Neurodevelopmental Phenotypes Research Articles

Copy Number Variation and Epilepsy: State of the Art in the Era of High-Throughput Sequencing—A Multicenter Cohort Study

BackgroundGenetic epilepsy diagnosis is increasing due to technological advancements. Although the use of molecular diagnosis is increasing, chromosomal microarray analysis (CMA) remains an important diagnostic tool for many patients. We aim to explore the role and indications of CMA in epilepsy, given the current genomic advances. MethodsWe obtained data from 378 epileptic described patients, who underwent CMA between 2015 and 2021. Different types of syndromic or nonsyndromic epilepsy were represented. ResultsAfter excluding patients who were undertreated or had missing data, we included 250 patients with treated epilepsy and relevant clinical information. These patients mostly had focal epilepsy or developmental and epileptic encephalopathy, with a median start age of 2 years. Ninety percent of the patients had intellectual disability, more than two thirds had normal head size, and 60% had an abnormal magnetic resonance imaging. We also included 10 patients with epilepsy without comorbidities. In our cohort, we identified 35 pathogenic copy number variations (CNVs) explaining epilepsy with nine recurrent CNVs enriched in patients with epilepsy, 12 CNVs related to neurodevelopmental disorder phenotype with possible epilepsy, five CNVs including a gene already known in epilepsy, and nine CNVs based on size combined with de novo occurrence. The diagnosis rate in our study reached 14% (35 of 250) with first-line CMA, as previously reported. Although targeted gene panel sequencing could potentially diagnose some of the reported epilepsy CNVs (34% [12 of 35]). ConclusionsCMA remains a viable option as the first-line genetic test in cases where other genetic tests are not available and as a second-line diagnostic technique if gene panel or exome sequencing yields negative results.

Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations.

Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, joint limitations, diverse cardiovascular and airway manifestations, and increased fibrosis often following trauma or surgery. In contrast, adults with MS are underreported obscuring potential clinical variability. Here, we describe 24 adults with MS, including 17 diagnosed after the age of 18 years old, and we review the literature on adults with MS. Overall, our cohort shows a milder phenotype as well as lower mortality rates compared to what has been published in literature. Individuals with a codon 500 variant in SMAD4 present with a more pronounced neurodevelopmental and systemic phenotype. However, in contrast to the literature, we observe cardiovascular abnormalities in individuals with the p.(Arg496Cys) variant. In addition, we describe scoliosis as a new manifestation and we report fertility in two additional males with the p.(Arg496Cys). In conclusion, our study contributes novel insights into the clinical variability of MS and underscores the importance of variant-specific considerations, and we provide recommendations for the management of MS in adulthood.

Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants

Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype-phenotype correlation analysis in a cohort of individuals with GABRB2 variants. Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

Pathogenic variants associated with speech/cognitive delay and seizures affect genes with expression biases in excitatory neurons and microglia in developing human cortex.

