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Nature Feb 2024Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease. The ZRS is arguably the most well-studied...
Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.
Topics: Humans; Enhancer Elements, Genetic; Extremities; Gain of Function Mutation; Homeodomain Proteins; Interferon Regulatory Factors; Organ Specificity; Penetrance; Phenotype; Polydactyly; Polymorphism, Single Nucleotide; Protein Binding; Proto-Oncogene Proteins c-ets; Transcription Factor AP-1
PubMed: 38233525
DOI: 10.1038/s41586-023-06922-8 -
Journal of Orthopaedic Surgery and... Jan 2024To investigate the functional and aesthetic results of a new modified Bilhaut-Cloquet procedure for the treatment of Wassel type III-IV thumb polydactyly.
BACKGROUND
To investigate the functional and aesthetic results of a new modified Bilhaut-Cloquet procedure for the treatment of Wassel type III-IV thumb polydactyly.
METHODS
Thirteen patients with Wassel type III-IV thumb polydactyly who visited the Department of Orthopedics of Hebei Provincial Children's Hospital from 2019 to 2022 were selected. The surgical procedure involved a modified Bilhaut-Cloquet surgery, where two-thirds of the distal part of the dominant finger was retained as the p body of the reconstructed thumb. The triangular bone block of the ablated distal thumb that did not contain the epiphysis and articular cartilage was sutured and fixed, and the neurovascular flap of the ablated distal thumb was used as an augmenting segment of the reconstructed thumb, with the nail bed and nail matrix exquisitely sutured. The evaluation performed according to the Japanese Society for Surgery of the Hand (JSSH) system.
RESULTS
All 13 children showed bone healing, no wound infection, nonunion, or deformity healing. None of the children showed a significant reduction in the active and passive mobility of the thumb postoperatively compared with preoperatively. Postoperative evaluation was performed based on the JSSH score, with a mean of 17.15 points (14-19 points), with 11 children rated as excellent and two as good. No severe nail ridges, nail gaps, or nail split deformities of the thumb were observed postoperatively. Postoperative metacarpophalangeal and interphalangeal joint movements were not reduced compared with preoperative movements. All parents were satisfied with the appearance and function of the reconstructed thumb.
CONCLUSION
The modified Bilhaut-Cloquet procedure designed in this study was satisfactory for Wassel type III-IV thumb polydactyly without affecting the stability of the interphalangeal joints and preserving joint mobility. The postoperative thumb has a comparable circumference and nail width and was cosmetically and functionally satisfactory, especially for the asymmetric two thumbs, which achieved favorable results.
Topics: Child; Humans; Infant; Polydactyly; Orthopedic Procedures; Thumb; Wound Healing
PubMed: 38229071
DOI: 10.1186/s13018-024-04553-x -
Taiwanese Journal of Obstetrics &... Jan 2024
Topics: Pregnancy; Female; Humans; Holoprosencephaly; Pregnancy Trimester, First; Trisomy 13 Syndrome; Polydactyly; Trisomy; Ultrasonography, Prenatal; Fingers; Toes
PubMed: 38216244
DOI: 10.1016/j.tjog.2023.10.007 -
African Journal of Disability 2023Bardet-Biedl syndrome (BBS) is a rare, systemic, hereditary disorder characterised by obesity, polydactyly, visual and auditory impairment, and cognitive disability....
BACKGROUND
Bardet-Biedl syndrome (BBS) is a rare, systemic, hereditary disorder characterised by obesity, polydactyly, visual and auditory impairment, and cognitive disability. Providing quality education in appropriate schools for children who present with such complex chronic conditions is challenging.
OBJECTIVES
This study explored the dimensions of psycho-educational support needs for a child with BBS in South Africa to contribute to the improvement of early detection and holistic interventions.
METHOD
A descriptive in-depth qualitative case study of Gezani, an adolescent Tsonga boy diagnosed with BBS, was undertaken. Semi-structured interviews were conducted with his parents and teachers to ascertain the boy's psycho-educational support needs. Medical reports provided information on the complexities and prognosis of the syndrome. Observations in the classroom corroborated the learner's symptoms and behaviours.
