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Frontiers in Endocrinology 2022To characterize the status of ovarian reserve and ART outcomes in BPES women and provide informative reference for clinical diagnosis and treatment.
OBJECTIVE
To characterize the status of ovarian reserve and ART outcomes in BPES women and provide informative reference for clinical diagnosis and treatment.
METHODS
Twenty-one women with BPES were screened for mutations in the gene and underwent assisted reproductive technology (ART) treatment. Indicators for ovarian reserve and ART outcomes were compared between patients with and without mutations. Additionally, ART outcomes were compared among patients with different subtypes of mutations.
RESULTS
A total of 13 distinct heterozygous variants in the gene were identified in 80.95% of BPES women, including 4 novel mutations with plausible pathogenicity (c.173_175dup, c.481C>T, c.576del and c.675_714del). Compared to non-mutation group, patients with mutations had elevated levels of FSH (P=0.007), decreased AMH levels (P=0.012) and less AFC (P=0.015). They also had worse ART outcomes with large amount of Gn dosage (P=0.008), fewer oocytes (P=0.001), Day3 good quality embryos (P=0.001) and good quality blastocysts (P=0.037), and a higher cancellation rate (P=0.272). High heterogeneity of ART outcomes existed in BPES patients with different mutation types.
CONCLUSIONS
BPES patients with mutations had diminished ovarian reserve and adverse ART outcomes. The genotype-reproductive phenotype correlations were highly heterogeneous and cannot be generalized. Genetic counseling for fertility planning and preimplantation or prenatal genetic diagnosis to reduce offspring inheritance are recommended.
Topics: Blepharophimosis; Female; Forkhead Box Protein L2; Forkhead Transcription Factors; Humans; Mutation; Ovarian Reserve; Phenotype; Reproductive Techniques, Assisted; Skin Abnormalities; Urogenital Abnormalities
PubMed: 35574016
DOI: 10.3389/fendo.2022.829153 -
Investigative Ophthalmology & Visual... Mar 2023Biallelic MAB21L1 variants have been reported to cause autosomal recessive cerebellar, ocular, craniofacial, and genital syndrome (COFG), whereas only five heterozygous... (Review)
Review
PURPOSE
Biallelic MAB21L1 variants have been reported to cause autosomal recessive cerebellar, ocular, craniofacial, and genital syndrome (COFG), whereas only five heterozygous pathogenic variants have been suspected to cause autosomal dominant (AD) microphthalmia and aniridia in eight families. This study aimed to report an AD ocular syndrome (blepharophimosis plus anterior segment and macular dysgenesis [BAMD]) syndrome based on clinical and genetic findings from patients with monoallelic MAB21L1 pathogenic variants in our cohort and reported cases.
METHODS
Potential pathogenic variants in MAB21L1 were detected from a large in-house exome sequencing dataset. Ocular phenotypes of the patients with potential pathogenic variants in MAB21L1 were summarized, and the genotype-phenotype correlation was analyzed through a comprehensive literature review.
RESULTS
Three heterozygous missense variants in MAB21L1, predicted to be damaging, were detected in 5 unrelated families, including c.152G>T in 2, c.152G>A in 2, and c.155T>G in one. All were absent from gnomAD. The variants were de novo in two families, transmitted from affected parents to offspring in two families, and with an unknown origin in the other family, demonstrating strong evidence of AD inheritance. All patients revealed similar BAMD phenotypes, including blepharophimosis, anterior segment dysgenesis, and macular dysgenesis. Genotype-phenotype analysis suggested that patients with monoallelic MAB21L1 missense variants had only ocular anomalies (BAMD), whereas patients with biallelic variants presented both ocular and extraocular symptoms.
CONCLUSIONS
Heterozygous pathogenic variants in MAB21L1 account for a new AD BAMD syndrome, which is completely different from COFG caused by homozygous variants in MAB21L1. Nucleotide c.152 is likely a mutation hot spot, and the encoded residue of p.Arg51 might be critical for MAB21L1.
Topics: Humans; Mutation, Missense; Blepharophimosis; Eye Abnormalities; Mutation; Phenotype; Syndrome; Pedigree; Homeodomain Proteins
PubMed: 36892533
DOI: 10.1167/iovs.64.3.19 -
Molecular Vision 2022To investigate the molecular pathogenesis of a large group of Han Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), and to evaluate the...
PURPOSE
To investigate the molecular pathogenesis of a large group of Han Chinese patients with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), and to evaluate the correlation between the phenotype and genotype for these patients.
METHODS
Seventy-six affected individuals, including 45 patients from 17 pedigrees and 31 sporadic patients, were recruited with their family members. All participants underwent complete clinical examinations and were classified as having type I or II based on whether they had premature ovarian failure. The patients' genomic DNA was extracted. A genetic test was performed with direct sequencing of the coding regions of the () gene. Variations were analyzed using online databases and programs. Genotype-phenotype correction was investigated.