Congenital brain malformations and neurodevelopmental disorders (NDDs) are common pediatric neurological disorders and result in chronic disability. With the expansion of genetic testing, new etiologies for NDDs are continually uncovered, with as many as one third attributable to single-gene pathogenic variants. While our ability to identify pathogenic variants has continually improved, we have little understanding of the underlying cellular pathophysiology in the nervous system that results from these variants. We therefore integrated phenotypic information from subjects with monogenic diagnoses with two large, single-nucleus RNA-sequencing (snRNAseq) datasets from human cortex across developmental stages in order to investigate cell-specific biases in gene expression associated with distinct neurodevelopmental phenotypes. Phenotypic data was gathered from 1) a single-institution cohort of 84 neonates with pathogenic single-gene variants referred to Duke Pediatric Genetics, and 2) a cohort of 4,238 patients with neurodevelopmental disorders and pathogenic single-gene variants enrolled in the Deciphering Developmental Disorders (DDD) study. Pathogenic variants were grouped into genesets by neurodevelopmental phenotype and geneset expression across cortical cell subtypes was compared within snRNAseq datasets from 86 human cortex samples spanning the 2nd trimester of gestation to adulthood. We find that pathogenic variants associated with speech/cognitive delay or seizures involve genes that are more highly expressed in cortical excitatory neurons than variants in genes not associated with these phenotypes (Speech/cognitive: p=2.25×10-7; Seizures: p=7.97×10-12). A separate set of primarily rare variants associated with speech/cognitive delay or seizures, distinct from those with excitatory neuron expression biases, demonstrated expression biases in microglia. We also found that variants associated with speech/cognitive delay and an excitatory neuron expression bias could be further parsed by the presence or absence of comorbid seizures. Variants associated with speech/cognitive delay without seizures tended to involve calcium regulatory pathways and showed greater expression in extratelencephalic neurons, while those associated with speech/cognitive delay with seizures tended to involve synaptic regulatory machinery and an intratelencephalic neuron expression bias (ANOVA by geneset p<2×10-16). By combining extensive phenotype datasets from subjects with neurodevelopmental disorders with massive human cortical snRNAseq datasets across developmental stages, we identified cell-specific expression biases for genes in which pathogenic variants are associated with speech/cognitive delay and seizures. The involvement of genes with enriched expression in excitatory neurons or microglia highlights the unique role both cell types play in proper sculpting of the developing brain. Moreover, this information begins to shed light on distinct cortical cell types that are more likely to be impacted by pathogenic variants and that may mediate the symptomatology of resulting neurodevelopmental disorders.

Emergence of the ZNF675 Gene During Primate Evolution-Influenced Human Neurodevelopment Through Changing HES1 Autoregulation.

In this study, we investigated recurrent copy number variations (CNVs) in the 19p12 locus, which are associated with neurodevelopmental disorders. The two genes in this locus, ZNF675 and ZNF681, arose via gene duplication in primates, and their presence in several pathological CNVs in the human population suggests that either or both of these genes are required for normal human brain development. ZNF675 and ZNF681 are members of the Krüppel-associated box zinc finger (KZNF) protein family, a class of transcriptional repressors important for epigenetic silencing of specific genomic regions. About 170 primate-specific KZNFs are present in the human genome. Although KZNFs are primarily associated with repressing retrotransposon-derived DNA, evidence is emerging that they can be co-opted for other gene regulatory processes. We show that genetic deletion of ZNF675 causes developmental defects in cortical organoids, and our data suggest that part of the observed neurodevelopmental phenotype is mediated by a gene regulatory role of ZNF675 on the promoter of the neurodevelopmental gene Hes family BHLH transcription factor 1 (HES1). We also find evidence for the recently evolved regulation of genes involved in neurological disorders, microcephalin 1 and sestrin 3. We show that ZNF675 interferes with HES1 auto-inhibition, a process essential for the maintenance of neural progenitors. As a striking example of how some KZNFs have integrated into preexisting gene expression networks, these findings suggest the emergence of ZNF675 has caused a change in the balance of HES1 autoregulation. The association of ZNF675 CNV with human developmental disorders and ZNF675-mediated regulation of neurodevelopmental genes suggests that it evolved into an important factor for human brain development.

Saturation genome editing of BAP1 functionally classifies somatic and germline variants

Many variants that we inherit from our parents or acquire de novo or somatically are rare, limiting the precision with which we can associate them with disease. We performed exhaustive saturation genome editing (SGE) of BAP1, the disruption of which is linked to tumorigenesis and altered neurodevelopment. We experimentally characterized 18,108 unique variants, of which 6,196 were found to have abnormal functions, and then used these data to evaluate phenotypic associations in the UK Biobank. We also characterized variants in a large population-ascertained tumor collection, in cancer pedigrees and ClinVar, and explored the behavior of cancer-associated variants compared to that of variants linked to neurodevelopmental phenotypes. Our analyses demonstrated that disruptive germline BAP1 variants were significantly associated with higher circulating levels of the mitogen IGF-1, suggesting a possible pathological mechanism and therapeutic target. Furthermore, we built a variant classifier with >98% sensitivity and specificity and quantify evidence strengths to aid precision variant interpretation.

