RESUMO
The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. Variants in BAF subunits cause Coffin-Siris syndrome (CSS), a congenital disorder characterized by coarse craniofacial features and intellectual disability. Approximately 50% of individuals with CSS harbor variants in one of the mutually exclusive BAF subunits, ARID1A/ARID1B. While Arid1a deletion in mouse neural crest causes severe craniofacial phenotypes, little is known about the role of ARID1A in CNCC specification. Using CSS-patient-derived ARID1A+/- induced pluripotent stem cells to model CNCC specification, we discovered that ARID1A-haploinsufficiency impairs epithelial-to-mesenchymal transition (EMT), a process necessary for CNCC delamination and migration from the neural tube. Furthermore, wild-type ARID1A-BAF regulates enhancers associated with EMT genes. ARID1A-BAF binding at these enhancers is impaired in heterozygotes while binding at promoters is unaffected. At the sequence level, these EMT enhancers contain binding motifs for ZIC2, and ZIC2 binding at these sites is ARID1A-dependent. When excluded from EMT enhancers, ZIC2 relocates to neuronal enhancers, triggering aberrant neuronal gene activation. In mice, deletion of Zic2 impairs NCC delamination, while ZIC2 overexpression in chick embryos at post-migratory neural crest stages elicits ectopic delamination from the neural tube. These findings reveal an essential ARID1A-ZIC2 axis essential for EMT and CNCC delamination.
Assuntos
Proteínas de Ligação a DNA , Transição Epitelial-Mesenquimal , Face , Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Pescoço , Crista Neural , Fatores de Transcrição , Crista Neural/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transição Epitelial-Mesenquimal/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Deficiência Intelectual/genética , Micrognatismo/genética , Animais , Face/anormalidades , Face/embriologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Pescoço/anormalidades , Pescoço/embriologia , Camundongos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/citologia , Haploinsuficiência , Elementos Facilitadores Genéticos/genética , Deformidades Congênitas do Pé/genética , Deformidades Congênitas do Pé/patologia , Regulação da Expressão Gênica no Desenvolvimento , Anormalidades MúltiplasRESUMO
While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.
Assuntos
Mutação em Linhagem Germinativa , Deficiência Intelectual , Proteína Smad4 , Humanos , Masculino , Proteína Smad4/genética , Deficiência Intelectual/genética , Contratura/genética , Adulto , Fácies , Espermatozoides/metabolismo , Espermatozoides/patologia , Criptorquidismo/genética , Transtornos do Crescimento/genética , Deformidades Congênitas da Mão/genética , Seleção Genética , Alelos , Idade Paterna , Testículo/patologia , Testículo/metabolismoRESUMO
PRC2 is a therapeutic target for several types of cancers currently undergoing clinical trials. Its activity is regulated by a positive feedback loop whereby its terminal enzymatic product, H3K27me3, is specifically recognized and bound by an aromatic cage present in its EED subunit. The ensuing allosteric activation of the complex stimulates H3K27me3 deposition on chromatin. Here we report a stepwise feedback mechanism entailing key residues within distinctive interfacing motifs of EZH2 or EED that are found to be mutated in cancers and/or Weaver syndrome. PRC2 harboring these EZH2 or EED mutants manifested little activity in vivo but, unexpectedly, exhibited similar chromatin association as wild-type PRC2, indicating an uncoupling of PRC2 activity and recruitment. With genetic and chemical tools, we demonstrated that targeting allosteric activation overrode the gain-of-function effect of EZH2Y646X oncogenic mutations. These results revealed critical implications for the regulation and biology of PRC2 and a vulnerability in tackling PRC2-addicted cancers.