RESULTS
Seventy-six affected and 75 unaffected individuals underwent clinical evaluations and genetic testing. Only one family was diagnosed with type I; the others could not be classified because of a lack of female patients or a definite history of premature ovarian failure. Twenty-seven variations were identified, including 12 novel and 15 previously reported variations. Six variations were detected repeatedly in different nonconsanguineous pedigrees. Four indel variations, located in the alanine/proline-rich region of the gene, presented with a relatively higher frequency. Two rare double variations were detected in two sporadic patients. gene variations were not detected in five sporadic patients. The phenotype varied among different families and patients, although they carried the same variations.
CONCLUSIONS
We identified 12 novel variations in the gene that would expand the spectrum of the variation database. In addition, we found that the alanine/proline-rich region is a variation hotspot in the gene. The genotype-phenotype correlation is not easy to establish due to clinical and genetic heterogeneity.
Topics: Humans; Female; Blepharophimosis; Pedigree; Primary Ovarian Insufficiency; Mutation; Forkhead Box Protein L2; Forkhead Transcription Factors; Alanine; China; Proline
PubMed: 36338666
DOI: No ID Found -
BMC Ophthalmology Aug 2018Goldenhar syndrome has variable presentations and can affect multiple regions of the body. Diagnoses are based on clinical manifestations. The association of Goldenhar...
BACKGROUND
Goldenhar syndrome has variable presentations and can affect multiple regions of the body. Diagnoses are based on clinical manifestations. The association of Goldenhar syndrome with blepharophimosis and limb deformities has not previously been reported. Here, we describe a patient who was diagnosed with Goldenhar syndrome in association with blepharophimosis, ocular hypertelorism, hearing loss and limb deformities.
CASE PRESENTATION
A 10-year-old male was first referred to our ophthalmology clinic on 2009-2-11 for ocular hypertelorism and microphthalmia when he had chin-up position. In the first ophthalmic examination, his palpebral fissure length was 19 mm on the right and 20 mm on the left, both palpebral fissure height was 4 mm, the inner intercanthal distance was 63 mm, both upper margin reflex distances were - 1 mm, the myodynamia of the levator palpebrae muscle was 2 mm on the right and 3 mm on the left, and his visual acuity was 20/40 on the right and 20/32 on the left. A physical examination revealed the patient had developed limb deformities in his hands, wrists, elbows and shoulders along with hearing loss. The patient was diagnosed with Goldenhar syndrome because his clinical presentations included ocular hypertelorism, hearing loss, and multiple acral joint deformities. He underwent a first operation in 2009 and a second in 2015. The second operation achieved a satisfactory result in which the horizontal fissure length was 28 mm on both sides, both palpebral fissure height was 10 mm, the inner intercanthal distance was 30 mm, and both of the upper margin reflex distances were 4 mm. He continued to wear hearing aids as usual. His hearing loss and joint deformities were slated for long-term follow-up at his parents' request.
CONCLUSION
The patient, diagnosed with Goldenhar syndrome in association with blepharophimosis, ocular hypertelorism, hearing loss and limb deformities, underwent two operations and achieved a satisfactory result. The patient was submitted to long-term follow-up observations and symptomatic treatments that vary with age and systemic associations, as needed. When treating patients with Goldenhar syndrome, ophthalmology specialists should cooperate with a multi-disciplinary team of clinicians and reach agreement regarding the appropriate systemic and comprehensive treatments.
Topics: Abnormalities, Multiple; Blepharophimosis; Child; Eyelids; Goldenhar Syndrome; Humans; Limb Deformities, Congenital; Male; Oculomotor Muscles; Ophthalmologic Surgical Procedures; Tomography, X-Ray Computed; Visual Acuity
PubMed: 30134872
DOI: 10.1186/s12886-018-0872-5 -
American Journal of Human Genetics Sep 2021
Topics: Blepharophimosis; Facies; Humans
PubMed: 34478655
DOI: 10.1016/j.ajhg.2021.07.004 -
Cureus Jul 2022A 14-year-old male presented to the outpatient department of ophthalmology with complaints of visual impairment. The patient was assessed with a detailed history and...
A 14-year-old male presented to the outpatient department of ophthalmology with complaints of visual impairment. The patient was assessed with a detailed history and physical examination. Marked amblyopia was observed on inspection, and his best-corrected vision was 6/36 in both eyes with no further improvement. Both the anterior and posterior segments of the eyes were normal. A diagnosis of blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) was suspected. Surgery was initiated in two stages, with the first stage utilizing Mustarde's double Z-plasty to correct the epicanthus inversus and telecanthus. The second stage was done three months later, involving a tarsofrontalis sling with prolene sutures to correct ptosis. The success of this operation speaks to the efficacy of a two-stage procedure for remedying a syndrome as complex as BPES.
PubMed: 36051713
DOI: 10.7759/cureus.27432 -
The Ocular Surface Oct 2012This review summarizes our recent findings regarding the Notch signaling pathway in regulating normal eyelid morphogenesis and its role in the pathogenesis of human... (Review)
Review
This review summarizes our recent findings regarding the Notch signaling pathway in regulating normal eyelid morphogenesis and its role in the pathogenesis of human congenital blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). We used genetic and molecular biological approaches to investigate the mechanism by which Notch1 activation controls expression of FoxL2, which in turn activates smooth muscle actin gene expression in periocular mesenchyma to control eyelid levator smooth muscle formation.