Consortium Profile: The Methylation, Imaging and NeuroDevelopment (MIND) Consortium.

Epigenetic processes, such as DNA methylation, show potential as biological markers and mechanisms underlying gene-environment interplay in the prediction of mental health and other brain-based phenotypes. However, little is known about how peripheral epigenetic patterns relate to individual differences in the brain itself. An increasingly popular approach to address this is by combining epigenetic and neuroimaging data; yet, research in this area is almost entirely comprised of cross-sectional studies in adults. To bridge this gap, we established the Methylation, Imaging and NeuroDevelopment (MIND) Consortium, which aims to bring a developmental focus to the emerging field of Neuroimaging Epigenetics by (i) promoting collaborative, adequately powered developmental research via multi-cohort analyses; (ii) increasing scientific rigor through the establishment of shared pipelines and open science practices; and (iii) advancing our understanding of DNA methylation-brain dynamics at different developmental periods (from birth to emerging adulthood), by leveraging data from prospective, longitudinal pediatric studies. MIND currently integrates 15 cohorts worldwide, comprising (repeated) measures of DNA methylation in peripheral tissues (blood, buccal cells, and saliva) and neuroimaging by magnetic resonance imaging across up to five time points over a period of up to 21 years (Npooled DNAm = 11,299; Npooled neuroimaging = 10,133; Npooled combined = 4,914). By triangulating associations across multiple developmental time points and study types, we hope to generate new insights into the dynamic relationships between peripheral DNA methylation and the brain, and how these ultimately relate to neurodevelopmental and psychiatric phenotypes.

Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD). KATNAL2, a member of Katanin family microtubule-severing ATPases, is a known ASD risk gene, but its roles in human brain development remain unclear. Here, we show that nonsense truncation of Katnal2 (Katnal2Δ17) in mice results in classic ciliopathy phenotypes, including impaired spermatogenesis and cerebral ventriculomegaly. In both humans and mice, KATNAL2 is highly expressed in ciliated radial glia of the fetal ventricular-subventricular zone as well as in their postnatal ependymal and neuronal progeny. The ventriculomegaly observed in Katnal2Δ17 mice is associated with disrupted primary cilia and ependymal planar cell polarity that results in impaired cilia-generated CSF flow. Further, prefrontal pyramidal neurons in ventriculomegalic Katnal2Δ17 mice exhibit decreased excitatory drive and reduced high-frequency firing. Consistent with these findings in mice, we identified rare, damaging heterozygous germline variants in KATNAL2 in five unrelated patients with neurosurgically treated CH and comorbid ASD or other neurodevelopmental disorders. Mice engineered with the orthologous ASD-associated KATNAL2 F244L missense variant recapitulated the ventriculomegaly found in human patients. Together, these data suggest KATNAL2 pathogenic variants alter intraventricular CSF homeostasis and parenchymal neuronal connectivity by disrupting microtubule dynamics in fetal radial glia and their postnatal ependymal and neuronal descendants. The results identify a molecular mechanism underlying the development of ventriculomegaly in a genetic subset of patients with ASD and may explain persistence of neurodevelopmental phenotypes in some patients with CH despite neurosurgical CSF shunting.

Evidence for neurobehavioral risk phenotypes at birth.

