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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 -
Molecular Genetics & Genomic Medicine Dec 2023Say-Barber-Biesecker-Young-Simpson (SBBYSS) variant of Ohdo syndrome is a rare, autosomal dominant and clinically heterogenous disorder, caused by pathogenic variants in...
BACKGROUND
Say-Barber-Biesecker-Young-Simpson (SBBYSS) variant of Ohdo syndrome is a rare, autosomal dominant and clinically heterogenous disorder, caused by pathogenic variants in the KAT6B gene located on chromosome 10q22.2. KAT6B encodes a highly conserved histone acetyltransferase belonging to the MYST family. Currently, diseases caused by pathogenic variants in KAT6B (KAT6B-related disorders) comprise two allelic entities: SBBYSS variant of Ohdo syndrome and genitopatellar syndrome (GPS). Increase in the number of cases with overlapping GPS/SBBYSS phenotype which makes it necessary to redefine this group of phenotypes as KAT6B-related disorders or KAT6B spectrum disorders. Individuals with SBBYSS usually present with facial abnormalities, hypotonia, joint laxity, feeding problems, and long thumbs/great toes. This syndrome also typically involves skeletal problems including patellar hypoplasia/agenesis.
METHODS
Here we report six SBBYS syndrome patients with the same dysmorphic features but a different course of the disease. One known and five novel KATB6 pathogenic variants were identified by molecular diagnostics using Next Generation Sequencing (NGS).
RESULTS
We present a detailed phenotypic analysis of six individuals with KAT6B-related disorders, in whom a heterozygous pathogenic variant in KAT6B gene was found. In all of our patients facial dysmorphism as well as developmental and speech delay were present. Additionally, all but one patients presented with hypotonia, ocular abnormalities and long thumbs. Most of our probands showed blepharophimosis and skeletal (mainly knee) defects. Contrary to previously reported severe patellar defects (hypoplasia/agenesis) anomalies presented by our patients were less severe (dysplasia, habitual dislocation, subluxation) referring to KAT6B-related disorders.
CONCLUSION
While most of the anomalies found in our patients comply with SBBYSS criteria, phenotypic differences in our probands support a broader spectrum of the disease phenotype. To establish the range of this spectrum, a detailed analysis of clinical variability among patients with SBBYSS requires further investigation.
Topics: Male; Humans; Mutation; Muscle Hypotonia; Poland; Intellectual Disability; Histone Acetyltransferases
PubMed: 37658610
DOI: 10.1002/mgg3.2265 -
International Journal of Molecular... 2023Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a rare neurodevelopmental disorder. MRXST is caused by pathogenic variants in the gene on... (Review)
Review
Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a rare neurodevelopmental disorder. MRXST is caused by pathogenic variants in the gene on chromosome Xp11.22. The gene encodes a ubiquitin ligase, which has downstream effects on the n-MYC protein and DLL3 Notch ligand, ultimately affecting neuronal differentiation. In addition to intellectual disability and developmental delay, other clinical features such as absent or delayed speech, skeletal abnormalities, abnormalities in hands or feet, seizures, and hypotonia have been described in case reports. Facial dysmorphic features and eye manifestations have been reported in patients with MRXST, but have not been identified as distinctive to this condition. We report two cases of individuals affected by -Related Intellectual Developmental Disorder and present a review of literature of male patients affected by this disorder. Based on the literature review and findings in our two patients, it is our observation that patients with MRXST present with distinctive features, which include broad nasal tip, root, or prominent nose (39%), blepharophimosis (27%), epicanthic folds (25%), ear abnormalities (25%), thin upper lip (23%), and deep set eyes (23%). Furthermore, we note that oculofacial abnormalities are seen more frequently in patients with missense variants than patients with duplications in the gene. The findings noted in this paper may help clinicians suspect a diagnosis of MRXST when presented with these distinctive ocular and facial features.
PubMed: 38021253
DOI: No ID Found -
Neurology India 2023We report a 24-year-old male with blepharophimosis, psychomotor retardation, brachycephaly, microstomia, immobile face, high arched palate, single palmar crease,...
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).
Topics: Male; Humans; Young Adult; Adult; Blepharophimosis; Syndrome; Abnormalities, Multiple; Contracture; Intellectual Disability
PubMed: 37635513
DOI: 10.4103/0028-3886.383870 -
Frontiers in Genetics 2024Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare inherited disorder. This study was aimed to identify and functionally validate variants in...
Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare inherited disorder. This study was aimed to identify and functionally validate variants in two Chinese families with BPES. The proband and his family members were subjected to whole-exome sequencing to identify disease-associated variants. Several bioinformatic tools were used to computationally predict altered proteins. functional assays were conducted by transfecting wild-type and mutant cDNAs into HEK-293 cells, followed by subcellular localization assays, luciferase reporter gene assays, and quantitative real-time polymerase chain reaction. The clinical features of BPES, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, were present in all affected patients. Two novel mutations were detected, c.292T>A and c.383G>T. Whole-exome sequencing analysis and prediction software suggested that these mutations were pathogenic. Functional studies showed that these two point mutations decreased FOXL2 protein expression, resulting in subcellular mislocalization and aberrant transcriptional activity of the steroidogenic acute regulatory protein gene promoter. Our results add to the current understanding of known variants in, and our experiments provide reference data and insights into the etiology of BPES. Further studies are needed to identify the possible mechanisms underlying the action of this mutation on the development of BPES.
PubMed: 38410153
DOI: 10.3389/fgene.2024.1343411 -
Dermatology and Therapy Feb 2024Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive disorder characterized by typical facial dysmorphism, generalized muscle stiffness, joint contracture, and...
Schwartz-Jampel syndrome (SJS) is a rare autosomal recessive disorder characterized by typical facial dysmorphism, generalized muscle stiffness, joint contracture, and skeletal abnormalities. This condition is caused by mutations in the heparan sulfate proteoglycan 2 (HSPG2) gene, which encodes perlecan, a component of the basement membrane. The management of patients with SJS primarily aims to alleviate symptoms related to muscle stiffness. In this report, we describe a male patient with SJS type 1A. Trio whole-exome sequencing identified a pathogenic mutation (NM_001291860.1: c.10897C>T; p.Arg3633Ter) and variants of unknown significance (NM_001291860.2: c.413+10G>T). The patient experienced difficulty in opening his eyes and mouth, which significantly limited his daily activities. Botulinum toxin A injection was administered and demonstrated significant clinical improvement after the treatment.
PubMed: 38285320
DOI: 10.1007/s13555-023-01088-7 -
BMC Ophthalmology Nov 2023Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare genetic disease with diverse ocular malformations. This study aimed to investigate the...
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.
Topics: Humans; Mutation; Exome Sequencing; Anisometropia; Blepharophimosis; Pedigree; Syndrome; Cataract; Myopia; Forkhead Box Protein L2
PubMed: 37932670
DOI: 10.1186/s12886-023-03189-5 -
Case Reports in Genetics 2023Bromodomain and PHD finger containing 1 ()-related neurodevelopmental disorder is characterized by intellectual disability, developmental delay, hypotonia, dysmorphic...
Bromodomain and PHD finger containing 1 ()-related neurodevelopmental disorder is characterized by intellectual disability, developmental delay, hypotonia, dysmorphic facial features, ptosis, and blepharophimosis. Both and inherited pathogenic variants have been previously reported in association with this disorder. We report two affected female siblings with a novel variant in c.2420_2433del (p.Q807Lfs27) identified through whole-exome sequencing. Their history of mild intellectual disability, speech delay, attention deficient hyperactivity disorder (ADHD), and ptosis align with the features previously reported in the literature. The absence of the variant in parental buccal samples provides evidence of a frameshift pathogenic variant, most likely as a result of parental gonadal mosaicism, which has not been previously reported. The frameshift pathogenic variant reported here lends further support to haploinsufficiency as the underlying mechanism of disease. We review the literature, compare the clinical features seen in our patients with others reported, and explore the possibility of genotype-phenotype correlation based on the location of pathogenic variants in . Our study helps to summarize available knowledge and report the first case of a frameshift pathogenic variant in in two siblings with this neurodevelopmental disorder.
PubMed: 37946714
DOI: 10.1155/2023/1692422 -
Frontiers in Genetics 2024[This corrects the article DOI: 10.3389/fgene.2024.1343411.].
[This corrects the article DOI: 10.3389/fgene.2024.1343411.].
PubMed: 38742166
DOI: 10.3389/fgene.2024.1414939