Topics: Actins; Blepharophimosis; Eyelids; Forkhead Box Protein L2; Forkhead Transcription Factors; Humans; Muscle, Skeletal; Receptor, Notch1
PubMed: 23084143
DOI: 10.1016/j.jtos.2012.07.003 -
International Journal of Ophthalmology 2023To discover the molecular pathogenic basis of the blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), and to predict the clinical subtype according to...
AIM
To discover the molecular pathogenic basis of the blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), and to predict the clinical subtype according to experiments, which is significant to the prognosis.
METHODS
A 3-year-old sporadic female patient with typical clinical manifestations of BPES was enrolled. The coding region of forkhead box L2 () gene was sequenced, and the functional assays were performed by Western blotting, subcellular localization experiment, luciferase reporter assay, and quantitative real-time polymerase chain reaction.
RESULTS
A novel point pathogenic variant (c.274G>T) was detected, resulting in a truncated protein (p.E92*). Functional studies demonstrated that the pathogenic variant induced the subcellular mislocalization and the abnormal transcriptional activity on promoters of the steroidogenic acute regulatory protein ( or ) gene and the odd-skipped related 2 transcription factor () gene.
CONCLUSION
A novel pathogenic variant is identified to expand the spectrum of the known mutations. The experiments provide reference data and more insights to the molecular pathogenesis of BPES. The predicted high risk of ovarian insufficiency makes it significant for the patient enrolled to have further follow-up and therapy concerning female endocrinology.
PubMed: 37206169
DOI: 10.18240/ijo.2023.05.02 -
Genetics in Medicine : Official Journal... Aug 2020Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B... (Review)
Review
PURPOSE
Genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome are caused by variants in the KAT6B gene and are part of a broad clinical spectrum called KAT6B disorders, whose variable expressivity is increasingly being recognized.
METHODS
We herein present the phenotypes of 32 previously unreported individuals with a molecularly confirmed diagnosis of a KAT6B disorder, report 24 new pathogenic KAT6B variants, and review phenotypic information available on all published individuals with this condition. We also suggest a classification of clinical subtypes within the KAT6B disorder spectrum.
RESULTS
We demonstrate that cerebral anomalies, optic nerve hypoplasia, neurobehavioral difficulties, and distal limb anomalies other than long thumbs and great toes, such as polydactyly, are more frequently observed than initially reported. Intestinal malrotation and its serious consequences can be present in affected individuals. Additionally, we identified four children with Pierre Robin sequence, four individuals who had increased nuchal translucency/cystic hygroma prenatally, and two fetuses with severe renal anomalies leading to renal failure. We also report an individual in which a pathogenic variant was inherited from a mildly affected parent.
CONCLUSION
Our work provides a comprehensive review and expansion of the genotypic and phenotypic spectrum of KAT6B disorders that will assist clinicians in the assessment, counseling, and management of affected individuals.
Topics: Blepharophimosis; Exons; Histone Acetyltransferases; Humans; Intellectual Disability; Mutation
PubMed: 32424177
DOI: 10.1038/s41436-020-0811-8 -
The Journal of Clinical Investigation Apr 2024Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally,...
Mutations in genes encoding chromatin modifiers are enriched among mutations causing intellectual disability. The continuing development of the brain postnatally, coupled with the inherent reversibility of chromatin modifications, may afford an opportunity for therapeutic intervention following a genetic diagnosis. Development of treatments requires an understanding of protein function and models of the disease. Here, we provide a mouse model of Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS) (OMIM 603736) and demonstrate proof-of-principle efficacy of postnatal treatment. SBBYSS results from heterozygous mutations in the KAT6B (MYST4/MORF/QFK) gene and is characterized by intellectual disability and autism-like behaviors. Using human cells carrying SBBYSS-specific KAT6B mutations and Kat6b heterozygous mice (Kat6b+/-), we showed that KAT6B deficiency caused a reduction in histone H3 lysine 9 acetylation. Kat6b+/- mice displayed learning, memory, and social deficits, mirroring SBBYSS individuals. Treatment with a histone deacetylase inhibitor, valproic acid, or an acetyl donor, acetyl-carnitine (ALCAR), elevated histone acetylation levels in the human cells with SBBYSS mutations and in brain and blood cells of Kat6b+/- mice and partially reversed gene expression changes in Kat6b+/- cortical neurons. Both compounds improved sociability in Kat6b+/- mice, and ALCAR treatment restored learning and memory. These data suggest that a subset of SBBYSS individuals may benefit from postnatal therapeutic interventions.
Topics: Animals; Humans; Mice; Abnormalities, Multiple; Acetylation; Acetylcarnitine; Blepharophimosis; Chromatin; Congenital Hypothyroidism; Craniofacial Abnormalities; Exons; Facies; Heart Defects, Congenital; Histone Acetyltransferases; Histones; Intellectual Disability; Joint Instability
PubMed: 38557491
DOI: 10.1172/JCI167672