Germline variants that disrupt components of the epigenetic machinery cause syndromic neurodevelopmental disorders. Using exome and genome sequencing, we identified de novo variants in KDM2A, a lysine demethylase crucial for embryonic development, in 18 individuals with developmental delays and/or intellectual disabilities. The severity ranged from learning disabilities to severe intellectual disability. Other core symptoms included feeding difficulties; growth issues, such as intrauterine growth restriction, short stature, and microcephaly; and recurrent facial features, such as epicanthic folds, upslanted palpebral fissures, thin vermillion of the lips, and low-set ears. Expression of human disease-causing KDM2A variants in a Drosophila melanogaster model led to neural degeneration, motor defects, and reduced lifespan. Interestingly, pathogenic variants in KDM2A affected physiological attributes, including subcellular distribution, expression, and stability in human cells. Genetic epistasis experiments indicated that KDM2A variants act via a dual mechanism-loss of nuclear function for some variants tested and additional cytoplasmic gain-of-function toxicity for c.704C>T (p.Pro235Leu), as eliminating endogenous Drosophila Kdm2 did not produce noticeable neurodevelopmental phenotypes. Data from enzymatic-methylation sequencing support the suggested gene-disease association by showing aberrant methylome profiles in affected individuals' peripheral blood. Combining our genetic, phenotypic, and functional findings, we establish de novo variants in KDM2A as causative for a syndromic neurodevelopmental disorder.

O'Donnell-Luria-Rodan syndrome (ODLURO) is a rare disorder caused by a pathogenic variant in KMT2E and associated with intellectual disability. To date, the neurobehavioral phenotype of this disorder remains elusive. Here, we aimed to characterize the cognitive and behavioral profiles associated with ODLURO and compare the trends with those of other disorders associated with epigenetic regulation of gene expression at H3K4, Wiedemann-Steiner syndrome (WDSTS) and Kabuki syndrome type 1 (KABUK1). Findings show prominent behavioral features in ODLURO include problems with anxiety (33%), attention (67%), and executive function (50%) (working memory, cognitive inflexibility), with similar severity ratings as WDSTS and KABUK1. Two-thirds of participants were rated in the moderate-to-severe range in overall autism-like behaviors on the SRS-2; however, study findings highlighted a pattern of most day-to-day difficulties in Restricted/Repetitive Behaviors paired with relatively fewer challenges in Social Motivation, comparable to trends reported in WDSTS. Sleep disturbances are common in ODLURO (85%) and associated with behavior regulation difficulties, highlighting the importance of early screening/intervention. In brief, ODLURO shares similarities in neurobehavioral functioning with other disorders of H3K4 modulation of gene expression, warranting further systematic research with cross-syndrome comparisons to elucidate the relationship between epigenetic regulation and pathogenesis of neurodevelopmental disorders.

We reported a rare case of 1p36 deletion syndrome diagnosed using whole-exome sequencing (WES) in a Tunisian neonate, and to highlight the utility of WES in detecting structural variants, particularly in resource-limited settings. Clinical and genetic investigations were conducted on a female neonate presenting with a severe polymalformative syndrome. WES was performed to detect potential genetic abnormalities, followed by validation through fluorescence in situ hybridization (FISH). Variant annotation and classification were done in accordance with ACMG guidelines. WES identified a heterozygous interstitial deletion in the 1p36 region, spanning 11.64 Mb and affecting 155 coding genes, including key genes such as MMP23B, GABRD, SKI, PRDM16, KCNAB2, RERE, UBE4B, and CASZ1. The deletion was classified as pathogenic, and FISH analysis confirmed its presence. Clinically, the patient exhibited intrauterine growth restriction, neonatal epilepsy, craniofacial dysmorphia, congenital heart defect, and agenesis of the corpus callosum. This is the first reported case in Tunisia of a 1p36 deletion identified via short-read WES. The findings support the expanding role of WES in structural variant detection and underscore its diagnostic value, especially in settings with limited access to chromosomal microarray or genome sequencing technologies.

