Increasing histone acetylation improves sociability and restores learning and memory in KAT6B-haploinsufficient mice.

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.

The First Korean Case with Cardiac, Facial, and Digital Anomalies with Developmental Delay Caused by De Novo TRAF7 p.Arg655Gln Variant.

TRAF7-related disorders represent some of the rarest inherited disorders, exhibiting clinical features that overlap with cardiac, facial, and digital anomalies with developmental delay (CAFDADD) syndrome, as well as blepharophimosis-mental retardation syndrome (BMRS). A 36-year-old male, presenting with total blindness, blepharophimosis, and intellectual disability, was admitted for the assessment of resting dyspnea several months previously. He had a history of being diagnosed with obstructive sleep apnea (OSA). Transesophageal and transthoracic echocardiography unveiled right ventricular dilatation without significant pulmonary hypertension, bicuspid aortic valve with aortic root aneurysm, and aortic regurgitation in the proband. Sanger sequencing identified a de novo TRAF7 variant (c.1964G>A; p.Arg655Gln). Subsequently, aortic root replacement using the Bentall procedure was performed. However, despite the surgery, he continued to experience dyspnea. Upon re-evaluating OSA with polysomnography, it was discovered that continuous positive airway pressure support alleviated his symptoms. The underlying cause of his symptoms was attributed to OSA, likely exacerbated by the vertebral anomaly and short neck associated with CAFDADD syndrome. Clinicians should be attentive to the symptoms associated with OSA as it is a potentially serious medical condition in patients with TRAF7 variants.

De novo KAT6B mutation causes Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome in an Iranian boy: a case report.

BACKGROUND: Say-Barber-Biesecker-Young-Simpson (SBBYS) (OMIM #603736, Ohdo syndrome variant) is a rare type of severe blepharophimosis intellectual disability syndrome, which is generally characterized by a global developmental delay, distinctive facial features, and intellectual disability with multiple congenital anomalies, including skeletal involvement, missing, or underdeveloped kneecaps, and genital anomalies, in affected males. It has been shown that mutations in the KAT6B gene, which is a lysine acetyltransferase-encoding gene, have been associated with SBBYS syndrome. All the known variants are dominant de novo mutations that result in protein truncation. CASE PRESENTATION: A 14-year-old Iranian Azeri boy with an intellectual disability, distinct dysmorphic facial features such as open-mouth expression, sparse medial eyebrows, widely spaced upward-slanted eyes, epicanthal folds, broad nasal bridge, low-set ears, anteverted ears, short philtrum, hypertelorism, microphthalmia is presented in this case study. Cryptorchidism was reported. Neurologically, the patient presented with poor eye contact, hypotonia, and speech difficulties. In the skeletal X-ray, underdeveloped kneecaps with some new features were observed. CONCLUSION: We present the first case of SBBYS syndrome in association with some new anomaly features in the Iranian population. Based on this diagnosis, we could provide the patient with a suitable plan of management as well as appropriate genetic counseling for his family.

Deletion of cis-regulatory Element in FOXL2 Promoter in a Chinese Family of Type II Blepharophimosis-ptosis-epicanthus Inversus Syndrome with Polydactyly.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a relatively uncommon autosomal-dominant genetic disorder, primarily attributed to mutations in the forkhead box L2 (FOXL2) gene. Albeit the involvement of protein-coding regions of FOXL2 has been observed in the majority of BPES cases, whether deficiencies in regulatory elements lead to the pathogenesis remains poorly understood. Herein, an autosomal-dominant BPES type II family was included. Peripheral venous blood has been collected, and genomic DNA has been extracted from leukocytes. A whole exome sequencing analysis has been performed and analyzed (Deposited in NODE database: OER422653). The promoter region of FOXL2 was amplified using polymerase chain reaction (PCR). The luciferase reporter assay was performed to identify the activity of this region. In this study, we present a Chinese family diagnosed with type II BPES, characterized by the presence of small palpebral fissures, ptosis, telecanthus, and epicanthus inversus. Notably, all male individuals within the family display polydactyly. A 225-bp deletion in the 556-bp 5'-upstream to transcription start site of FOXL2 , decorated by multiple histone modifications, was identified in affected members of the family. This deletion significantly decreased FOXL2 promoter activity, as measured by the luciferase assay. Conclusively, a novel 255-bp-deletion of the FOXL2 promoter was identified in Chinese families with BPES. Our results expand the spectrum of known FOXL2 mutations and provide additional insight into the genotype-phenotype relationships of the BPES pathogenesis. In addition, this study indicates the important role of genetic screening of cis-regulatory elements in testing heritable diseases.

Expanded phenotypic spectrum of FOXL2 Variant c.672_701dup revealed by whole-exome sequencing in a rare blepharophimosis, ptosis, and epicanthus inversus syndrome family.

