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American Journal of Medical Genetics.... Jan 2023We describe the phenotype of 22 male patients (20 probands) carrying a hemizygous missense variant in MED12. The phenotypic spectrum is very broad ranging from...
We describe the phenotype of 22 male patients (20 probands) carrying a hemizygous missense variant in MED12. The phenotypic spectrum is very broad ranging from nonspecific intellectual disability (ID) to the three well-known syndromes: Opitz-Kaveggia syndrome, Lujan-Fryns syndrome, or Ohdo syndrome. The identified variants were randomly distributed throughout the gene (p = 0.993, χ test), but mostly outside the functional domains (p = 0.004; χ test). Statistical analyses did not show a correlation between the MED12-related phenotypes and the locations of the variants (p = 0.295; Pearson correlation), nor the protein domain involved (p = 0.422; Pearson correlation). In conclusion, establishing a genotype-phenotype correlation in MED12-related diseases remains challenging. Therefore, we think that patients with a causative MED12 variant are currently underdiagnosed due to the broad patients' clinical presentations.
Topics: Male; Humans; Mediator Complex; Mental Retardation, X-Linked; Intellectual Disability; Blepharophimosis; Mutation, Missense; Phenotype; Syndrome
PubMed: 36271811
DOI: 10.1002/ajmg.a.63004 -
The Journal of Reproduction and... Mar 2014FOXL2 is an essential transcription factor that is required for proper development of the ovary and eyelid. Mutations in FOXL2 cause an autosomal dominant genetic...
FOXL2 is an essential transcription factor that is required for proper development of the ovary and eyelid. Mutations in FOXL2 cause an autosomal dominant genetic disorder, blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). BPES type I patients have eyelid malformation and premature ovarian failure leading to infertility, whereas women with type II BPES are fertile or subfertile. In the present study, we evaluated and compared apoptotic and antiproliferative activities of wild-type (WT) and mutant FOXL2 proteins found in BPES type I and II in human granulosa cell tumor-derived KGN cells. Ectopic expression of WT FOXL2 induced apoptosis and inhibited cell cycle progression in human granulosa cells. In contrast, mutated FOXL2s found in BPES type I significantly reduced these activities, whereas mutated FOXL2s in BPES type II showed intermediate activities. Furthermore, mutant FOX L2 proteins were defective in activating transcription of target genes including Caspase 8, TNF-R1, FAS, p21, and BMP4, which regulate apoptosis, proliferation, and differentiation of granulosa cells. Thus, decreased apoptotic and antiproliferative activities caused by mutant forms of FOXL2 found in BPES patients may at least partially contribute to the pathophysiology of ovarian dysfunction.
Topics: Animals; Apoptosis; Blepharophimosis; Cell Cycle; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Female; Forkhead Box Protein L2; Forkhead Transcription Factors; Granulosa Cells; Humans; Mice; Mice, Inbred ICR; Mutation; Primary Ovarian Insufficiency; Skin Abnormalities; Urogenital Abnormalities
PubMed: 24240106
DOI: 10.1262/jrd.2013-090 -
BMC Developmental Biology Jul 2015Haploinsufficiency of the FOXL2 transcription factor in humans causes Blepharophimosis/Ptosis/Epicanthus Inversus syndrome (BPES), characterized by eyelid anomalies and...
BACKGROUND
Haploinsufficiency of the FOXL2 transcription factor in humans causes Blepharophimosis/Ptosis/Epicanthus Inversus syndrome (BPES), characterized by eyelid anomalies and premature ovarian failure. Mice lacking Foxl2 recapitulate human eyelid/forehead defects and undergo female gonadal dysgenesis. We report here that mice lacking Foxl2 also show defects in postnatal growth and embryonic bone and cartilage formation.
