Generation of a human induced pluripotent stem cell line from a CHARGE syndrome patient with CHD7 mutation (c.3982C>T).

CHARGE syndrome is a heterogeneous genetic disorder with an evolving phenotype, particularly in adults. This study examined whether dysautonomic symptoms are common in adolescents and adults with CHARGE syndrome. Adolescents and adults with CHARGE syndrome completed a CHARGE-specific checklist and modified items from COMPASS-31 with the cardiovascular items from the ASP to assess dysautonomic symptoms. Participants were 25 individuals (20 female, 5 male), aged 12-33 years (mean = 21.3 years), with clinically confirmed diagnoses, 16 of whom had a CHD7 mutation. Dysautonomic symptoms were common: 50%-60% reported fatigue, heat intolerance, constipation, nausea, and headaches; 40%-50% reported postural tachycardia, tachycardia, dyspnea, weakness, exercise intolerance, and anxiety. These rates appear at a high frequency. A detailed case study of one participant is included in the supplemental material. Findings suggest dysautonomia may be prevalent in individuals with CHARGE syndrome and highlight the need for greater awareness of symptoms and triggers. Interventions such as vagal nerve stimulation may help restore autonomic balance and improve quality of life.

This study aimed to report a 10-year single-centre experience of cochlear implantation in children with CHARGE syndrome (manifests as coloboma, heart defects, atresia of the choanae, growth retardation and genital and ear anomalies) and evaluate surgical strategies and outcomes. Children with CHARGE syndrome who underwent cochlear implantation between 2014 and 2024 were retrospectively reviewed. Patient characteristics and post-operative auditory outcomes were analysed. Six patients (nine ears) were included. Most had airway anomalies, one-third required post-operative intensive care. Temporal bone malformations were present in 78 per cent of ears. Standard posterior tympanotomy was feasible in one-third; the remainder required transcanal or combined approaches. Full-electrode insertion was achieved in all ears. Median follow-up was 3.4 years; aided thresholds ranged 25 to 50 dB hearing level. Three patients developed reliable open-set speech perception, two achieved closed-set recognition and one demonstrated environmental sound awareness. Cochlear implantation provides meaningful auditory benefit in selected children with CHARGE syndrome. Pre-operative cochlear nerve imaging, flexible surgical planning and coordinated peri-operative airway management are essential.

Generation of induced pluripotent stem cells from a patient with CHARGE syndrome with athymia, harboring a heterozygous mutation in CHD7.

Importance of Preoperative Radiological Airway Assessment in Children with Charge Syndrome: An Anaesthetic Perspective

Olfactory dysfunction (OD) is an underrecognized feature of CHARGE syndrome (CS), often associated with CHD7 mutations and structural anomalies of the olfactory system. This systematic review examines the burden, assessment methods, and clinical correlates of OD in CS. A systematic review was conducted in accordance with PRISMA guidelines and registered with PROSPERO (CRD420251040500). A comprehensive search of six databases up to May 2025 was performed. Two independent reviewers screened, extracted data, and assessed study quality. A narrative synthesis was performed. From 1,643 records, 16 studies met inclusion criteria. Most were retrospective cohort studies and employed clinical diagnostic criteria for CS, with a subset reporting CHD7 mutation data. OD was most frequently identified radiologically. Psychophysical testing and self/parent reports were less common. Neurodevelopmental delays, feeding/swallowing issues, and reduced quality of life were reported in association with OD, but causal relationships remain unclear. OD is highly prevalent in CS, often exceeding 80%, yet remains underrecognized. Radiologic imaging and electrophysiological techniques may be alternatives when psychophysical testing is not feasible. Future research should focus on validating paediatric-specific and developmentally appropriate olfactory assessments and integrating olfaction into quality-of-life frameworks. OD should be considered for inclusion in revised CHARGE diagnostic criteria.

Genetic variants of CHD7, encoding a chromatin remodeler, lead to CHARGE syndrome with congenital deficits in multiple organs. One crucial unsolved question is the causal mechanisms of most protein-altering variants of CHD7. One hypothesis is that these variants impair the enzymatic activity of CHD7, that is ATPase and nucleosome remodeling activities. Herein, we compared the phenotype of two new mouse models for CHARGE syndrome in parallel, with the Dppa3-cre/Chd7f/+ line carrying a Chd7 truncation variant and the Chd7S824F/+ line carrying an enzymatic-deficient missense variant. While the Dppa3-cre/Chd7f/+ line displayed typical disease-relevant phenotypes of CHARGE syndrome as other reported lines, some of these phenotypes, such as body growth and circling behavior, were surprisingly mild in the ATPase-deficient Chd7S824F/+ mouse line. Thus, our results demonstrated the different contribution of the enzymatic activity of CHD7 in growth and organogenesis.

