The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.

[Oral language development in maltreated and foster children]. / Le développement du langage oral chez les enfants maltraités et placés.

Language disorders, which are still very poorly detected, are often present in abused children. While the consequences are well known and long-lasting, little is known about the development and specific characteristics of these children, depending on where they were placed, the type of abuse they suffered and the age at which they were placed. This finding led to a review of the literature aimed at better defining the state of knowledge on the subject, for the benefit of better detection and treatment.

Determinants of speech and language delay among children aged 12 months to 12 years at Yekatit 12 Hospital, Addis Ababa, Ethiopia: a case-control study.

BACKGROUND: Speech and language delay among children can result in social interaction problems, attention difficulties, decreased writing and reading abilities, and poor cognitive and behavioral development. Despite the mounting prevalence of speech and language delays in Ethiopia, there is a lack of literature addressing the factors contributing to this delay. Consequently, this study aims to identify determinants of speech and language delay among children aged 12 months to 12 years at Yekatit 12 Hospital in Addis Ababa, Ethiopia. METHODS: We conducted an institutional-based at Yekatit 12 Hospital, unmatched case-control study with 50 cases and 100 controls aged 12 months to 12 years. Interviewer-administered questionnaires were used to collect data from the parents or caregivers of the participating children. Epi Info v7 was used for sample calculation, and SPSS v26 was used for analysis. The chi-square test was performed to determine the relationship between speech and language delay and determining factors, which was then followed by logistic regression. The significant determining factors were identified based on the adjusted odds ratio (AOR), with a 95% CI and p-value (< 0.05). RESULTS: Case group constituted 23 males and 27 females, totaling 50 children. Upon completing the multivariate analysis, birth asphyxia [AOR = 4.58, 95CI (1.23-16.99)], bottle-feeding [AOR = 4.54, 95CI (1.29-16.04)], mother-child separation [AOR = 2.6, 95CI (1.05-6.43)], multilingual family [AOR = 2.31, 95CI (1.03-5.18)], and screen time greater than two hours [AOR = 3.06, 95CI (1.29-7.28)] were found to be statistically significant determinants of speech and language delay. CONCLUSIONS: Our study found that birth asphyxia, bottle-feeding, mother-child separation, being from a multilingual family, and excessive screen time contribute significantly to speech and language delay. As a result, it is important to develop interventions that target these modifiable factors, while also ensuring that early diagnosis and treatment options are readily accessible.

Unsupervised Screen Exposure and Poor Language Development: A Scoping Review to Assess Current Evidence and Suggest Priorities for Research.

Screen exposure has both negative and positive effects on the level of language skills a child acquires. The purpose of this review is to address current literature on the possible relationship between unsupervised screen exposure and language development in children and to provide recommendations to caregivers regarding screen exposure of children, taking into consideration the possible effects. A scoping review was conducted using the PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online) database. A total of 590 articles were retrieved and considered for inclusion. Twenty-one articles were finally included and reviewed with an emphasis on language, communication, and executive skills as well as cognitive development. The negative effects of screen exposure for children outweigh the positive effects. The largest number of studies demonstrate that unsupervised screen exposure may negatively impact a child's language usage and cognitive and executive skills, disrupt playtime, and affect the quality of sleep. On the other hand, supervised screen use is associated with improved language skills. More evidence is needed on unsupervised exposure in children to new types of screens. As technology could play a significant role in schools in the future, additional research is required to create educational media for schoolchildren with specific guidelines.

Classic and Atypical Late Infantile Neuronal Ceroid Lipofuscinosis in Latin America: Clinical and Genetic Aspects, and Treatment Outcome with Cerliponase Alfa.

