Lynne M. Bird

Meier‐Gorlin syndrome (MGORS) is a rare primordial dwarfism syndrome characterized by the triad of pre‐ and postnatal growth restriction, microtia, and patellar aplasia or hypoplasia. Pathogenic variants in genes involved in DNA replication licensing and initiation have been implicated in MGORS, including the uncommon disease‐associated gene CDC6 , for which only two affected families have been reported to date. We report a male infant born at 37 weeks' gestation to a 40‐year‐old primigravida via cesarean delivery due to intrauterine growth restriction and fetal intolerance of labor. He presented with severe proportionate short stature (40 cm at birth; Z score −5.22), microcephaly, bilateral microtia, cryptorchidism, hypospadias, nonpalpable patellae, and characteristic facial features including a tiny mouth and short palpebral fissures. Cardiac evaluation was normal. He developed persistent respiratory insufficiency requiring prolonged respiratory support and remains hospitalized due to tracheobronchomalacia and chronic respiratory failure. A clinical diagnosis of MGORS was suspected. Targeted gene panel testing identified a heterozygous variant in CDC6 , c.920_927del (p.Ser307ThrfsTer9). Trio genome sequencing subsequently identified a second rare intronic variant, CDC6 c.461‐24A>G, and confirmed that the variants were in trans . A minigene splicing assay demonstrated retention of intron 3 associated with c.461‐24A>G, resulting in a predicted frameshift, p.Thr155LeufsTer8, and likely nonsense‐mediated decay. We report the third family with CDC6‐associated MGORS and provide functional evidence supporting the pathogenicity of a novel intronic CDC6 variant. These findings expand the mutational spectrum of CDC6 ‐related MGORS and highlight the importance of functional studies in the interpretation of noncanonical splice variants.

We provide a comprehensive phenotypic characterization of loss-of-function (LoF) variants in WDFY3 based on the largest cohort reported to date ( n = 32). Our findings define a monogenic disorder marked by neuropsychiatric features (including autism and ADHD), mild to moderate neurodevelopmental delay, and variable brain growth – most commonly macrocephaly and in one case reduced head circumference. To investigate the effect of WDFY3 LoF we performed knockdown (KD) in the human neuroblastoma cell line SH-SY5Y and used a Wdfy3 -haploinsufficient mouse model. WDFY3 KD impaired clearance of protein aggregates and decreased protein levels of the ubiquitin-binding protein p62. Transcriptomic analyses identified dysregulation in gene networks that are primarily involved in nervous system development, neuron projection, MAPK/ERK1/2, and WNT/β-catenin signaling. This was confirmed at protein level. Neuronal cell proliferation was increased, as evidenced by elevated cell counts and proliferation markers Ki-67 and PCNA . Conversely, neuronal cell differentiation was impaired, as indicated by reduced neurite outgrowth. We show that β-catenin is downregulated, while GSK3B is upregulated. LiCl activates WNT/β-catenin signaling by inhibiting GSK3B. We thus tested LiCl treatment, which significantly increased WDFY3 expression. Moreover, in vitro treatment improved the neurite branching capacity of Wdfy3 -haploinsufficient neurons above the level of the wild type, although this specific effect appeared independent of WNT/β-catenin signaling. In sum, we expand on the phenotype related to WDFY3 LoF and provide insights into the pathophysiology using in vitro human and murine neuronal models. Our findings suggest that LiCl may serve as a potential therapeutic strategy for patients with WDFY3 LoF variants.

CHARGE syndrome (OMIM #214800) is an autosomal dominant disorder caused by mutations in the CHD7 gene in most cases. Although originally defined by the CHARGE acronym (coloboma, heart defects, choanal atresia, growth restriction, genital hypoplasia, and ear anomalies), the recognized phenotype has expanded considerably to include highly prevalent manifestations such as cranial nerve dysfunction, vestibular anomalies, feeding and gastrointestinal complications, endocrine abnormalities, and musculoskeletal involvement. Skeletal abnormalities have been described previously; however, the frequency, spectrum, and clinical significance of spinal abnormalities remain incompletely characterized and are likely underrecognized. We conducted a retrospective review of 54 individuals with CHARGE syndrome to characterize spinal involvement and evaluate implications for management. Skeletal imaging was available in 40 of the 54, among whom abnormalities demonstrated considerable phenotypic heterogeneity, highlighting the importance of systematic musculoskeletal evaluation. Skeletal abnormalities were identified in 70% of individuals and included vertebral segmentation defects, intervertebral disc space narrowing, rib anomalies, and scoliosis. Scoliosis or kyphosis of any degree was present in 60% of the imaged individuals. Cervical spine involvement was identified in 43%. Two individuals (4%) were found to have os odontoideum , one of whom developed clinically significant atlantoaxial instability requiring surgical stabilization. Osteopenia was identified in 33% of individuals. Our findings further support previous reports demonstrating that spinal abnormalities are common in CHARGE syndrome while identifying os odontoideum as a previously unrecognized cervical spine manifestation with important clinical implications. Given that neuroimaging is frequently performed in CHARGE syndrome for evaluation of inner ear and cranial nerve abnormalities, careful assessment of the cervical spine during these studies may facilitate early recognition of clinically significant abnormalities without substantially increasing imaging burden. Our findings also emphasize the importance of longitudinal orthopedic surveillance, proactive bone health management beginning in childhood, and multidisciplinary care incorporating rehabilitation strategies to optimize long‐term musculoskeletal outcomes.