The clinical features of neurocristopathy-related hearing loss, and the correlation between these features and patient improvements after cochlear implantation (CI) are unknown. This study enrolled 16 children with sensorineural hearing loss due to four types of neurocristopathies, Waardenburg syndrome (WS), Noonan syndrome (NS), Kabuki syndrome (KS), and CHARGE syndrome (CS), who underwent CI. Neurodevelopmental assessment was conducted using the Gesell Developmental Schedules, ear development was evaluated using temporal bone computed tomography, and the post-CI auditory nerve response was assessed via neural response telemetry. Auditory performance was evaluated using the categories of the auditory performance scale. Genetic features were examined using whole-exome sequencing. WS/NS Groups achieved excellent auditory-speech outcomes (CAP_3 year/SIR_3 year: WS 7.3/4.0 n = 3, NS 8.0/4.0 n = 1), using Categories of Auditory Performance (CAP) and Speech Intelligibility Rating (SIR), with minimal impact from SOX10 (WS) or PTPN11 (NS) mutations on neurodevelopment. CS Group showed poor recovery (CAP_3 year/SIR_3 year: 3.3/1.8 n = 3) due to CHD7-related cochlear nerve dysplasia and central auditory deficits, Gesell_mean showed a significant positive correlation with CAP_1 year (ρ = 0.83 n = 6 p = 0.042), CAP_3 year was significantly correlated with both implantation CI_age_mon and Gesell_mean independently (ρ = 1.0, n = 3, p < 0.001). Non-CS Groups(WS/NS/KS)showed older CI_age_mon predicted higher 1-year SIR (ρ = 0.77 n = 10 p = 0.009), while structural abnormalities (abnormal_sum) trended toward worse 3-year SIR (ρ=-0.79 n = 5). The integration of genetic, ear structure, and neurodevelopmental assessments can assist in clinical decision making for CI.

Butyrate modifies epigenetic and immune pathways in peripheral mononuclear cells from children with neurodevelopmental disorders associated with chromatin dysregulation.

Abstract Ependymoma in children is rarely associated with pathogenic germline variants. We describe co-occurrence of posterior fossa group A ependymoma, constitutional KMT2D (MLL2) variant of unknown clinical significance (VUS), and congenital solitary kidney in a child. KMT2D encodes a histone methyltransferase. Its constitutional loss-of-function variants are associated with Kabuki syndrome Type 1. A healthy 3-year-old identical twin boy presented with headache, ataxia, dysphagia and dysarthria. Brain MRI revealed calcified right-sided posterior fossa mass. Spine MRI showed solitary right kidney. His identical twin also had solitary right kidney. Tumor was partially resected. Pathology showed posterior fossa group A ependymoma with loss of H3K27me3 trimethylation and EZHIP expression. OncoKids somatic panel showed VUSs in KMT2D (NM_003482.3: c.7490C&amp;gt;T, p.Ala2497Val) and CHD7 (NM_017780:c.2830C&amp;gt;T, p.Arg944Cys) at variant allele frequencies of 49%. Targeted Sanger sequencing of blood demonstrated that the KMT2D variant was of germline origin. Germline testing for the CHD7 variant was not performed, but also presumed germline. Patient did not have overt features suggestive of Kabuki or CHARGE syndromes. KMT2D is implicated in neural crest cell development and migration. Loss of function variants in KMT2D are associated with autosomal dominant Kabuki syndrome affecting multiple systems including renal and cerebellar anomalies. To date, KMT2D Ala2497Val has not been linked to Kabuki syndrome. Case reports have associated various cancers with Kabuki syndrome, including one report of a spinal ependymoma, suggesting a cancer predisposition. CHD7 is also required for renal and cerebellar development. Germline variants of CHD7 are associated with CHARGE syndrome. The KMT2D and CHD7 variants are not predicted to reach pathogenic classification on their own. However, variants in both genes may contribute to cancer and syndromic disorders with renal and cerebellar anomalies. We posit that the combination of both variants contributed to this patient’s ependymoma and congenital solitary kidney. Additional studies are required to confirm this.