Observations of newborn behavior provide clinicians and researchers with a first description of the neurobehavioral organization of the newborn that is largely independent of the postnatal environment. The Neonatal Network Neurobehavioral Scale (NNNS) was developed in 2004 to evaluate how prenatal exposure to substances such as cocaine is related to neurobehavioral outcomes. There are now 156 empirical articles published using the NNNS, which we review and summarize. Z-scores from published studies using the NNNS were compiled and aggregated supporting the replicability of three newborn neurobehavioral phenotypes: one typical and two that are predictive of later cognitive and behavioral delay; hyper- and hypo-dysregulated newborns. These phenotypes emerged from independent samples and research groups and were identified in a variety of populations, including infants with prenatal substance exposure, preterm infants, and healthy term infants. Our findings show that newborn neurobehavior can be measured in a reliable and valid manner and that certain behavioral phenotypes, identifiable at birth, can predict neurodevelopmental challenges. These findings have important clinical utility. Intervening early with infants exhibiting these risk phenotypes may prevent later neurodevelopmental delay. IMPACT: We reviewed all empirical studies published using the Neonatal Network Neurobehavioral Scale and found evidence for two replicable stress phenotypes that predict later behavioral outcomes. This study highlights the utility of the Neonatal Network Neurobehavioral Scale for early identification of newborn neurodevelopmental risk phenotypes. Early identification of neurodevelopmental risk, when neuroplasticity is high, may ultimately reduce the burden of subsequent neurobehavioral problems through early intervention.

Biallelic ZBTB11 Variants: A Neurodevelopmental Condition with Progressive Complex Movement Disorders.

Biallelic ZBTB11 variants have previously been associated with an ultrarare subtype of autosomal recessive intellectual developmental disorder (MRT69). The aim was to provide insights into the clinical and genetic characteristics of ZBTB11-related disorders (ZBTB11-RD), with a particular emphasis on progressive complex movement abnormalities. Thirteen new and 16 previously reported affected individuals, ranging in age from 2 to 50 years, with biallelic ZBTB11 variants underwent clinical and genetic characterization. All patients exhibited a range of neurodevelopmental phenotypes with varying severity, encompassing ocular and neurological features. Eleven new patients presented with complex abnormal movements, including ataxia, dystonia, myoclonus, stereotypies, and tremor, and 7 new patients exhibited cataracts. Deep brain stimulation was successful in treating 1 patient with generalized progressive dystonia. Our analysis revealed 13 novel variants. This study provides additional insights into the clinical features and spectrum of ZBTB11-RD, highlighting the progressive nature of movement abnormalities in the background of neurodevelopmental phenotype. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Unraveling genetic contributions to neurodevelopmental disorders and epilepsy in a pediatric cohort from a Mexican state

Neurodevelopmental disorders (NDDs) encompass a broad spectrum of conditions that significantly impact personal, social, academic, or occupational functioning from an early age. Epilepsy emerges as a significant comorbid condition, featuring a complex interplay between neurodevelopmental processes and epileptogenesis, likely rooted in genetic abnormalities. This research is a descriptive observational study designed to assess the contribution of genetic variations to the clinical presentation of NDDs in a pediatric population from the Mexican state of Jalisco, aiming to enhance diagnostic and management strategies. The patients underwent comprehensive clinical evaluations and personalized genetic testing using next-generation sequencing techniques, and their relatives were studied only on a case-by-case basis if information regarding the mode of inheritance was needed. This study included 24 patients and 30 relatives. Diagnoses of Mendelian inheritance diseases were identified in 14 patients, including cases with mutations not previously associated with NDDs. Genetic testing revealed a variety of pathogenic and likely pathogenic mutations, as well as variants of uncertain significance, across a range of genes implicated in NDDs. Notable findings included new mutations related to low-prevalence genetic syndromes and the identification of both inherited and de novo mutations contributing to the neurodevelopmental phenotypes observed. Our findings underscore the complex genetic landscape of NDDs and epilepsy, highlighting the crucial role of genetic evaluation in elucidating the etiology of these disorders within the studied population. The integration of genetic testing into the diagnostic process for NDDs not only facilitates a more precise diagnosis but also informs prognostic outlooks and guides tailored intervention strategies. Moreover, this study advocates for the continued exploration of genetic underpinnings in NDDs to further refine diagnostic accuracy, improve therapeutic approaches, and support familial decision-making, and emphasizing the importance of genetics in advancing neurodevelopmental medicine.

CELF2 Deficiency Demonstrates Autism-Like Behaviors and Interferes with Late Development of Cortical Neurons in Mice.