Assuntos
Regulação Alostérica/fisiologia , Cromatina/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Anormalidades Múltiplas/metabolismo , Linhagem Celular Tumoral , Hipotireoidismo Congênito/metabolismo , Anormalidades Craniofaciais/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Deformidades Congênitas da Mão/metabolismo , Histonas/metabolismo , Humanos , Neoplasias/metabolismoRESUMO
Mutations of human TBC1D24 are associated with deafness, epilepsy, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, cognitive disability, and seizures). The causal relationships between TBC1D24 variants and the different clinical phenotypes are not understood. Our hypothesis is that phenotypic heterogeneity of missense mutations of TBC1D24 results, in part, from perturbed binding of different protein partners. To discover novel protein partners of TBC1D24, we conducted yeast two-hybrid (Y2H) screen using mouse full-length TBC1D24 as bait. Kidney and brain protein (KIBRA), a scaffold protein encoded by Wwc1, was identified as a partner of TBC1D24. KIBRA functions in the Hippo signaling pathway and is important for human cognition and memory. The TBC1D24 TLDc domain binds to KIBRA full-length and to its C2 domain, confirmed by Y2H assays. No interaction was detected with Y2H assays between the KIBRA C2 domain and TLDc domains of NCOA7, MEAK7, and OXR1. Moreover, the C2 domains of other WWC family proteins do not interact with the TLDc domain of TBC1D24, demonstrating specificity. The mRNAs encoding TBC1D24 and KIBRA proteins in mouse are coexpressed at least in a subset of hippocampal cells indicating availability to interact in vivo. As two epilepsy-associated recessive variants (Gly511Arg and Ala515Val) in the TLDc domain of human TBC1D24 disrupt the interaction with the human KIBRA C2 domain, this study reveals a pathogenic mechanism of TBC1D24-associated epilepsy, linking the TBC1D24 and KIBRA pathways. The interaction of TBC1D24-KIBRA is physiologically meaningful and necessary to reduce the risk of epilepsy.
Assuntos
Epilepsia , Proteínas Ativadoras de GTPase , Peptídeos e Proteínas de Sinalização Intracelular , Mutação de Sentido Incorreto , Animais , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/metabolismo , Camundongos , Humanos , Epilepsia/genética , Epilepsia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Domínios Proteicos , Células HEK293 , Ligação Proteica , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/metabolismo , Técnicas do Sistema de Duplo-Híbrido , Perda Auditiva Neurossensorial , Deficiência Intelectual , Unhas Malformadas , Anormalidades CraniofaciaisRESUMO
Synaptotagmin-1 (SYT1) plays a pivotal role in regulating presynaptic processes, including neurotransmitter release. SYT1 variants perturb synaptic vesicle endocytosis and exocytosis, resulting in a series of neurodevelopmental disorders defined as Baker-Gordon syndrome. Herein, we report the case of a newborn with dysmorphic facial appearance, severe hypotonia, poor feeding, gastroesophageal reflux, and an inability to eat and breathe, diagnosed with Baker-Gordon syndrome. A retrospective search was performed on a newborn with Baker-Gordon syndrome. Medical charts were reviewed, with focus on the clinical presentation, diagnostic process, and treatment outcomes. Whole-genome high-throughput DNA sequencing was performed to identify genetic variants. Whole-exome sequencing identified the likely pathogenic variant as SYT1 C.551 T > C(p.V184A). Sanger sequencing results indicated that this variant was a de novo mutation in a conservative site located in the C2A domain of the protein. The patient died at 57 days old because of severe feeding and breathing problems. Our findings of a novel lethal variant in the C2A domain of SYT1 in the youngest patient diagnosed infantile Baker-Gordon syndrome who presented with the most severe hypotonia reported to date expands the spectrum of SYT1- associated neurodevelopmental disorders.
Assuntos
Artrogripose , Fissura Palatina , Pé Torto Equinovaro , Deformidades Congênitas da Mão , Hipotonia Muscular , Transtornos do Neurodesenvolvimento , Recém-Nascido , Humanos , Hipotonia Muscular/genética , Estudos Retrospectivos , Transmissão Sináptica/genética , Transtornos do Neurodesenvolvimento/genética , Sinaptotagmina IRESUMO
ARID1B is the most frequently mutated gene in Coffin-Siris syndrome (CSS). To date, the vast majority of causative variants reported in ARID1B are truncating, leading to nonsense-mediated mRNA decay. In the absence of experimental data, only few ARID1B amino acid substitutions have been classified as pathogenic, mainly based on clinical data and their de novo occurrence, while most others are currently interpreted as variants of unknown significance. The present study substantiates the pathogenesis of ARID1B non-truncating/NMD-escaping variants located in the SMARCA4-interacting EHD2 and DNA-binding ARID domains. Overexpression assays in cell lines revealed that the majority of EHD2 variants lead to protein misfolding and formation of cytoplasmic aggresomes surrounded by vimentin cage-like structures and co-localizing with the microtubule organisation center. ARID domain variants exhibited not only aggresomes, but also nuclear aggregates, demonstrating robust pathological effects. Protein levels were not compromised, as shown by quantitative western blot analysis. In silico structural analysis predicted the exposure of amylogenic segments in both domains due to the nearby variants, likely causing this aggregation. Genome-wide transcriptome and methylation analysis in affected individuals revealed expression and methylome patterns consistent with those of the pathogenic haploinsufficiency ARID1B alterations in CSS cases. These results further support pathogenicity and indicate two approaches for disambiguation of such variants in everyday practice. The few affected individuals harbouring EHD2 non-truncating variants described to date exhibit mild CSS clinical traits. In summary, this study paves the way for the re-evaluation of previously unclear ARID1B non-truncating variants and opens a new era in CSS genetic diagnosis.