Ring 14 Syndrome is a rare genetic disorder caused by an anomaly in the 14th chromosome that often leads to intractable epilepsy, moderate to severe intellectual disabilities, slow growth, ocular abnormalities, and more. The presentation and severity of symptoms can greatly vary, making Ring 14 syndrome a complex condition to understand, manage, and treat. Conceptual disease models, also known as disease concept models, provide a formal framework based on the lived experience of patients and families that helps to describe the functional and quality of life impacts of a disease across various domains using qualitative methods. To inform the development of a conceptual disease model on Ring 14 Syndrome, 17 caregivers representing 12 patients with Ring 14 Syndrome participated in semi-structured interviews over the course of four months. Data were analyzed using a mix of deductive and inductive inquiry through NVivo Software. Concepts were grouped into domains of patient symptoms and caregiver symptoms, with patient symptoms consisting of two sub-domains: functional impacts (which included cognitive impacts, physical impacts, behavioral impacts, and social-emotional-expressive impacts) and quality of life impacts (which included ADLs, medication side effects, and school/social/community). Caregiver impacts were categorized by mental health, family and social aspects, and medical care. Patient impacts listed under the cognitive and physical categories align closely with patient impacts referenced in the medical literature. However, impacts listed under the patient quality of life domain as well as the caregiver domain are inadequately represented in the literature, suggesting that the patient perspective has previously been neglected in the medical literature on Ring 14 Syndrome. Further, the numerous mental and physical health impacts on caregivers, grouped with the negative quality of life impacts on Ring 14 patients themselves, warrants further attention, as both have profound effects on health-related quality of life. Finally, while many of the impacts listed in the conceptual disease model may be considered negative aspects of the disorder, there were also positive impacts identified (such as happy demeanor, resilience, and social support) by the community as well. Background on Ring 14 syndrome: Ring 14 Syndrome is a rare genetic condition caused by changes in the 14th chromosome. It can lead to serious challenges, including difficult-to-control seizures, intellectual disabilities, slow growth, and vision problems. What was this study about?: This study aimed to create a Conceptual Disease Model for Ring 14 Syndrome. This type of model helps researchers, doctors, and families understand how a disease affects daily life; not just medically, but also emotionally and socially. How was the study conducted?: A researcher interviewed 17 caregivers of 12 individuals with Ring 14 Syndrome over four months, both in person and online. The researcher asked questions that allowed families to share their experiences in their own words. What did the study find?: (i) For the most part, the cognitive and physical effects of Ring 14 Syndrome match what is already known in the medical literature. (ii) However, the impact on patients’ quality of life (such as struggles with daily activities, school, and social interactions) and the burden on caregivers are not well-documented in medical literature. (iii) Despite these challenges, families also reported positive aspects, such as resilience, strong social support, and the happy demeanor of many individuals with Ring 14 Syndrome. Why does this matter?: This study helps fill gaps in understanding how Ring 14 Syndrome affects everyday life, not just for patients, but for their families too. By recognizing both the challenges and the strengths of those affected, this research can help improve care, support services, and future studies on the condition.

Autism spectrum disorders (ASD) represent a substantial social problem affecting at least 1 in 100 children worldwide. These conditions are very often accompanied by intellectual disability (ID) and speech delay; thus, they can be considered within a clinical continuum of neurodevelopmental disorders. Given the high heterogeneity of ASD, the subjective nature of diagnostic criteria, and the presence of phenocopies, identifying genetic determinants of these disorders remains a challenge. To investigate the spectrum and frequency of rare genetic variants in genes with proven association with ASD in Russian children. 110 patients from 106 families were recruited into the study (mean age at diagnosis 6 years; boy-to-girl ratio 3:1. Most of the patients (84%) demonstrated a combination of ASD with developmental delay (DD) or ID. Patients with syndromic features were subjected to the chromosomal microarray analysis. The remained children underwent clinical exome sequencing aimed at identifying presumably monogenic causes of ASD. The study focused on rare (minor allele frequency ≤ 0.001) variants affecting high-confidence ASD-associated genes. Pathogenic copy number variations were detected in three (7%) of the patients examined. Clinical exome sequencing revealed pathogenic/likely pathogenic variants in 12 of 105 cases (11%), indicating the presence of monogenic syndromes with established clinical significance (Pitt-Hopkins syndrome, ZTTK syndrome, syndromic X-linked ID of Billuart type, Snijders-Blok-Campeau, Helsmoortel-van der Aa, Coffin-Siris, Clark-Baraitser, Keefstra syndromes, etc.). In addition, 27 patients (26%) had 37 rare variants of unknown clinical significance in DSCAM, SHANK2, AUTS2, ADNP, ANKRD11, APBA2, ARID1B, ASTN2, ATRX, SCN1A, CHD2, DEAF1, EHMT1, GRIN2B, NBEA, NR4A2, TRIO, TRIP12, POGZ, EP300, FOXP1, PCDH19, GRIN2A, NCKAP1, and CHD8 genes. No specific variant was detected more than once in unrelated patients. Among the genes with rare variants found in 2 or more patients were TRIP12 (n = 4), AUTS2 (n = 3), ARID1B (n = 3), PCDH19 (n = 3), EP300 (n = 3), TRIO (n = 2), ASTN2 (n = 2), EHMT1 (n = 2), and CHD2 (n = 2). Of note, 5 male ASD/DD patients from 3 unrelated families had PCDH19 missense variants, confirming that at least some hemizygous males with non-mosaic PCDH19 variants may present with neurobehavioral abnormalities. These variants did not cause epilepsy restricted to females in patients' mothers or sisters. These data confirm a tremendous diversity of genetic causes of ASD. Clinical exome sequencing may serve as a reasonable alternative to whole-exome sequencing.