METHODS
Foxl2 (-/-) male mice at different stages of development have been characterized and compared to wild type. Body length and weight were measured and growth curves were created. Skeletons were stained with alcian blue and/or alizarin red. Bone and cartilage formation was analyzed by Von Kossa staining and immunofluorescence using anti-FOXL2 and anti-SOX9 antibodies followed by confocal microscopy. Genes differentially expressed in skull vaults were evaluated by microarray analysis. Analysis of the GH/IGF1 pathway was done evaluating the expression of several hypothalamic-pituitary-bone axis markers by RT-qPCR.
RESULTS
Compared to wild-type, Foxl2 null mice are smaller and show skeletal abnormalities and defects in cartilage and bone mineralization, with down-regulation of the GH/IGF1 axis. Consistent with these effects, we find FOXL2 expressed in embryos at 9.5 dpc in neural tube epithelium, in head mesenchyme near the neural tube, and within the first branchial arch; then, starting at 12.5 dpc, expressed in cartilaginous tissue; and at PO and P7, in hypothalamus.
CONCLUSIONS
Our results support FOXL2 as a master transcription factor in a spectrum of developmental processes, including growth, cartilage and bone formation. Its action overlaps that of SOX9, though they are antagonistic in female vs male gonadal sex determination but conjoint in cartilage and skeletal development.
Topics: Animals; Blepharophimosis; Bone Development; Cartilage; Female; Forkhead Box Protein L2; Forkhead Transcription Factors; Humans; Insulin-Like Growth Factor I; Male; Mice; Signal Transduction; Skin Abnormalities; Urogenital Abnormalities
PubMed: 26134413
DOI: 10.1186/s12861-015-0072-y -
Genetics in Medicine : Official Journal... Jul 2020Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients...
PURPOSE
Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts.
METHODS
We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts.
RESULTS
We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts.
CONCLUSION
We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies.
Topics: Exome; Germ Cells; Humans; Intellectual Disability; Mutation, Missense; Phenotype; Transcriptome; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
PubMed: 32376980
DOI: 10.1038/s41436-020-0792-7 -
BMC Ophthalmology May 2022To evaluate the surgical outcome of epicanthus and telecanthus correction by C-U medial canthoplasty with lateral canthoplasty in Blepharophimosis Syndrome.
PURPOSE
To evaluate the surgical outcome of epicanthus and telecanthus correction by C-U medial canthoplasty with lateral canthoplasty in Blepharophimosis Syndrome.
PATIENTS AND METHODS
This was a retrospective single arm interventional study including 18 eyes of 9 patients with Blepharophimosis-ptosis-epicanthus inversus syndrome who presented to oculoplastic clinic, ophthalmology department, Qena university hospital in the period of between July 2020 to April 2021. All the patients had BPES with epicanthus and telecanthus. All cases were subjected to by C plasty with medial and lateral canthoplasty for correction of epicanthus and telecanthus correction followed by frontalis suspension surgery to correct the co-existing blepharoptosis.
RESULTS
The study included 9 cases of BPES, 6 boys and 3 girls, the mean age was 5.4 ± 1.5 in the study group, all patients had a positive family history for BPES. After surgery, the mean IICD decreased from 38.44 mm preoperatively to 32.8 mm postoperatively, with a mean difference of 6.2 mm (P < 0.001). Likewise, the mean PFL increased from 20.78 mm preoperatively to 26.63 mm postoperatively, with a mean difference of 5.8 mm (P < 0.001). Epicanthus skin fold disappeared in all cases and medical canthus could be seen with well healed difficulty seen scars.
CONCLUSION
C-U medial canthoplasty with lateral canthoplasty in Blepharophimosis Syndrome was found to be an effective procedure in the correction of epicanthus and telecanthus.
Topics: Blepharophimosis; Blepharoptosis; Child; Child, Preschool; Craniofacial Abnormalities; Female; Humans; Male; Retrospective Studies; Skin Abnormalities; Treatment Outcome; Urogenital Abnormalities
PubMed: 35590300
DOI: 10.1186/s12886-022-02455-2 -
Molecular Syndromology Apr 2021Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder which represents a phenotype mainly involving craniofacial and neurodevelopmental...