Introduction: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), is a neurodegenerative autosomal recessive disease caused by TPP1 gene variants, with a spectrum of classic and atypical phenotypes. The aim of treatment is to slow functional decline as early as possible in an attempt to improve quality of life and survival. This study describes the clinical characteristics as well as the response to treatment with cerliponase alfa. Materials and methods: A retrospective study was conducted in five Latin-American countries, using clinical records from patients with CLN2. Clinical follow-up and treatment variables are described. A descriptive and bivariate statistical analysis was performed. Results: A total of 36 patients were observed (range of follow-up of 61-110 weeks post-treatment). At presentation, patients with the classic phenotype (n = 16) exhibited regression in language (90%), while seizures were the predominant symptom (87%) in patients with the atypical phenotype (n = 20). Median age of symptom onset and time to first specialized consultation was 3 (classical) and 7 (atypical) years, while the median time interval between onset of symptoms and treatment initiation was 4 years (classical) and 7.5 (atypical). The most frequent variant was c.827 A > T in 17/72 alleles, followed by c.622C > T in 6/72 alleles. All patients were treated with cerliponase alfa, and either remained functionally stable or had a loss of 1 point on the CLN2 scale, or up to 2 points on the Wells Cornel and Hamburg scales, when compared to pretreatment values. Discussion and conclusion: This study reports the largest number of patients with CLN2 currently on treatment with cerliponase alfa in the world. Data show a higher frequency of patients with atypical phenotypes and a high allelic proportion of intron variants in our region. There was evidence of long intervals until first specialized consultation, diagnosis, and enzyme replacement therapy. Follow-up after the initiation of cerliponase alfa showed slower progression or stabilization of the disease, associated with adequate clinical outcomes and stable functional scores. These improvements were consistent in both clinical phenotypes.

Audiological and Speech and Language Characteristics of a Case with Hunter's Syndrome.

Hearing loss is a common manifestation of Hunter's syndrome, with reported rates ranging from 67.3 to 94%. The aim is to highlight the audiological profile and pathophysiology of mixed hearing loss in individuals with hunter's syndrome. A 7.6-year-old male child was brought to the department of audiology with a complaint of not responding to name call and regression in the speech and language skills. Detailed audiological showed severe to profound mixed hearing loss. REELS and 3DLAT results showed RLA to be 9 to 10 months and ELA to be 6 to 7 months. Owing to the progressive nature and high prevalence of hearing loss in hunter's syndrome, this case report highlights the importance of middle ear evaluation in the pediatric hearing assessment apart from OAE and ABR. Speech- language therapy must be considered with a focus on functional communication.

A Comparison of Parent Reports, the Mental Synthesis Evaluation Checklist (MSEC) and the Autism Treatment Evaluation Checklist (ATEC), with the Childhood Autism Rating Scale (CARS).

This study compares two parent reports, the Mental Synthesis Evaluation Checklist (MSEC) and the Autism Treatment Evaluation Checklist (ATEC), with the Childhood Autism Rating Scale (CARS). The ATEC consists of four subscales, as follows: (1) expressive language, (2) sociability, (3) sensory awareness, and (4) health. The MSEC is complementary to the ATEC in measuring complex language comprehension. The parents of 143 autistic children, from 2 to 22 years of age (mean 6.7 ± 5.1 years), completed the MSEC and the ATEC questionnaires and a clinician assessed their CARS score. The CARS score correlated strongly with all parent reports, the complex language comprehension MSEC (r = 0.60, p < 0.0001), expressive language (r = 0.66, p < 0.0001), sociability (r = 0.58, p < 0.0001), sensory awareness (r = 0.71, p < 0.0001), and health (r = 0.53, p < 0.0001), as well as the total ATEC score (r = 0.75, p < 0.0001). The strongest correlation was between the CARS score and the composite of all five parent-reported scores (total ATEC + MSEC, r = 0.77, p < 0.0001). These results suggest a high fidelity of the MSEC and ATEC parent reports and especially of their composite score, total ATEC + MSEC.

Differences in Sleep EEG Coherence and Spindle Metrics in Toddlers With and Without Language Delay: A Prospective Observational Study.