Assuntos
Proteínas de Ligação a DNA , Face , Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Pescoço , Fatores de Transcrição , Humanos , Deficiência Intelectual/genética , Micrognatismo/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Deformidades Congênitas da Mão/genética , Pescoço/anormalidades , Face/anormalidades , Anormalidades Múltiplas/genética , Mutação , Masculino , Agregados ProteicosRESUMO
Coffin-Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants in ARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collected. Our results indicate that overweight and obesity are frequent in adults with CSS. Visual impairment, scoliosis, and behavioral anomalies are more prevalent than in published pediatric or mixed cohorts. Cognitive outcomes range from profound intellectual disability (ID) to low normal IQ, with most individuals having moderate ID. The present study describes the first exclusively adult cohort of CSS individuals. We were able to delineate some features of CSS that develop over time and have therefore been underrepresented in previously reported largely pediatric cohorts, and provide recommendations for follow-up.
Assuntos
Anormalidades Múltiplas , Face/anormalidades , Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Adulto , Humanos , Criança , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico , Micrognatismo/genética , Micrognatismo/diagnóstico , Deformidades Congênitas da Mão/genética , Pescoço/anormalidades , Fenótipo , DNA Helicases/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genéticaRESUMO
We report the case of a 12-year-old girl and her father who both had marked postnatal tall stature, camptodactyly and clinodactyly, scoliosis and juvenile-onset hearing loss. The CATSHL (CAmptodactyly - Tall stature - Scoliosis - Hearing Loss syndrome) syndrome was suspected, and molecular analysis revealed a hitherto unreported, monoallelic variant c.1861C>T (p.Arg621Cys) in FGFR3. This variant affects the same residue, but is different than, the variant p.Arg621His reported in the two families with dominant CATSHL described so far. Interestingly, peg-shaped incisors were observed in the proband, a feature never reported in CATSHL but typical of another FGFR3-related condition, LADD (Lacrimo - Auricolo - Dento - Digital) syndrome. The FGFR3 p.Arg621Cys variant seems to be a newly identified cause of CATSHL syndrome with some phenotypic overlap with the LADD syndrome.
Assuntos
Anormalidades Múltiplas , Doenças do Desenvolvimento Ósseo , Surdez , Deformidades Congênitas da Mão , Perda Auditiva , Doenças do Aparelho Lacrimal , Deformidades Congênitas dos Membros , Escoliose , Sindactilia , Anormalidades Dentárias , Feminino , Humanos , Criança , Escoliose/genética , Perda Auditiva/genética , SíndromeRESUMO
Split-hand/foot malformation (SHFM) is a genetically heterogeneous congenital limb reduction defect characterized by the deficiencies of central rays of the autopod. Tandem duplications at 10q24 locus account for approximately 20% of all SHFM cases. Here, we report five affected individuals from four unrelated Indian families with SHFM3 caused by microduplication of 10q24 locus showing varied clinical presentations. This report substantiates and extends the current understanding of this rare, multifaceted, and complex condition.