INTRODUCTION: Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare genetic disease with diverse ocular malformations. This study aimed to investigate the disease-causing gene in members of a BPES pedigree presenting with the rare features of anisometropia, unilateral pathologic myopia (PM), and congenital cataracts. METHODS: The related BPES patients underwent a comprehensive ocular examination. Next, whole-exome sequencing (WES) was performed to screen for the disease-causing genetic variants. A step-wise variant filtering was performed to select candidate variants combined with the annotation of the variant's pathogenicity, which was assessed using several bioinformatic approaches. Co-segregation analysis and Sanger sequencing were then conducted to validate the candidate variant. RESULTS: The variant c.672_701dup in FOXL2 was identified to be the disease-causing variant in this rare BPES family. Combined with clinical manifestations, the two affected individuals were diagnosed with type II BPES. CONCLUSION: This study uncovered the variant c.672_701dup in FOXL2 as a disease causal variant in a rare-presenting BPES family with anisometropia, unilateral pathogenic myopia, and/or congenital cataracts, thus expanding the phenotypic spectrum of FOXL2.

A 24-year-Old Male with Marden-Walker Syndrome and Epilepsy: Case Report.

We report a 24-year-old male with blepharophimosis, psychomotor retardation, brachycephaly, microstomia, immobile face, high arched palate, single palmar crease, kyphoscoliosis, talipes equinovarus, inguinal hernia, pyloric stenosis, recurrent infections, bilateral camptodactyly, wide-set eyes, decreased muscle mass, hypotonia, exotropia, and ptosis in the left eye, growth retardation, multiple congenital contractures, and hyporreflexia. Contractures improved with aging, but intellectual disability and blepharophimosis remained. He also presented epilepsy, outbursts of laughter, and predisposition to drug adverse effects (skin lesions with carbamazepine and secondary parkinsonism).

Intraoral findings of a patient with Nablus mask-like facial syndrome and dental treatment approaches: a case report and literature review.

Nablus mask-like facial syndrome (NMLFS) (OMIM: 608156) is an extremely rare genetic syndrome first reported by Ahmad Teebi in 2000. Although it is a rare condition, it is characterized by distinctive facial features such as, expressionless facial appearance, tight, glistening facial skin, low anterior hairline, sparse eyebrows, small palpebral fissures (blepharophimosis), hypertolerism, bulbous nose with prominent columella, abnormally short nose and flat nasal bridge, abnormal ear configuration, bilateral longitudinal cheek dimples, everted lower lip, long philtrum, and maxillary hypoplasia. In addition, a happy and friendly disposition is considered to be the common symptom of this syndrome. Previous studies revealing the intraoral findings of this rare symptom are inadequate and the present report is the first one that presents a dental case involving Nablus syndrome in detail. The aim of this report is to contribute to the current literature through our oral findings in an NMFLS patient, presented at our clinic with toothache and through our treatment approach.

Missense Mutations in MAB21L1: Causation of Novel Autosomal Dominant Ocular BAMD Syndrome.

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.

Association between blepharophimosis-ptosis-epicanthus inversus syndrome and lacrimal system anomalies.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a congenital eyelid syndrome. Several associations, including the horizontal displacement of the puncta, canalicular stenosis, and ectropion have been so far described. Herein, we report a one-year-old boy presented to the Oculoplastic Clinic of Farabi Eye Hospital with complaint of watery discharge from both eyes since his birth. Based on the general appearance, the diagnosis of BPES was made. Mild tear regurgitation from the inferior punctum was noted. Detailed examination showed bilateral superior punctal agenesis with coloboma of both upper eyelids and lateral displacement of the inferior puncta. Multiple unsuccessful attempts of probing were suggestive of the presence of NLDO. The patient was managed by performing canaliculodacryocystorhinostomy. Osteotomy was performed to pass the canalicular and nasolacrimal obstruction followed by a successful canaliculoplasty. Finally, the lacrimal drainage system was intubated with a mono-Crawford from the inferior punctum into the nasal cavity. On the 1st-month follow-up visit, the complaint of watery discharge was resolved. This is an extremely rare report of nasolacrimal duct and sac anomaly in a patient with blepharophimosis. Thus, we recommend the evaluation of the nasolacrimal drainage system in these patients after the first month of birth.

Missense MED12 variants in 22 males with intellectual disability: From nonspecific symptoms to complete syndromes.

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, χ2 test), but mostly outside the functional domains (p = 0.004; χ2 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.

[Diagnosis of a child with Say-Barber-Biesecker-Young-Simpson syndrome due to variant of KAT6B gene].