Background: Sleep plays a crucial role in early language development, and sleep disturbances are common in children with neurodevelopmental disorders. Examining sleep microarchitecture in toddlers with and without language delays can offer key insights into neurophysiological abnormalities associated with atypical neurodevelopmental trajectories and potentially aid in early detection and intervention. Methods: Here, we investigated electroencephalogram (EEG) coherence and sleep spindles in 16 toddlers with language delay (LD) compared with a group of 39 typically developing (TD) toddlers. The sample was majority male (n = 34, 62%). Participants were aged 12-to-22 months at baseline, and 34 (LD, n=11; TD, n=23) participants were evaluated again at 36 months of age. Results: LD toddlers demonstrated increased EEG coherence compared to TD toddlers, with differences most prominent during slow-wave sleep. Within the LD group, lower expressive language skills were associated with higher coherence in REM sleep. Within the TD group, lower expressive language skills were associated with higher coherence in slow-wave sleep. Sleep spindle density, duration, and frequency changed between baseline and follow-up for both groups, with the LD group demonstrating a smaller magnitude of change than the TD group. The direction of change was frequency-dependent for both groups. Conclusions: These findings indicate that atypical sleep EEG connectivity and sleep spindle development can be detected in toddlers between 12 and 36 months and offers insights into neurophysiological mechanisms underlying the etiology of neurodevelopmental disorders. Trial registration: https://clinicaltrials.gov/study/NCT01339767; Registration date: 4/20/2011.

Haploinsufficiency of NKX2-1 is likely to contribute to developmental delay involving 14q13 microdeletions.

Nucleotide variations or deletions in the NK2 homeobox 1 gene (NKX2-1), located at 14q13.3, lead to symptoms associated with the brain, lungs, and thyroid, and the combination of these phenotypes is clinically recognized as the brain-lung-thyroid syndrome. Many types of nucleotide variants of NKX2-1 have been identified, and phenotypic variability has been reported. Chromosomal deletions involving NKX2-1 have also been reported; however, phenotypic differences between patients with nucleotide variants of NKX2-1 and patients with chromosomal deletions involving NKX2-1 have not been well established. Recently, we identified seven patients with 14q13 microdeletions involving the NKX2-1. Most patients exhibited developmental delay. This inquiry arises regarding the potential existence of haploinsufficiency effects beyond those attributed to NKX2-1 within the 14q13 microdeletion. However, a literature review has shown that developmental delay is not rare in patients with nucleotide alterations in NKX2-1. Rather, motor function impairment may have affected the total developmental assessment, and the haploinsufficiency of genes contiguous to NKX2-1 is unlikely to contribute to developmental delay.

Health supervision for children and adolescents with 16p11.2 deletion syndrome.

Rare genetic conditions are challenging for the primary care provider to manage without proper guidelines. This clinical review is designed to assist the pediatrician, family physician, or internist in the primary care setting to manage the complexities of 16p11.2 deletion syndrome. A multidisciplinary medical home with the primary care provider leading the care and armed with up-to-date guidelines will prove most helpful to the rare genetic patient population. A special focus on technology to fill gaps in deficits, review of case studies on novel medical treatments, and involvement with the educational system for advocacy with an emphasis on celebrating diversity will serve the rare genetic syndrome population well.

Screening and determinant of suspected developmental delays among Egyptian preschool-aged children: a cross-sectional national community-based study.

BACKGROUND: Early childhood life is critical for optimal development and is the foundation of future well-being. Genetic, sociocultural, and environmental factors are important determinants of child development. AIM: The objectives were to screen for suspected developmental delays (DDs) among Egyptian preschool children, and to explore the determinants of these delays based on sociodemographic, epidemiological, maternal, and child perinatal risk factors. METHODS: A national Egyptian cross-sectional developmental screening of a representative sample of preschool children (21,316 children) aged 12 to 71 months. The Revised Denver Prescreening Developmental Questionnaire (R-PDQ) followed by the Denver Developmental Screening Test, 2nd edition (DDST) was used. RESULTS: Each screened child manifested at least one of six developmental categories. Either typical development, gross motor delay (GM), fine motor adaptive delay (FMA), Language delay (L), Personal-social delay (PS), or multiple DDs. The prevalence of preschool children with at least one DD was 6.4%, while 4.5% had multiple DDs. Developmental language delay was the most prevalent, affecting 4.2% of children. The least affected domain was GM (1.9% of children). Boys were more likely to have DD than girls. Children in urban communities were more likely to have at least one DD than those in rural areas (OR = 1.28, 95%CI: 1.14-1.42), and children of middle social class than of low or high social class (OR = 1.49, 95%CI: 1.30-1.70 & OR = 1.40, 95%CI: 1.23-1.59 respectively). The strong perinatal predictors for at least one DD were children with a history of postnatal convulsions (OR = 2.68, 95%CI: 1.97-3.64), low birth weight (OR = 2.06, 95%CI: 1.69-2.52), or history of postnatal cyanosis (OR = 1.77, 95%CI: 1.26-2.49) and mothers had any health problem during pregnancy (OR = 1.73, 95%CI: 1.44-2.07). Higher paternal and maternal education decreased the odds of having any DD by 43% (OR = 0.57, 95% CI: 0.47-0.68) and 31% (OR = 0.69, 95%CI: 0.58-0.82) respectively. CONCLUSION: This study demonstrates a considerable attempt to assess the types and the prevalence of DD among preschool children in Egypt. Perinatal factors are among the most common determinants of DD in preschool children and the majority could be preventable risk factors.