Assuntos
Deformidades Congênitas do Pé , Deformidades Congênitas da Mão , Deformidades Congênitas dos Membros , Humanos , Deformidades Congênitas da Mão/diagnóstico , Deformidades Congênitas da Mão/genética , Deformidades Congênitas do Pé/diagnóstico , Deformidades Congênitas do Pé/genética , Índia/epidemiologia , Deformidades Congênitas dos Membros/diagnóstico , Deformidades Congênitas dos Membros/genética , LinhagemRESUMO
Coffin-Siris Syndrome (CSS, MIM 135900) is now a well-described genetic condition caused by pathogenic variants in the Bromocriptine activating factor (BAF) complex, including ARID1B, ARID1A, ARID2, SMARCA4, SMARCE1, SMARCB1, SOX11, SMARCC2, DPF2, and more recently, BICRA. Individuals with CSS have a spectrum of various medical challenges, most often evident at birth, including feeding difficulties, hypotonia, organ-system anomalies, and learning and developmental differences. The classic finding of fifth digit hypo- or aplasia is seen variably. ARID2, previously described, is one of the less frequently observed gene changes in CSS. Although individuals with ARID2 have been reported to have classic features of CSS including hypertrichosis, coarse facial features, short stature, and fifth digit anomalies, as with many of the other CSS genes, there appears to be a spectrum of phenotypes. We report here a cohort of 17 individuals with ARID2 variants from the Coffin-Siris/BAF clinical registry and detail their medical challenges as well as developmental progress. Feeding difficulties, hypotonia, and short stature occur often, and hip dysplasia appears to occur more often than with other genes, however more severe medical challenges such as significant brain and cardiac malformations are rarer. Individuals appear to have mild to moderate intellectual impairment and may carry additional diagnoses such as ADHD. Further phenotypic description of this gene will aid clinicians caring for individuals with this rarer form of CSS.
Assuntos
Anormalidades Múltiplas , Face/anormalidades , Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Pescoço , Pescoço/anormalidades , Fenótipo , Fatores de Transcrição , Humanos , Micrognatismo/genética , Micrognatismo/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Pescoço/patologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/diagnóstico , Masculino , Feminino , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Criança , Pré-Escolar , Lactente , Mutação/genética , Adolescente , Proteínas de Ligação a DNA/genética , Predisposição Genética para DoençaRESUMO
De novo germline variants of the SRY-related HMG-box 11 gene (SOX11) have been reported to cause Coffin-Siris syndrome-9 (CSS-9), a rare congenital disorder associated with multiple organ malformations, including ear anomalies. Previous clinical and animal studies have found that intragenic pathogenic variant or haploinsufficiency in the SOX11 gene could cause inner ear malformation, but no studies to date have documented the external ear malformation caused by SOX11 deficiency. Here, we reported a Chinese male with unilateral microtia and bilateral sensorineural deafness who showed CSS-like manifestations, including dysmorphic facial features, impaired neurodevelopment, and fingers/toes malformations. Using trio-based whole-exome sequencing, a de novo missense variant in SOX11 (NM_003108.4: c.347A>G, p.Y116C) was identified and classified as pathogenic variant as per American College of Medical Genetics guidelines. Moreover, a systematic search of the literature yielded 12 publications that provided data of 55 SOX11 intragenic variants affecting various protein-coding regions of SOX11 protein. By quantitatively analyzing phenotypic spectrum information related to these 56 SOX11 variants (including our case), we found variants affecting different regions of SOX11 protein (high-mobility group [HMG] domain and non-HMG regions) appear to influence the phenotypic spectrum of organ malformations in CSS-9; variants altering the HMG domain were more likely to cause the widest range of organ anomalies. In summary, this is the first report of CSS with external ear malformation caused by pathogenic variant in SOX11, indicating that the SOX11 gene may be not only essential for the development of the inner ear but also critical for the morphogenesis of the external ear. In addition, thorough clinical examination is recommended for patients who carry pathogenic SOX11 variants that affect the HMG domain, as these variants may cause the widest range of organ anomalies underlying this condition.