Kaufman oculocerebrofacial syndrome is a rare autosomal recessive disorder which represents a phenotype mainly involving craniofacial and neurodevelopmental manifestations due to gene mutations. The vast majority of the affected individuals exhibit microcephaly, eye abnormalities, and typical facial gestalt including blepharophimosis, ptosis, telecanthus, upslanting palpebral fissures, dysplastic ears, and micrognathia. We encountered 2 siblings in whom severe psychomotor delay, distinctive facial features, hearing loss, and respiratory distress were observed. Some clinical manifestations of the patients, including epibulbar dermoid, microtia, and multiple preauricular tags, were reminiscent of the oculoauriculovertebral spectrum. However, 2 affected siblings exhibited a similar clinical picture consisting of microcephaly, severe developmental and cognitive disabilities, failure to thrive, and dysmorphic features, which were not fully consistent with oculoauriculovertebral spectrum. Also, hypoplastic nails, considered as a core manifestation of Coffin-Siris syndrome, were present in our patients. Therefore, whole-exome sequencing was carried out in order to identify the underlying genetic alterations, contributing to the complex phenotype shared by the 2 siblings. A homozygous pathogenic mutation was found in both affected siblings in the gene which caused Kaufman oculocerebrofacial syndrome. Kaufman oculocerebrofacial syndrome should be considered among the autosomal recessive causes of blepharophimosis-mental retardation syndromes, particularly in populations with a high rate of consanguineous marriages, even if there are dysmorphic facial features that are not typically associated with the phenotype.
PubMed: 34012380
DOI: 10.1159/000513078 -
BMC Molecular and Cell Biology Jun 2019The forkhead transcription factor (FOXL2) plays a crucial role in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), sex determination, ovary growth and...
BACKGROUND
The forkhead transcription factor (FOXL2) plays a crucial role in blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), sex determination, ovary growth and development, and cell cycle regulation. Emerging investigations have focused on the downstream targets of FOXL2, while little is known about its upstream regulation.
RESULTS
In this study, we show that FOXL2 could be regulated by STAT3 in cancer cells and that STAT3 binds to FOXL2 at the 5'- GCCTGATGTTTGTCTTCCCAGTCTGTGGCAA-3' site using EMSA and ChIP. We further found that knockdown of STAT3 or FOXL2 could significantly induce cancer cell apoptosis, indicating the importance of these two genes in cancer cell growth and apoptosis. Our data also indicated that the increased apoptotic cell rate may be caused by changes in apoptosis-related genes, such as TNF, TRAIL and GnRHR.
CONCLUSION
This study presents a new upstream regulator of FOXL2 and demonstrats that this new STAT3-FOXL2 pathway has an important function in HeLaHeLa cell apoptosis, providing new insights regarding the targeting of FOXL2 for cancer prevention and treatment.
Topics: Apoptosis; Binding Sites; Cell Survival; Forkhead Box Protein L2; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; HeLa Cells; Humans; Neoplasms; Promoter Regions, Genetic; RNA Interference; RNA, Small Interfering; Receptors, LHRH; STAT3 Transcription Factor; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Transfection; Tumor Necrosis Factor-alpha
PubMed: 31221094
DOI: 10.1186/s12860-019-0206-3 -
Molecular Syndromology Jan 2017Say-Barber/Biesecker/Young-Simpson syndrome (SBBYSS; OMIM 603736) is a rare syndrome with multiple congenital anomalies/malformations. The clinical diagnosis is usually...