CELF2 variants have been linked to neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD). However, the molecular mechanisms remain unclear. We generated Celf2 Nestin-Cre knockout mice.Our findings revealed that Celf2 Nestin-Cre heterozygous knockout mice exhibited social impairment and anxiety, an autism-like behavior, though no manifestations of repetitive stereotyped behavior, learning cognitive impairment, or depression were observed. Immunofluorescence assay showed an underdeveloped cerebral cortex with significantly reduced cortical thickness, albeit without abnormal cell density. Further in vitro neuronal culture demonstrated a significant reduction in dendritic spine density and affected synaptic maturation in Celf2 deficient mice, with no notable abnormalities in total neurite and axon length. RNA-seq and RIP-seq analysis of the cerebral cortex revealed differentially expressed genes post Celf2 gene knockout compared with the control group. Enrichment analysis highlighted significant enrichment in dendrite and synapse-related biological processes and pathways. Our study delineated the behavioral and neurodevelopmental phenotypes of Celf2, suggesting its potential involvement in autism through the regulation of target genes associated with dendritic spines and synapse development. Further research is needed to elucidate the specific mechanisms involved.

Conceptualizing avoidant/restrictive food intake disorder via an executive functioning lens.

Avoidant/restrictive food intake disorder (ARFID) is a heterogeneous disorder wherein restrictive eating is primarily attributed to non-shape/weight-based reasons (e.g., sensory sensitivity) that empirical research continues to explore. Mounting evidence suggests that ARFID often presents alongside neurodevelopmental diagnoses (NDs) or divergent neurodevelopment broadly. Executive functioning (EF) differences often characterize divergent neurodevelopmental trajectories. Additionally, restrictive eating in anorexia nervosa has been conceptualized as related to EF factors (e.g., set shifting). Given the neurodevelopmental phenotype that may be associated with ARFID and the role of EF in anorexia nervosa, this paper proposes EF as a potentially important, yet understudied factor in ARFID pathology. We posit that various observed ARFID behavioral/cognitive tendencies can be conceptualized in relation to EF differences. We contextualize commonly observed ARFID presentations within "core" EF components (i.e., cognitive flexibility, working memory, inhibitory control), leading to hypotheses about EF in ARFID. Finally, we offer additional considerations/directions for future research on EF in ARFID. Increased research on EF in ARFID is needed to consider this potential common factor in the etiology and maintenance of this heterogeneous disorder. We aim to promote further consideration of EF in ARFID etiology, maintenance, and treatment-outcome research. PUBLIC SIGNIFICANCE: This article proposes that aspects of executive functioning (EF) may play a role in the onset and maintenance of avoidant/restrictive food intake disorder (ARFID), although this notion is largely untested by existing research. Further research on the role of EF in ARFID may assist with refining models and treatments for this heterogeneous disorder.

ARID1B controls transcriptional programs of axon projection in an organoid model of the human corpus callosum

Mutations in ARID1B, a member of the mSWI/SNF complex, cause severe neurodevelopmental phenotypes with elusive mechanisms in humans. The most common structural abnormality in the brain of ARID1B patients is agenesis of the corpus callosum (ACC), characterized by the absence of an interhemispheric white matter tract that connects distant cortical regions. Here, we find that neurons expressing SATB2, a determinant of callosal projection neuron (CPN) identity, show impaired maturation in ARID1B+/- neural organoids. Molecularly, a reduction in chromatin accessibility of genomic regions targeted by TCF-like, NFI-like, and ARID-like transcription factors drives the differential expression of genes required for corpus callosum (CC) development. Through an invitro model of the CC tract, we demonstrate that this transcriptional dysregulation impairs the formation of long-range axonal projections, causing structural underconnectivity. Our study uncovers new functions of the mSWI/SNF during human corticogenesis, identifying cell-autonomous axonogenesis defects in SATB2+ neurons as a cause of ACC in ARID1B patients.