CHARGE syndrome is a rare congenital disorder characterized by a spectrum of anomalies, including coloboma, heart defects, choanal atresia, and ear abnormalities. Spinal deformities, particularly scoliosis, are frequently observed and may significantly impair quality of life by limiting pulmonary function, reducing mobility, and increasing pain. This study provides the first comprehensive evaluation of scoliosis management and outcomes in CHARGE syndrome, assessing both surgical and nonsurgical approaches. An international multicenter registry was queried to identify patients with a confirmed diagnosis of CHARGE syndrome and scoliosis. Demographic, clinical, and radiographic data were collected. Complications were categorized using the modified Clavien-Dindo-Sink system. Patient-reported outcomes were assessed using the EOSQ-24 and compared with a normative syndromic early-onset scoliosis cohort. Eleven patients were identified: 5 underwent growth-friendly surgery (2 TGR, 1 VEPTR, and 2 MCGR), of which 3 progressed to fusion; 3 had primary fusion; and 3 were braced. Growth-friendly surgery reduced the average major curve from 74 to 49 degrees postoperatively, but this correction regressed over time, with major curves averaging 58 degrees at 5 years. In contrast, fusion provided more stable outcomes, reducing major curve from 54 degrees pre-fusion to 36 degrees at 2 years postoperatively. Four complications were reported in 2 of 8 surgical patients, yielding an instrument-related complication rate of 25%. All complications occurred after growth-friendly procedures and included hardware dislodgement and rod fractures. EOSQ-24 scores were similar to other syndromic cohorts across most domains. Scoliosis in CHARGE syndrome is frequently severe and may require surgical intervention. While growth-friendly implants offer initial deformity correction, the benefit tends to diminish over time-potentially influenced by atypical growth patterns in CHARGE patients. Spinal fusion demonstrated greater long-term stability and a lower complication burden. The 25% complication rate observed in this cohort exceeds rates reported in other syndromic scoliosis populations, emphasizing the need for tailored perioperative planning for this population. Larger studies are needed to guide optimal treatment strategies in this complex patient population. Level IV-retrospective case series.

To analyze the clinical phenotype and genetic basis of four children with CHARGE syndrome. A retrospective analysis was conducted on four children diagnosed with CHARGE syndrome at Xiamen Children's Hospital from May 2019 to May 2025. Peripheral venous blood samples were collected from the children and their parents and subjected to trio-whole exome sequencing. Candidate variants were verified by Sanger sequencing. Online tools were used for the conservation analysis and protein structure prediction. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2024-126). The four children have included two neonates, one infant and one child, with their age at the initial diagnosis ranging from 16 days after birth to 11 years old. Their initial manifestations were not typical of CHARGE syndrome. All children were found to harbor missense variants of the CHD7 gene, including c.3059T>C (p.L1020S), c.3302G>A (p.C1101Y), c.5879C>T (p.S1960F) and c.8093C>T (p.S2698L). Sanger sequencing confirmed that two were de novo variants, and two were inherited from their parents. In child 1, the leucine at position 1020 was highly conserved, and the p.L1020S variant did not alter the spatial structure and hydrogen bond connections of the CHD7 protein, though the shape of the binding cavity and the number and distribution of binding probe clusters have changed. In child 4, an unreported variant in the epilepsy gene SCN9A (c.2152T>C, p.Y718H) was detected, along with bilateral lower limb deformities. Literature review suggested that missense variants of the CHD7 gene were most common (32.1%) among the Chinese population, whilst nonsense variants had the highest lethality rate (41.2%) in neonates. Variants of the CHD7 gene probably underlay the pathogenesis in the four children. Changes in the binding sites and binding cavity morphology play an important role in CHARGE syndrome. The types of genetic variants in CHARGE patients may vary between different regions and races.

