont été sélectionnées et étudiées fonctionnellement. Parallèlement à l'analyse fonctionnelle, une comparaison des paramètres in silico associés aux faux-sens pathogènes précédemment publiés ou rapportées dans les bases de données témoins a été réalisée.Les variants faux-sens sont regroupés majoritairement dans les exons 15-17 et 25-31. Nous avons constaté que les patients porteurs de variations faux-sens présentaient un phénotype plus sévère avec une épilepsie fréquente. Des différences significatives ont été identifiées entre les faux-sens pathogènes et neutres pour les scores de conservation, les différences physico-chimiques entre acides aminés suivant le score de Grantham, la conservation de la séquence dans la protéine MED13 et la proximité de sites de phosphorylation. Fonctionnement, les variations p.Pro866Leu et p.Pro869Ser étaient susceptibles d'induire une hyper-phosphorylation du domaine MED13L823-930. Les résidus Cys1131 et Thr2162 pourraient impacter la conformation de MED13L avec une modification de la structure 3D. Une dégradation accrue médiée par le protéasome ainsi qu’une relocalisation cytoplasmique et une modification de l’intégration dans le module kinase CDK8 ont été observées uniquement pour le faux-sens p.Gly1899Arg.Cette étude confirme que les variations faux-sens de MED13L sont une cause du Syndrome MED13L avec des particularités cliniques et moléculaires. Les faux-sens de MED13L associées aux phénotypes typiques (p.Gly1899Arg et p.Thr2162Met) induisent probablement une perte de fonction, tandis que les variations associées aux phénotypes sévères provoqueraient probablement un effet dominant-négatif.