Homeostatic Type I IFN Response at the Placenta Contributes to Sex-biased Neurodevelopmental Outcome

Abstract The maternal-fetal interface, placenta, plays pivotal roles in fetal development. Recent evidence shows that the placenta contributes to the sex-biased prevalence of some developmental disorders such as neurodevelopmental disorders. Commencing an exploration into the molecular intricacies of fetal sex-specific transcriptional changes within the placenta, our study leveraged single-cell RNA sequencing. We uncovered a diminished expression of interferon (IFN)-responsive genes (ISGs) in male fetus-associated trophoblasts compared to female, which have pivotal roles in the process of spiral artery remodeling. We further found maternal NK cells associated with male fetus placenta showed a reduction in the interferon production pathway. The introduction of maternal immune activation (MIA), which induces neurodevelopmental abnormalities in male offspring, it reversed these sex-specific disparities in the placenta. In pursuit of unraveling the potential link between sex-specific ISGs expression and neurodevelopmental outcomes in MIA offspring, we selectively removed IFN alpha and beta receptor subunit 1 (IFNAR1) in a trophoblast-specific manner. Blunting IFNAR1 in the placenta protected male offspring from MIA-induced behavioral abnormalities. Our data suggests the intricate landscape of sex-specific IFN response at the maternal-fetal interface and underscore its role in shaping the sex-bias observed in MIA-induced neurodevelopmental phenotypes.

Further evidence supporting the role of GTDC1 in glycine metabolism and neurodevelopmental disorders

Copy number variants (CNVs) represent the genetic cause of about 15–20% of neurodevelopmental disorders (NDDs). We identified a ~67 kb de novo intragenic deletion on chromosome 2q22.3 in a female individual showing a developmental encephalopathy characterised by epilepsy, severe intellectual disability, speech delay, microcephaly, and thin corpus callosum with facial dysmorphisms. The microdeletion involved exons 5-6 of GTDC1, encoding a putative glycosyltransferase, whose expression is particularly enriched in the nervous system. In a previous study, a balanced de novo translocation encompassing GTDC1 was reported in a male child with global developmental delay and delayed speech and language development. Based on these premises, we explored the transcriptomic profile of our proband to evaluate the functional consequences of the novel GTDC1 de novo intragenic deletion in relation to the observed neurodevelopmental phenotype. RNA-seq on the proband’s lymphoblastoid cell line (LCL) showed expression changes of glycine/serine and cytokine/chemokine signalling pathways, which are related to neurodevelopment and epileptogenesis. Subsequent analysis by ELISA (enzyme-linked immunosorbent assay) and HPLC (high-performance liquid chromatography) revealed increased levels of glycine in the proband’s LCL and serum compared to matched controls. Given that an increased level of glycine has been observed in the plasma samples of individuals with Rett syndrome, a condition sharing epilepsy, microcephaly, and intellectual disability with our proband, we proposed that the GTDC1 downregulation is implicated in neurodevelopmental impairment by altering glycine metabolism. Furthermore, our findings expanded the phenotypic spectrum of the novel GTDC1-related condition, including microcephaly and epilepsy among relevant clinical features.

Developmental and behavioral phenotypes of pediatric patients with PTEN hamartoma tumor syndrome.

Our study characterized the neurodevelopmental spectrum of individuals with PTEN Hamartoma Tumor Syndrome (PHTS), a syndrome that predisposes to both neurodevelopmental phenotypes and cancer risk. We aim to better understand life-impacting neurodevelopmental features of PHTS. Our study recruited 20 children/adolescents with PHTS, who were then administered assessments for autism spectrum disorder (ASD) and other neurocognitive measures, including assessment of IQ, executive and adaptive functioning, and health-related quality of life. Thirteen individuals (65%) were identified as having ASD, of which five were newly diagnosed during the study. Of those, ASD symptom severity was in the mild-moderate range for 77%. Overall, IQ was in the average range, with a mean of 92.61 (SD 24.45, p = 0.5), though there was a non-statistically significant trend toward individuals without ASD having a higher mean IQ (102.7 vs 82.3; p = 0.1). Subjects had significant impairment in processing speed (mean 75.38, SD 24.75, p < 0.05), decreased adaptive functioning skills across all domains, and a trend toward having more executive functioning problems. Individuals with PHTS are at increased risk of neurodevelopmental disorders, including ASD and impaired executive and adaptive functioning. Although clear guidelines exist for cancer surveillance for individuals with PHTS, additional guidelines and screening for neurodevelopmental disorders are warranted.