RESULTS
Thematic content analysis revealed the key areas of support needs. Gezani's cognitive disability required a modified, slow-paced curriculum. His visual impairment required mobility orientation training and learning Braille. His emotional needs were supported with psychotherapy to maintain a sense of well-being. Medical monitoring was recommended with interventions for walking and managing his diet and weight. Speech therapy supported his communication skills.
CONCLUSION
Learners with multiple disabilities require carefully planned, individualised psycho-educational support programmes addressing their unique needs and delays with targeted remedial interventions in appropriate special needs schools.
CONTRIBUTION
This study informs educators about BBS and provides multi-faceted, holistic support. The Department of Basic Education could bring special schools and national policies in tighter alignment for learners presenting with complex disabilities.
PubMed: 38204908
DOI: 10.4102/ajod.v12i0.1181 -
Journal of Indian Association of... 2023Bardet-Biedl syndrome is an autosomal-recessive ciliopathic disorder affecting multiple organ systems. Characteristic features include progressive retinal dystrophy,...
Bardet-Biedl syndrome is an autosomal-recessive ciliopathic disorder affecting multiple organ systems. Characteristic features include progressive retinal dystrophy, obesity, polydactyly hypogonadism, mental retardation, and renal disorders. Other manifestations include congenital heart diseases, hepatic fibrosis, ataxia, and diabetes. Approximately 30% of patients with Biedl-Bardet syndrome (BBS) have hepatobiliary disorders such as periportal fibrosis, nonalcoholic fatty liver disease, and cystic dilation of the bile ducts. The association of BBS with choledochal cysts (CDC) is extremely rare. Here, we report a case of a 14-year-old boy with a novel variant of BBS and associated type IV CDC. The patient was managed surgically with CDC excision and Roux-en-Y hepaticojejunostomy.
PubMed: 38173646
DOI: 10.4103/jiaps.jiaps_124_23 -
Cell Transplantation 2024This study compared the proliferation and differentiation potential of bone marrow-derived mesenchymal stem cells (BMSCs) derived from infants with polydactyly and...
This study compared the proliferation and differentiation potential of bone marrow-derived mesenchymal stem cells (BMSCs) derived from infants with polydactyly and adults with basal joint arthritis. The proliferation rate of adult and infant BMSCs was determined by the cell number changes and doubling times. The γH2AX immunofluorescence staining, age-related gene expression, senescence-associated β-galactosidase (SA-β-gal) staining were analyzed to determine the senescence state of adult and infant BMSCs. The expression levels of superoxide dismutases (SODs) and genes associated with various types of differentiation were measured using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR). Differentiation levels were evaluated through histochemical and immunohistochemical staining. The results showed that infant BMSCs had a significantly higher increase in cell numbers and faster doubling times compared with adult BMSCs. Infant BMSCs at late stages exhibited reduced γH2AX expression and SA-β-gal staining, indicating lower levels of senescence. The expression levels of senescence-related genes (, , and ) in infant BMSCs were also lower than in adult BMSCs. In addition, infant BMSCs demonstrated higher antioxidative ability with elevated expression of , , and compared with adult BMSCs. In terms of differentiation potential, infant BMSCs outperformed adult BMSCs in chondrogenesis, as indicated by higher expression levels of chondrogenic genes (, , and ) and positive immunohistochemical staining. Moreover, differentiated cells derived from infant BMSCs exhibited significantly higher expression levels of osteogenic, tenogenic, hepatogenic, and neurogenic genes compared with those derived from adult BMSCs. Histochemical and immunofluorescence staining confirmed these findings. However, adult BMSCs showed lower adipogenic differentiation potential compared with infant BMSCs. Overall, infant BMSCs demonstrated superior characteristics, including higher proliferation rates, enhanced antioxidative activity, and greater differentiation potential into various lineages. They also exhibited reduced cellular senescence. These findings, within the context of cellular differentiation, suggest potential implications for the use of allogeneic BMSC transplantation, emphasizing the need for further investigation.
