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Sexual Development : Genetics,... 2022FOXL2 encodes a transcription factor that regulates a wide array of target genes including those involved in sex development, eyelid development, ovarian function and... (Review)
Review
FOXL2 encodes a transcription factor that regulates a wide array of target genes including those involved in sex development, eyelid development, ovarian function and maintenance, genomic integrity as well as cellular pathways such as cell-cycle progression, proliferation, and apoptosis. The role of FOXL2 has been widely studied in humans and animals. Consistent with its role in ovarian and eyelid development, over 100 germline variants in FOXL2 are associated with blepharophimosis, ptosis, and epicanthus inversus syndrome in humans, an autosomal dominant condition characterised by ovarian dysgenesis/premature ovarian insufficiency, as well as defective eyelid development. Reflecting its role in apoptosis and proliferation, a somatic variant in FOXL2 causes adult granulosa cell tumours in humans. Despite being widely studied and having clear relevance to human disease, much remains unknown about the genes FOXL2 regulates and how it exerts its wide-reaching effect on multiple organs. This review focuses on FOXL2 and its varied roles as a transcription factor in sex determination, ovarian maintenance and function, eyelid development, genome integrity, and cell regulation, followed by discussion of the in vivo disruption of FOXL2 in humans and other species.
Topics: Adult; Animals; Female; Humans; Blepharophimosis; Eyelids; Forkhead Box Protein L2; Mutation; Primary Ovarian Insufficiency
PubMed: 34727551
DOI: 10.1159/000519836 -
Journal of Ovarian Research Feb 2023Premature ovarian insufficiency refers to the loss of ovarian function before 40 years of age. The etiology is heterogeneous, and genetic factors account for 20-25% of...
BACKGROUND
Premature ovarian insufficiency refers to the loss of ovarian function before 40 years of age. The etiology is heterogeneous, and genetic factors account for 20-25% of cases. However, how to transform genetic findings to clinical molecular diagnose remains a challenge. To identify potential causative variations for POI, a next generation sequencing panel with 28 known causative genes of POI was designed, and a large cohort of 500 Chinese Han patients was screened directly. Pathogenic evaluation of the identified variants and the phenotype analysis were performed according to monogenic or oligogenic variants.
RESULTS
A total of 14.4% (72/500) of the patients carried 61 pathogenic or likely pathogenic variants in 19 of the genes in the panel. Interestingly, 58 variants (95.1%, 58/61) were firstly identified in patients with POI. FOXL2 harbored the highest occurrence frequency (3.2%, 16/500), among whom presented with isolated ovarian insufficiency instead of blepharophimosis-ptosis-epicanthus inversus syndrome. Moreover, luciferase reporter assay confirmed variant p.R349G, which account for 2.6% of POI cases, impaired the transcriptional repressive effect of FOXL2 on CYP17A1. The novel compound heterozygous variants in NOBOX and MSH4 were confirmed by pedigree haplotype analysis, and digenic heterozygous variants in MSH4 and MSH5 were firstly identified. Furthermore, nine patients (1.8%, 9/500) with digenic or multigenic pathogenic variants presented with delayed menarche, early onset of POI and high prevalence of primary amenorrhea compared with those with monogenic variation(s).
CONCLUSIONS
The genetic architecture of POI has been enriched through the targeted gene panel in a large cohort of patients with POI. Specific variants in pleiotropic genes may result in isolated POI rather than syndromic POI, whereas oligogenic defects might have cumulative deleterious effects on the severity of POI phenotype.
Topics: Humans; Female; Primary Ovarian Insufficiency; Ovarian Diseases; Menopause, Premature; Phenotype; High-Throughput Nucleotide Sequencing
PubMed: 36793102
DOI: 10.1186/s13048-023-01104-6 -
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 -
Genes Mar 2021Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 () gene. It shows... (Review)
Review
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 () gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype-phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia.
Topics: Blepharophimosis; Female; Forkhead Box Protein L2; Frameshift Mutation; Humans; Loss of Function Mutation; Male; Phenotype; Primary Ovarian Insufficiency; Protein Domains; Skin Abnormalities; Urogenital Abnormalities
PubMed: 33806295
DOI: 10.3390/genes12030364 -
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 -
Genes Apr 2021MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and... (Review)
Review
MED12 is a member of the Mediator complex that is involved in the regulation of transcription. Missense variants in MED12 cause FG syndrome, Lujan-Fryns syndrome, and Ohdo syndrome, as well as non-syndromic intellectual disability (ID) in hemizygous males. Recently, female patients with de novo missense variants and de novo protein truncating variants in MED12 were described, resulting in a clinical spectrum centered around ID and Hardikar syndrome without ID. The missense variants are found throughout MED12, whether they are inherited in hemizygous males or de novo in females. They can result in syndromic or nonsyndromic ID. The de novo nonsense variants resulting in Hardikar syndrome that is characterized by facial clefting, pigmentary retinopathy, biliary anomalies, and intestinal malrotation, are found more N-terminally, whereas the more C-terminally positioned variants are de novo protein truncating variants that cause a severe, syndromic phenotype consisting of ID, facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. This broad range of distinct phenotypes calls for a method to distinguish between pathogenic and non-pathogenic variants in MED12. We propose an isogenic iNeuron model to establish the unique gene expression patterns that are associated with the specific MED12 variants. The discovery of these patterns would help in future diagnostics and determine the causality of the MED12 variants.
Topics: Abnormalities, Multiple; Agenesis of Corpus Callosum; Anus, Imperforate; Blepharophimosis; Blepharoptosis; Cholestasis; Cleft Palate; Constipation; Craniofacial Abnormalities; Heart Defects, Congenital; Humans; Intellectual Disability; Marfan Syndrome; Mediator Complex; Mental Retardation, X-Linked; Muscle Hypotonia; Phenotype; Retinitis Pigmentosa
PubMed: 33925166
DOI: 10.3390/genes12050663