Objectives: Children with congenital anomalies of the posterior segment of the eye are in the process of visual development, and thus, their refractive errors should be detected by cycloplegic refraction testing to prescribe full-correction glasses, if required, and to help their visual acuity develop with growth. This study aimed to review refractive correction in children with congenital ocular fundus anomalies.Methods: A retrospective review was conducted on 18 consecutive children (11 female and seven male children) who were diagnosed with ocular fundus anomalies and followed for 10 years or more by a single ophthalmologist at a referral-based hospital. The age at the initial visit ranged from 10 days after birth to 11 years, with a median of one year and four months, and the age at the last visit ranged from 10 to 32 years, with a median of 15 years. The follow-up periods ranged from 10 to 21 years at a median of 15 years.Results: The diagnoses were familial exudative vitreoretinopathy (FEVR) in eight children, persistent fetal vasculature (PFV) in five, morning glory disc anomaly in two, optic nerve and choroidal coloboma (CHARGE syndrome) in two, and Coats disease in one. Full-correction glasses were prescribed in eight children, while the remaining 10 children did not wear glasses. Among nine children with the uncorrected visual acuity of 1.0 or better in one eye and the visual acuity in the other eye ranging from light perception to 0.01, eight children did not wear glasses, and one child wore glasses with hyperopic correction. The diagnoses in these nine children were PFV in five children, morning glory disc anomaly in two, FEVR in one, and Coats disease in one. In seven children who wore full-correction glasses, the best corrected visual acuity in the better eye ranged from 0.2 to 0.9 at a median of 0.5. In contrast, the visual acuity in the other eye ranged from light perception to 0.1 at a median of 0.03. The diagnoses of these seven children were FEVR in five children and CHARGE syndrome in two. The five children with FEVR showed myopic astigmatism in both eyes, while the two children with CHARGE syndrome showed hyperopic astigmatism in both eyes.Conclusion: Children with unilateral eye anomalies such as PFV and morning glory disc anomaly did not wear glasses since their healthy eyes had good uncorrected visual acuity. In contrast, children with involvement of both eyes in FEVR and CHARGE syndrome wore full-correction glasses. Rough information regarding full-correction glasses in each category would help clinicians cope with rare congenital eye diseases. However, this conclusion is generally applicable to the standard practice of pediatric ophthalmology.

CHD7 and CHD8 are chromatin remodeling proteins that regulate several neurodevelopmental events. Mutations in these chromatin remodeling genes occur in neurodevelopmental disorders including CHARGE Syndrome and Autism Spectrum Disorders. Kismet (Kis) is the sole Drosophila homolog of CHD7 and CHD8. We investigated the possibility that Kis influences retrograde synaptic signaling given that Kis restricts the synaptic levels of several cell adhesion molecules and facilitates endocytosis. Our data indicate that Kis restricts synaptic pMad while facilitating the localization of pMad to presynaptic motor neuron nuclei. While the increase in pMad at kis mutant synapses may contribute to the loss of Endophilin B, it may not influence the mislocalization of glutamate receptors relative to active zones or the locomotor phenotypes observed in kis mutants. Kis may antagonize Polycomb Repressive Complex 2 (PRC2) signaling to restrict synaptic pMad. Kis, including its chromatin remodeling/ATPase activity, is required in presynaptic motor neurons for proper synaptic pMad levels. In contrast, an ATPase-deficient Kis can rescue synaptic pMad when expressed in all tissues. Similarly, expression of human CHD7 in all tissues of kis mutants rescues synaptic pMad. Our data suggest a model where Kis restricts synaptic pMad both by transcription-dependent and transcription-independent mechanisms. These data may aid in a better understanding of the importance of chromatin remodeling for synaptic structure and function and the molecular changes correlated with neurodevelopmental disorders.

CHARGE syndrome is an autosomal dominant disorder caused by variations in the CHD7 gene. The characteristic findings of the syndrome include coloboma (C), heart anomalies (H), choanal atresia (A), growth and developmental delay (R), genitourinary system anomalies (G), and ear anomalies and/or hearing loss (E). A 7.7-years-old male patient was initially referred after a partial empty sella appearance was noted on brain imaging during evaluation for developmental delay at 10 months of age. He had undergone surgery for choanal atresia and congenital heart disease. The patient exhibited severe postnatal growth retardation, hypertelorism, epicanthal folds, cleft palate, a thin upper lip, bilateral ear anomalies, preaxial polydactyly, and bilateral undescended testes. He had motor and mental developmental delay. Ophthalmologic examination showed retinal atrophy and coloboma. Genetic analysis identified a novel heterozygous c.5050+2T>C variant in intron 22 of the CHD7 gene, confirming the diagnosis of CHARGE syndrome. Furthermore, the patient had undergone bilateral orchiopexy at two years of age, and growth hormone therapy was initiated after a diagnosis of complete growth hormone deficiency at 19 months of age. A novel heterozygous variant in the CHD7 gene was identified in a patient, who presented with classical signs of CHARGE sydrome. Early recognition and diagnosis is important to enable initiation of timely treatment of potential complications associated with the disorder.

Bilateral vestibular hypofunction in children.

Trends in U.S. National Institutes of Health Funding for CHARGE Syndrome Research, 2000 to 2024.