Topics: Adult; Child; Humans; Bone Marrow; Cell Proliferation; Cell Differentiation; Osteogenesis; Cells, Cultured; Mesenchymal Stem Cells; Bone Marrow Cells; Arthritis; Polydactyly
PubMed: 38164917
DOI: 10.1177/09636897231221878 -
Molecular Genetics & Genomic Medicine Mar 2024Meckel syndrome (MKS) is the most severe form of an autosomal recessive ciliopathy and is clinically characterized by occipital encephalocele, severely polycystic...
BACKGROUND
Meckel syndrome (MKS) is the most severe form of an autosomal recessive ciliopathy and is clinically characterized by occipital encephalocele, severely polycystic kidneys, and postaxial polydactyly (toes). The association of TXNDC15-related MKS has been reported. We report the case of a homozygous mutation in the TXNDC15 gene, causing MKS14 in the Chinese population.
METHODS
The fetal skin tissue and parental peripheral blood were retained for whole-exome sequencing and Sanger sequencing, which investigated the potential pathogenic variants associated with MKS.
RESULTS
The fetus was homozygous for a mutation in the TXNDC15 gene (NM_024715.3), specifically c.560delA (p.Asn187llefsTer4), and both parents were heterozygous for this mutation.
CONCLUSION
Our study identified a new mutation that adds to the mutational landscape of MKS, which provide a basis for genetic counseling and the selection of reproductive options.
Topics: Humans; Encephalocele; Polycystic Kidney Diseases; Ciliary Motility Disorders; Mutation; Retinitis Pigmentosa
PubMed: 38156946
DOI: 10.1002/mgg3.2343 -
Acta Medica Okayama Dec 2023A patient was born with a mass at the base of the thumb approximately 1.5 cm in diameter on the radial side of the fingers. The mass had globular swelling filled with...
A patient was born with a mass at the base of the thumb approximately 1.5 cm in diameter on the radial side of the fingers. The mass had globular swelling filled with hemorrhagic fluid and was dark red. X-rays and histology of the excised specimen suggested the diagnosis of gangrene and torsion of polydactyly. Prenatal torsion of polydactyly is not a common occurrence; moreover, prenatal torsion of polydactyly has only been found in ulnar polydactyly. Our case is a novel case of radial polydactyly that was gangrenous at birth owing to prenatal torsion. Diagnosing such a mass at the base of the thumb is important.
Topics: Infant, Newborn; Humans; Thumb; Gangrene; Polydactyly; Fingers
PubMed: 38145940
DOI: 10.18926/AMO/66158 -
American Journal of Human Genetics Jan 2024Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding...
Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAX (Max) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAX individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.
Topics: Humans; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Dimerization; Megalencephaly; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-myc
PubMed: 38141607
DOI: 10.1016/j.ajhg.2023.11.010 -
Genes Dec 2023Cornelia de Lange syndrome is a genetic and clinically heterogeneous entity, caused by at least five genes. It is characterized by short stature, gestalt facies,...
Cornelia de Lange syndrome is a genetic and clinically heterogeneous entity, caused by at least five genes. It is characterized by short stature, gestalt facies, microcephaly, neurodevelopmental disorders, and other anomalies. In this report, we present a 13-year-old female patient with microcephaly, cleft palate, polydactyly, short stature, triangular facies, frontal bossing, a bulbous nose, an overfolded helix, limited pronosupination, and an anomalous uterus. No neurodevelopmental disorders were reported. A chromosomal microarray analysis of 6.5 million markers was performed in the proband and her parents. The results showed a de novo heterozygous microdeletion of exons 9-14 within , which confirmed the diagnosis of Cornelia de Lange syndrome type 4. Our patient did not show any neurologic phenotype (until the time of diagnosis), although neurodevelopmental disorders are frequently present in patients with Cornelia de Lange syndrome type 4, and despite carrying a deletion that was larger than previously reported. Therefore, unknown genetic modifiers or intrinsic mechanisms of variants may exist and should be studied.
Topics: Humans; Female; Adolescent; De Lange Syndrome; Cell Cycle Proteins; Gene Deletion; Microarray Analysis
PubMed: 38137034
DOI: 10.3390/genes14122212