Assuntos
Anormalidades Múltiplas , Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Fatores de Transcrição SOXC , Humanos , Masculino , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Orelha Externa/anormalidades , Orelha Externa/patologia , Sequenciamento do Exoma , Face/anormalidades , Face/patologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Micrognatismo/genética , Micrognatismo/patologia , Micrognatismo/diagnóstico , Mutação de Sentido Incorreto/genética , Pescoço/anormalidades , Pescoço/patologia , Fenótipo , Fatores de Transcrição SOXC/genéticaRESUMO
Pathogenic variants of polycomb repressive complex-2 (PRC2) subunits are associated with overgrowth syndromes and neurological diseases. EZH2 is a major component of PRC2 and mediates the methylation of H3K27 trimethylation (H3K27me3). Germline variants of EZH2 have been identified as a cause of Weaver syndrome (WS), an overgrowth/intellectual disability (OGID) syndrome characterized by overgrowth, macrocephaly, accelerated bone age, intellectual disability (ID), and characteristic facial features. Germline variants of SUZ12 and EED, other components of PRC2, have also been reported in the WS or Weaver-like syndrome. EZH1 is a homolog of EZH2 that interchangeably associates with SUZ12 and EED. Recently, pathogenic variants of EZH1 have been reported in individuals with dominant and recessive neurodevelopmental disorders. We herein present sisters with biallelic loss-of-function variants of EZH1. They showed developmental delay, ID, and central precocious puberty, but not the features of WS or other OGID syndromes.
Assuntos
Deficiência Intelectual , Mutação com Perda de Função , Complexo Repressor Polycomb 2 , Puberdade Precoce , Humanos , Feminino , Complexo Repressor Polycomb 2/genética , Mutação com Perda de Função/genética , Puberdade Precoce/genética , Puberdade Precoce/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Criança , Alelos , Pré-Escolar , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Fenótipo , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Hipotireoidismo Congênito , Deformidades Congênitas da Mão , Anormalidades CraniofaciaisRESUMO
Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.
Assuntos
Fenótipo , Proteína Smad4 , Humanos , Feminino , Masculino , Criança , Adolescente , Proteína Smad4/genética , Pré-Escolar , Adulto , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Criptorquidismo/genética , Criptorquidismo/patologia , Massachusetts/epidemiologia , Adulto Jovem , Fácies , Transtornos do Crescimento/genética , Transtornos do Crescimento/patologia , Transtornos do Crescimento/epidemiologia , Genótipo , Hospitais Gerais , Pé Torto Equinovaro/genética , Pé Torto Equinovaro/patologia , Pé Torto Equinovaro/epidemiologia , Mutação/genética , Deformidades Congênitas da MãoRESUMO
Coffin-Siris syndrome is an autosomal dominant disorder with neurological, cardiovascular, and gastrointestinal symptoms. Patients with Coffin-Siris syndrome typically have variable degree of developmental delay or intellectual disability, muscular hypotonia, dysmorphic facial features, sparse scalp hair, but otherwise hirsutism and fifth digit nail or distal phalanx hypoplasia or aplasia. Coffin-Siris syndrome is caused by pathogenic variants in 12 different genes including SMARCB1 and ARID1A. Pathogenic SMARCB1 gene variants cause Coffin-Siris syndrome 3 whereas pathogenic ARID1A gene variants cause Coffin-Siris syndrome 2. Here, we present two prenatal Coffin-Siris syndrome cases with autosomal dominant pathogenic variants: SMARCB1 gene c.1066_1067del, p.(Leu356AspfsTer4) variant, and a novel ARID1A gene c.1920+3_1920+6del variant. The prenatal phenotype in Coffin-Siris syndrome has been rarely described. This article widens the phenotypic spectrum of prenatal Coffin-Siris syndrome with severely hypoplastic right ventricle with VSD and truncus arteriosus type III, persisting left superior and inferior caval vein, bilateral olfactory nerve aplasia, and hypoplastic thymus. A detailed clinical description of the patients with ultrasound, MRI, and post mortem pictures of the affected fetuses showing the wide phenotypic spectrum of the disease is presented.