Say-Barber/Biesecker/Young-Simpson syndrome (SBBYSS; OMIM 603736) is a rare syndrome with multiple congenital anomalies/malformations. The clinical diagnosis is usually based on a phenotype with a mask-like face and severe blepharophimosis and ptosis as well as other distinctive facial traits. We present a girl with dysmorphic features, an atrial septal defect, and developmental delay. Previous genetic testing (array-CGH, 22q11 deletion, and mutation analysis) gave normal results. We performed whole-exome sequencing (WES) and identified a heterozygous nonsense mutation in the gene, NM_001256468.1: c.4943C>G (p.S1648*). The mutation led to a premature stop codon and occurred de novo. sequence variants have previously been identified in patients with SBBYSS, and the phenotype of the girl is similar to other patients diagnosed with SBBYSS. This case report provides additional evidence for the correlation between the mutation and SBBYSS. If a patient is suspected of having a blepharophimosis syndrome or SBBYSS, we recommend sequencing the gene. This is a further example showing that WES can assist diagnosis.
PubMed: 28232779
DOI: 10.1159/000452258 -
Genetics in Medicine : Official Journal... Nov 2020Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with...
De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides-Baraitser syndrome.
PURPOSE
Nontruncating variants in SMARCA2, encoding a catalytic subunit of SWI/SNF chromatin remodeling complex, cause Nicolaides-Baraitser syndrome (NCBRS), a condition with intellectual disability and multiple congenital anomalies. Other disorders due to SMARCA2 are unknown.
METHODS
By next-generation sequencing, we identified candidate variants in SMARCA2 in 20 individuals from 18 families with a syndromic neurodevelopmental disorder not consistent with NCBRS. To stratify variant interpretation, we functionally analyzed SMARCA2 variants in yeasts and performed transcriptomic and genome methylation analyses on blood leukocytes.
RESULTS
Of 20 individuals, 14 showed a recognizable phenotype with recurrent features including epicanthal folds, blepharophimosis, and downturned nasal tip along with variable degree of intellectual disability (or blepharophimosis intellectual disability syndrome [BIS]). In contrast to most NCBRS variants, all SMARCA2 variants associated with BIS are localized outside the helicase domains. Yeast phenotype assays differentiated NCBRS from non-NCBRS SMARCA2 variants. Transcriptomic and DNA methylation signatures differentiated NCBRS from BIS and those with nonspecific phenotype. In the remaining six individuals with nonspecific dysmorphic features, clinical and molecular data did not permit variant reclassification.
CONCLUSION
We identified a novel recognizable syndrome named BIS associated with clustered de novo SMARCA2 variants outside the helicase domains, phenotypically and molecularly distinct from NCBRS.
Topics: Blepharophimosis; Facies; Foot Deformities, Congenital; Humans; Hypotrichosis; Intellectual Disability; Phenotype; Transcription Factors
PubMed: 32694869
DOI: 10.1038/s41436-020-0898-y -
International Journal of Surgery Case... Mar 2022Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant genetic disorder characterized by complex orbito-palpebral anomalies. We report...
INTRODUCTION
Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant genetic disorder characterized by complex orbito-palpebral anomalies. We report a rare case of BPES associated with bilateral congenital cataract.
OBSERVATION
This study reports the case of a 6-month-old infant with BPES in whom a bilateral congenital cataract was diagnosed, after the parents noticed leukocoria and signs of poor vision in their child. No other ophthalmologic manifestations commonly associated with this syndrome were found. The infant underwent cataract surgery first, with lens phacoaspiration and posterior capsulotomy coupled with anterior vitrectomy and placement of a 3-piece foldable hydrophobic posterior chamber lens in the capsular bag. The surgery was a real challenge due to the orbito-palpebral anomalies that limited a small surgical space, and the placement of the IOL was a matter of discussion.
DISCUSSION
Publications on the association of congenital cataract with BPES are very rare. The link between these two anomalies is difficult to establish since different genes on different chromosomes code for the two diseases. A lateral canthotomy can be considered to overcome the surgical difficulties due to the reduced working space. The surgical management of pediatric cataract varies in the literature.
CONCLUSION
This case highlights the difficulty of cataract surgery in children, even more so when associated with BPES, and the challenge of improving vision in these children given the high risk of amblyopia.
PubMed: 35219116
DOI: 10.1016/j.ijscr.2022.106845