CHARGE syndrome is a developmental disorder that affects 1 in 10,000 births, and patients exhibit both physical and behavioral characteristics. De novo mutations in CHD7 (chromodomain helicase DNA binding protein 7) cause 67% of CHARGE syndrome cases. CHD7 is a DNA-binding chromatin remodeler with thousands of predicted binding sites in the genome, making it challenging to define molecular pathways linking loss of CHD7 to CHARGE phenotypes. To address this problem, here we used a previously characterized zebrafish CHARGE model to generate transcriptomic and proteomic datasets from larval zebrafish head tissue at two developmental time points. By integrating these datasets with differential expression, pathway, and upstream regulator analyses, we identified multiple consistently dysregulated pathways and defined a set of candidate genes that link loss of chd7 with disease-related phenotypes. Finally, to functionally validate the roles of these genes, CRISPR/Cas9-mediated knockdown of capgb, nefla, or rdh5 phenocopies behavioral defects seen in chd7 mutants. Our data provide a resource for further investigation of molecular mediators of CHD7 and a template to reveal functionally relevant therapeutic targets to alleviate specific aspects of CHARGE syndrome.

IntroductionBalanced chromosomal abnormalities (BCAs) are structural variations that can underlie a wide spectrum of neurodevelopmental disorders, often remaining undetected by conventional diagnostic approaches. Whole-genome sequencing (WGS) allows for base-pair resolution of structural variants across the entire genome, making it a powerful tool to detect cryptic chromosomal rearrangements and refine breakpoint mapping. RNA sequencing (RNA-Seq), by enabling the detection of gene expression changes and fusion transcripts, provides complementary functional insights into the consequences of genomic alterations. This study integrated WGS and RNA-Seq to precisely characterize the breakpoints and assess the functional impact of de novo BCAs in two unsolved cases of Neurodevelopmental Disorders.Materials and methodsShort read WGS was used to identify the chromosomal breakpoints and gene disruptions caused by BCAs. RNA-Seq on blood RNA was employed to detect differential gene expression and potential fusion transcripts of disrupted genes.ResultsIn the first case, the inversion inv(8) (p11.2q13) disrupted two genes at the breakpoints, namely, CHD7 and SLC20A2. These genes are in opposite orientations, and the inversion realigned them in the same direction, generating two novel fusion genes. Disruption of CHD7 confirmed the suspected diagnosis of CHARGE syndrome. The interruption of SLC20A2, commonly associated with neurological symptoms, prompted further clinical evaluation. RNA-Seq identified in-frame fusion transcripts from the chimeric genes in the blood, suggesting a potential deleterious phenotypic effect. In the second case, WGS revealed a balanced translocation t(17; 22) (q25; q13) that disrupted EP300 at 22q25, confirming Rubinstein-Taybi syndrome. The concurrent disruption of RBFOX3 at 17q13 suggested additional neurological implications, particularly related to epilepsy. Transcriptomic analysis demonstrated the monoallelic and significantly reduced expression of EP300.ConclusionThese findings highlight the crucial role of WGS in identifying disease-associated BCAs and underscore the complementary value of RNA-Seq in assessing their functional consequences. This integrated approach enhanced diagnostic accuracy and clinical management, paving the way for more comprehensive and personalized care in these two patients.

CHARGE syndrome is a rare, complex congenital disorder caused predominantly by mutations in the CHD7 gene, characterized by a multisystem involvement including Coloboma, Heart defects, Atresia of the choanae, Retardation of growth and development, genital anomalies, and ear abnormalities. Each patient presents a unique spectrum of anomalies, posing significant challenges for perioperative management. This case report presents the perioperative anaesthetic management of a 5 year old male child with genetically confirmed CHARGE syndrome (CHD7 mutation: c.6213delA) scheduled for full mouth rehabilitation under general anaesthesia. The child presented with multiple classical features including bilateral coloboma, atrial septal defect (ASD), bilateral sensorineural hearing loss, retrognathia, and global developmental delay. Given the known association with choanal atresia, nasal patency was assessed preoperatively. Airway examination revealed retrognathia and high arched palate, raising concerns for difficult intubation. A multidisciplinary strategy was planned. Inhalational induction with sevoflurane was used to preserve spontaneous ventilation, followed by intravenous propofol and atracurium to ensure smooth intubation while maintaining hemodynamic stability. Anticipating airway difficulty, nasal intubation was performed using a C-MAC video laryngoscope. Intraoperative management emphasized normothermia and normocapnia to ensure cerebral and hemodynamic stability. The surgery proceeded uneventfully, and the child recovered without complications. This case highlights the importance of a tailored, pathophysiology-driven anaesthetic plan and interdepartmental coordination in managing syndromic children. Key takeaways include early identification of airway and systemic risks, detailed preoperative planning, and the use of advanced airway tools to ensure safe outcomes in pediatric patients with complex congenital anomalies. Keywords: CHARGE syndrome; congenital heart defects; CHD7 mutation; general anesthesia; difficult airway