Assuntos
Anormalidades Múltiplas , Face/anormalidades , Deformidades Congênitas da Mão , Deficiência Intelectual , Micrognatismo , Pescoço/anormalidades , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Face/patologia , FenótipoRESUMO
Patients with Aarskog-Scott syndrome (AAS) have short stature, facial anomalies, skeletal deformities, and genitourinary malformations. FYVE, RhoGEF, and PH domain-containing 1 (FGD1) is the only known causative gene of AAS. However, the diagnosis of AAS remains difficult, and specific treatments are still absent. Patients suspected with AAS were recruited, and clinical information was collected. Genetic testing and functional analysis were carried out for the diagnosis. By literature review, we summarized the clinical and genetic characteristics of FGD1-related AAS and analyzed the genotype-phenotype correlation. Five patients were recruited, and four novel FGD1 variants were identified. The diagnosis of AAS was confirmed by genetic analysis and functional study. Three patients treated with growth hormone showed improved heights during the follow-up period. By literature review, clinical features of AAS patients with FGD1 variants were summarized. Regarding FGD1 variations, substitutions were the most common form, and among them, missense variants were the most frequent. Moreover, we found patients with drastic variants showed higher incidences of foot and genitourinary malformations. Missense variants in DH domain were related to a lower incidence of cryptorchidism. Conclusion: We reported four novel pathogenic FGD1 variations in AAS patients and confirmed the efficacy and safety of growth hormone treatment in FGD1-related AAS patients with growth hormone deficiency. Additionally, our literature review suggested the crucial role of DH domain in FGD1 function. What is Known: ⢠Aarskog-Scott syndrome is a rare genetic disease, and the only known cause is the variant in FGD1 gene. The typical clinical manifestations of AAS include facial, skeletal, and urogenital deformities and short stature. What is New: ⢠We reported four novel FGD1 variants and reported the treatment of growth hormone in FGD1-related AAS patients. Our genotype-phenotype correlation analysis suggested the crucial role of DH domain in FGD1 function.
Assuntos
Anormalidades Múltiplas , Face , Doenças Genéticas Ligadas ao Cromossomo X , Genitália Masculina , Fatores de Troca do Nucleotídeo Guanina , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico , Nanismo/genética , Nanismo/diagnóstico , Nanismo/tratamento farmacológico , Face/anormalidades , Estudos de Associação Genética , Genitália Masculina/anormalidades , Fatores de Troca do Nucleotídeo Guanina/genética , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/diagnóstico , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/diagnóstico , Fenótipo , Dermatoses do Couro Cabeludo/genética , Dermatoses do Couro Cabeludo/diagnóstico , Dermatoses do Couro Cabeludo/tratamento farmacológico , Dermatoses do Couro Cabeludo/congênito , Anormalidades Urogenitais/genética , Anormalidades Urogenitais/diagnósticoRESUMO
BACKGROUND Congenital hypoplasia of the thumb type IV, also known as floating thumb, is a condition in which 2 small phalanges are attached to the hand with a thin skin bridge. Surgical management options for this condition vary from amputation to flap reconstruction. MATERIAL AND METHODS This retrospective study analyzed 11 infants with congenital hypoplasia of the thumb type IV who underwent surgical reconstruction using a modified vascularized polydactylous hallux flap. The study included 6 male and 5 female infants, aged 6 to 24 months. Functional evaluations and radiographic studies were conducted postoperatively. RESULTS All 11 patients underwent the complete surgical protocol. Successful vascular and nerve anastomoses were performed during the initial procedure, ensuring sufficient blood supply and neural connectivity to the transferred toes. The second operation showed promising outcomes, including improvements in thumb opposition, grasp strength, and overall function. Postoperative assessments demonstrated satisfactory radiographic alignment and no major complications during the follow-up period. CONCLUSIONS The modified vascularized polydactylous hallux flap reconstruction is a viable surgical option for managing congenital hypoplasia of the thumb type IV in infants. This technique effectively restores thumb opposition, grasp strength, and overall hand function, with satisfactory radiographic alignment and minimal complications. The study findings support the efficacy and safety of this surgical approach in addressing this rare congenital anomaly.
Assuntos
Procedimentos de Cirurgia Plástica , Retalhos Cirúrgicos , Polegar , Humanos , Polegar/anormalidades , Polegar/cirurgia , Polegar/diagnóstico por imagem , Masculino , Feminino , Estudos Retrospectivos , Lactente , Procedimentos de Cirurgia Plástica/métodos , Resultado do Tratamento , Pré-Escolar , Radiografia/métodos , Força da Mão/fisiologia , Deformidades da Mão/cirurgia , Deformidades Congênitas da Mão/cirurgia , Deformidades Congênitas da Mão/diagnóstico por imagemRESUMO
Alignment, longitudinal growth, and function of the musculoskeletal unit of the pediatric hand is complex due to the combination of open growth plates, ossification variations, and their relationship with finger tendinous and ligamentous attachments. This review presents the basics of normal development, acquired and congenital variations, and traumatic conditions of the pediatric hand from the perspective of the pediatric musculoskeletal radiologist and hand surgeon. This multimodality imaging article focuses on non-oncologic and non-rheumatologic conditions of the pediatric hand, inclusive of fingers, thumb, and metacarpal bones.