OBJECTIVE: To analyze the genotype and clinical phenotype of a 3-month-old female infant featuring unresponsiveness. METHODS: The infant was subjected to genetic testing, and her clinical features were compared with syndromes associated with variants of the candidate gene. RESULTS: The patient has featured long fingers, long and overlapped toes, musk-like face, blepharophimosis, ptosis, and lacrimal duct anomaly. She was found to harbor a heterozygous de novo variant NM_012330.3: c.3040C>T (p.Gln1014*) in exon 16 of the KAT6B gene. Her clinical phenotype and genotype have both conformed to Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS). CONCLUSION: The child was diagnosed with SBBYSS syndrome due to the c.3040C>T (p.Gln1014*) variant of the the KAT6B gene. Discovery of the unique features has expanded the phenotypic spectrum of this syndrome.

Clinical and genetic studies of 17 Han Chinese pedigrees and 31 sporadic patients with blepharophimosis-ptosis-epicanthus inversus syndrome.

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 forkhead transcriptional factor 2 (FOXL2) 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 FOXL2 gene, presented with a relatively higher frequency. Two rare double variations were detected in two sporadic patients. FOXL2 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 FOXL2 gene that would expand the spectrum of the FOXL2 variation database. In addition, we found that the alanine/proline-rich region is a variation hotspot in the FOXL2 gene. The genotype-phenotype correlation is not easy to establish due to clinical and genetic heterogeneity.

Surgical outcome of epicanthus and telecanthus correction by C-U medial canthoplasty with lateral canthoplasty in treatment of 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.

Novel prenatally diagnosed compound heterozygous PXDN variants in fetal congenital primary aphakia and blepharophimosis.

OBJECTIVE: To precision survey a fetal congenital primary aphakia molecular etiology. CASE REPORT: A case of 42 years old pregnancy woman prenatal diagnostic examination by amniocentesis conducted at 17 weeks' gestation and demonstrated a normal female karyotype. Trio studies based on chromosome microarray analysis (CMA) and Sanger's genetic analysis did not detect a pathologic variant of the FOXE3 gene. Fetal congenital primary aphakia accompanied with microphthalmia detected by sonography in the second trimester (22 weeks). MRI indicated bilateral absence of the lenses, consistent with primary congenital aphakia. Due to the poor prognosis of congenital aphakia, the parents decided to terminate the fetus and provided consent for an autopsy. Pathological analysis revealed dysplasia of the anterior segment of both eyes. However, post fetal mortem extended trio whole exon sequencing (WES) and Sanger's genetic analysis identified compound heterozygous variants in the chromosomal location 2p25.3 in the PXDN gene. CONCLUSION: Extended whole exon sequencing is an important tool to study primary congenital aphakia.

Ovarian Reserve and ART Outcomes in Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome Patients With FOXL2 Mutations.

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 FOXL2 gene and underwent assisted reproductive technology (ART) treatment. Indicators for ovarian reserve and ART outcomes were compared between patients with and without FOXL2 mutations. Additionally, ART outcomes were compared among patients with different subtypes of FOXL2 mutations. Results: A total of 13 distinct heterozygous variants in the FOXL2 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 FOXL2 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 FOXL2 mutation types. Conclusions: BPES patients with FOXL2 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.

A human paradigm of LHX4 and NR5A1 developmental gene interaction in the pituitary gland and ovary?

The pituitary gland, as a nodal component of the endocrine system, is responsible for the regulation of growth, reproduction, metabolism, and homeostasis. Although pituitary formation though the hierarchical action of different transcription factors is well studied in mouse models, there is little evidence of the analogous developmental processes in humans. Herein, we present a female patient with a phenotype that includes blepharoptosis-ptosis-epicanthus syndrome and premature ovarian failure. Clinical exome sequencing revealed two heterozygous variants in two genes, LHX4 (pathogenic) and NR5A1 (VUS) genes and no mutation in FOXL2 gene. We propose a model of genetic interaction between LHX4 and NR5A1 during pituitary and ovarian development that may lead to a similar phenotype mediated by reduced FOXL2 expression.

Two novel variants in SCARF2 gene underlie van den Ende-Gupta syndrome.

Van den Ende-Gupta syndrome (VDEGS) (MIM#600920) is characterized by skeletal and craniofacial abnormalities that include prominent ears, downslanting palpebral fissures, blepharophimosis, hypoplastic maxilla with or without a cleft palate, a narrow and convex nasal bridge and an everted lower lip, camptodactyly and arachnodactyly. Intelligence is normal. Recent studies have reported that patients with VDEGS have pathogenic variants in the SCARF2 gene on chromosome 22q11.21. Here, we report two Turkish patients with two novel variants [c.2291_2292insC (p.Ser765LeufsTer6) and c.488G>A (p.Cys63Tyr)] in the SCARF2 gene. In silico analysis predicted that both of these novel variants were pathogenic. To the best of our knowledge, this is the first case report of this syndrome in Turkey.