Comprehensive phenotypes of patients with SYNGAP1-related disorder reveals high rates of epilepsy and autism.

To delineate the comprehensive phenotypic spectrum of SYNGAP1-related disorder in a large patient cohort aggregated through a digital registry. We obtained de-identified patient data from an online registry. Data were extracted from uploaded medical records. We reclassified all SYNGAP1 variants using American College of Medical Genetics criteria and included patients with pathogenic/likely pathogenic (P/LP) single nucleotide variants or microdeletions incorporating SYNGAP1. We analyzed neurodevelopmental phenotypes, including epilepsy, intellectual disability (ID), autism spectrum disorder (ASD), behavioral disorders, and gait dysfunction for all patients with respect to variant type and location within the SynGAP1 protein. We identified 147 patients (50% male, median age 8 years) with P/LP SYNGAP1 variants from 151 individuals with data available through the database. One hundred nine were truncating variants and 22 were missense. All patients were diagnosed with global developmental delay (GDD) and/or ID, and 123 patients (84%) were diagnosed with epilepsy. Of those with epilepsy, 73% of patients had GDD diagnosed before epilepsy was diagnosed. Other prominent features included autistic traits (n = 100, 68%), behavioral problems (n = 100, 68%), sleep problems (n = 90, 61%), anxiety (n = 35, 24%), ataxia or abnormal gait (n = 69, 47%), sensory problems (n = 32, 22%), and feeding difficulties (n = 69, 47%). Behavioral problems were more likely in those patients diagnosed with anxiety (odds ratio [OR] 3.6, p = .014) and sleep problems (OR 2.41, p = .015) but not necessarily those with autistic traits. Patients with variants in exons 1-4 were more likely to have the ability to speak in phrases vs those with variants in exons 5-19, and epilepsy occurred less frequently in patients with variants in the SH3 binding motif. We demonstrate that the data obtained from a digital registry recapitulate earlier but smaller studies of SYNGAP1-related disorder and add additional genotype-phenotype relationships, validating the use of the digital registry. Access to data through digital registries broadens the possibilities for efficient data collection in rare diseases.

Cerebral visual impairment: genetic diagnoses and phenotypic associations

BackgroundCerebral visual impairment (CVI) is the most common form of paediatric visual impairment in developed countries. CVI can arise from a host of genetic or acquired causes, but there has...

FOXG1 variants can be associated with milder phenotypes than congenital Rett syndrome with unassisted walking and language development.

Since 2008, FOXG1 haploinsufficiency has been linked to a severe neurodevelopmental phenotype resembling Rett syndrome but with earlier onset. Most patients are unable to sit, walk, or speak. For years, FOXG1 sequencing was only prescribed in such severe cases, limiting insight into the full clinical spectrum associated with this gene. Next-generation sequencing (NGS) now enables unbiased diagnostics. Through the European Reference Network for Rare Malformation Syndromes, Intellectual and Other Neurodevelopmental Disorders, we gathered data from patients with heterozygous FOXG1 variants presenting a mild phenotype, defined as able to speak and walk independently. We also reviewed data from three previously reported patients meeting our criteria. We identified five new patients with pathogenic FOXG1 missense variants, primarily in the forkhead domain, showing varying nonspecific intellectual disability and developmental delay. These features are not typical of congenital Rett syndrome and were rarely associated with microcephaly and epilepsy. Our findings are consistent with a previous genotype-phenotype analysis by Mitter et al. suggesting the delineation of five different FOXG1 genotype groups. Milder phenotypes were associated with missense variants in the forkhead domain. This information may facilitate prognostic assessments in children carrying a FOXG1 variant and improve the interpretation of new variants identified with genomic sequencing.