Assuntos
Traumatismos da Mão , Humanos , Criança , Traumatismos da Mão/diagnóstico por imagem , Mãos/diagnóstico por imagem , Deformidades Congênitas da Mão/diagnóstico por imagemRESUMO
Schinzel-Giedion syndrome (SGS) is a severe multisystem disorder characterized by distinctive facial features, profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies. SGS is attributed to gain-of-function (GoF) variants in the SETBP1 gene, with reported variants causing canonical SGS located within a 12 bp hotspot region encoding SETBP1 residues aa868-871 (degron). Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron. The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS. This is the first report of a typical SGS caused by a, SETBP1 non-degron missense variant. This case expands the genetic spectrum of SGS and provides new insights into genotype-phenotype correlations.
Assuntos
Anormalidades Múltiplas , Proteínas de Transporte , Deformidades Congênitas da Mão , Mutação de Sentido Incorreto , Unhas Malformadas , Humanos , Feminino , Anormalidades Múltiplas/genética , Proteínas de Transporte/genética , Recém-Nascido , Proteínas Nucleares/genética , Deficiência Intelectual/genética , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/complicações , Pé Torto Equinovaro/genética , Fenótipo , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/complicações , DegronsRESUMO
BACKGROUND: Wu et al. introduced a modified radiographic system that allows classification of all forms of CTD with excellent interobserver and intraobserver reliability. No study to date has evaluated the radiographic characteristics of Wu et al. type C3 CTD with osseous attachment at the level of the metacarpal. OBJECTIVE: This study aimed to evaluate the radiographic features of type C3 CTD according to the system of Wu et al., to describe the different anatomical subtypes of the duplication, and to propose a categorization approach to distinguish diverse surgical strategies based on the radiographic anatomy of this specific subtype of duplication. METHODS: We performed a retrospective analysis of 215 patients (221 thumbs) diagnosed with Wu et al. type C3 CTD at our Institution between 2015 and 2021. We evaluated all CTDs by examining the alignment of the interphalangeal (IP) and metacarpophalangeal (MP) joints and by assessing the presence of abnormal hypertrophic epiphysis of the primary thumb on posteroanterior (PA) radiographs. The proposed classification system has four types: Type I with good alignment of both MP and IP joints, Type II with ulnar deviation of the MP joint, Type III with radial deviation in the MP joint and Type IV with abnormal hypertrophic epiphysis of the distal phalanx of the main thumb with ulnar deviation of the IP joint with or without ulnar deviation of the MP joint. RESULTS: There were 140 male and 75 female patients with CTD (221 thumbs). There were 65 left, 144 right and 6 bilateral forms. The right-to-left, male-to-female and unilateral-to-bilateral ratios were 2.2:1, 1.9:1 and 35.8:1 respectively. The mean age at surgery was 22.3 ± 11.8 months (range, 8-80). The proposed classification system allowed the classification of all CTDs (n = 221). Specifically, 53 fingers were classified as Type I (24%), 136 as Type II (61.5%), 21 as Type III (9.5%), and 11 as Type IV (5%). CONCLUSION: The proposed system is based on radiographic pathoanatomy and complements that of Wu et al. by identifying four distinct subtypes of deformity. It has the potential to improve inter-professional communication and guide surgery in patients with Wu et al. type C3 CTD. However, our results are preliminary and further research is needed to validate them. LEVEL OF EVIDENCE: III.
Assuntos
Polegar , Humanos , Polegar/anormalidades , Polegar/diagnóstico por imagem , Polegar/cirurgia , Feminino , Masculino , Estudos Retrospectivos , Criança , Pré-Escolar , Lactente , Radiografia , Reprodutibilidade dos Testes , Deformidades Congênitas da Mão/diagnóstico por imagem , Deformidades Congênitas da Mão/classificação , Deformidades Congênitas da Mão/cirurgia , Articulação Metacarpofalângica/diagnóstico por imagem , Articulação Metacarpofalângica/cirurgia , Articulação Metacarpofalângica/anormalidadesRESUMO
Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons (SPNs). SPNs, strategically positioned at the interface of cortical gray and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pancortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate axon-thalamocortical axon cofasciculation ("handshake"), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.