Purpose: This study examined longitudinal trajectories of adaptive functioning in 331 individuals with Angelman syndrome (AS) using the Vineland Adaptive Behavior Scales, Third Edition (Vineland-3) and examined differences by molecular subtype. Methods: A total of 331 individuals (156 females, 47%) with genetically confirmed AS (ages 6 months to 52 years) were assessed between 2018 and 2025, including 207 with a deletion subtype, 63 with uniparental disomy or imprinting defect, and 61 with a UBE3A point mutation. Growth scale values were analyzed using linear mixed-effects models with log ₂ -transformed age. Results: Individuals with deletion subtypes demonstrated significantly lower adaptive functioning across domains compared to those with non-deletion subtypes. Adaptive skills across all Vineland-3 subdomains increased nonlinearly with age, showing faster growth early in life that slowed over time, with largely parallel trajectories across subtypes. Conclusion: Individuals with AS demonstrate slow but steady growth in adaptive functioning that continues into adulthood, with progress varying by molecular subtype. These findings provide updated natural history benchmarks and demonstrate the utility of the Vineland-3 for clinical trials.

Background: Epilepsy is a core feature of Angelman syndrome (AS) and a major contributor to morbidity and caregiver burden. The current study provides updated caregiver-reported data on seizure characteristics, triggers, and management in AS.Methods: Caregivers of 130 individuals with AS enrolled in the Linking Angelman and Dup15q Data for Expanded Research (LADDER) Database completed an online questionnaire assessing seizure characteristics, age at first seizure and diagnosis, perceived triggers, and management strategies. Participants were grouped by molecular subtype (deletion vs. non-deletion). Descriptive statistics and group comparisons were conducted.Results: Seizures were more frequently reported in individuals with deletion subtypes compared to those with non-deletion subtypes. The most common seizure-related manifestations (myoclonic, atonic, and atypical absence features) did not differ between groups. Individuals with deletion subtypes experienced earlier epilepsy diagnosis than those with non-deletion subtypes, though age at first seizure prompting medical attention did not differ significantly between the groups. About half of caregivers were unsure of seizure triggers; among identified triggers, illness or infection with a fever was most common. Pharmacological treatment was the primary management approach, with levetiracetam most frequently reported. Side effects were the most common reason for medication discontinuation, and only 69% of caregivers reported access to or use of an acute seizure rescue medication.Conclusions: Caregiver-reported data from the LADDER Database provide an updated characterization of seizures in AS. Gaps in trigger identification and availability or use of rescue medications highlight opportunities to improve standard-of-care implementation in AS.

The KDM2B ‐related neurodevelopmental disorder is a recently identified Mendelian disorder of the epigenetic machinery associated with pathogenic variants in KDM2B . Global developmental delay, intellectual disability, congenital anomalies, and systemic manifestations characterize the disorder. Variants in KDM2B that primarily affect the CxxC DNA‐binding domain are strongly linked to a specific epigenetic signature. We present three children with KDM2B ‐related neurodevelopmental disorder, each with a heterozygous variant in the CxxC domain of KDM2B . Patient 1 is a 2‐year‐old boy with developmental delay, solitary kidney, atrial septal defect, feeding difficulties, hemangiomas, and myopic astigmatism. Patient 2 is a 2‐year‐old girl with global developmental delay, hip dysplasia, feeding difficulties, hemangiomas, and myopic astigmatism. Patient 3 is a 5‐year‐old girl with autism, developmental delay, atrial septal defect, and ventricular septal defect, hypertrichosis, atopic dermatitis, and myopic astigmatism. Genetic analysis revealed a variant in KDM2B in each patient. Targeted methylation analysis for the epigenetic signature associated with the KDM2B ‐related syndrome revealed an abnormal methylation pattern consistent with a positive epigenetic signature of the disorder in individuals 2 and 3. These results provided supportive functional evidence for KDM2B ‐related neurodevelopmental disorder in the context of the clinical findings and KDM2B variants. Our findings emphasize the value of integrating genomic and epigenomic analyses for variant interpretation. This case series reinforces the consistent phenotype of KDM2B ‐related neurodevelopmental disorder and highlights ocular and dermatologic manifestations as recurring features in affected individuals.