Association between interruption of intervention and language performance in young children with language delay-a cohort study during COVID-19 pandemic.

Introduction: To assess the association between a three-month interruption of language intervention programs and the language performance of children with language delay during the COVID-19 pandemic, and to identify which children are more vulnerable to such interruptions. Materials and methods: This is a retrospective study involving 33 children with language delay who experienced a three-month suspension of language interventions due to the COVID-19 pandemic. We collected their demographic data and language performance scores from the Comprehensive Developmental Inventory for Infants and Toddlers-Diagnostic test (CDIIT-DT) at four different time points. The scores were analyzed using a Wilcoxon Signed Ranks test. Results: The median scores of language comprehension and overall language ability showed a decreasing trend during the interruption period. However, resuming interventions post-interruption showed a statistically significant increase in all language domains. Children in the borderline delay group (CDIIT-DT DQ scores between 71 and 85) were more likely to experience a decline in their language abilities during the interruption. Discussion: This is the first study to reveal a decreasing trend in language performance during interruption periods, and highlighting the significance of post-interruption language interventions in facilitating improvements. Furthermore, our study brings attention to the heightened vulnerability of children exhibiting borderline language delay in overall language ability tests when faced with interruptions in language interventions.

Relationship Between Speech Delay and Smart Media in Children: A Systematic Review.

The increasing prevalence of smart media usage among children has raised concerns about its potential impact on various aspects of child development. One such area of worry is speech delay, as early language acquisition is critical for cognitive, social, and educational development. The purpose of this systematic review was to investigate and synthesize available research data in order to determine the association between speech delay and the usage of smart media in children. To perform this systematic review, a thorough literature search was conducted using relevant keywords in electronic databases, such as PubMed, Scopus, PsycINFO, Google Scholar, Web of Science, and Embase. We included studies published during the last 10 years investigating the impact of smart media on children's speech delay using various research designs. The findings showed that extended exposure to electronic media for children was negatively associated with expressive vocabulary and language skills in children, in addition to decreased language scores and speech delays. Educational apps and shared media engagement with parents correlated with stronger language skills. The introduction of smart devices at a later stage of development (24 months of age and older) was associated with positive language development, whereas early introduction was associated with speech delay. However, six-month abstinence from devices led to speech improvement in the affected children. These findings highlight the need to balance interactive screen time and other forms of interaction to enhance speech development.

Assessment of Language Development in Dual Language Learners: A Case Report.

Propelled by immigration, language diversity is increasing in the United States, and more young children are exposed to two or more languages at home from birth. Known as dual language learners (DLLs), the benefits of this exposure include multilingual and multiliterate outcomes. However, DLLs introduce complexity for the pediatric provider's assessment of language development, identification of potential language delays, and timely referrals. If language delays are not promptly identified and followed with early intervention, they can persist and lead to poor outcomes across multiple domains.

The development and productivity of a measure for identifying low language abilities in children aged 24-36 months.

BACKGROUND: Accurate early identification of children with low language ability is important but existing measures generally have low sensitivity. This remains an area of concern for preventive and public health services. This study aimed to create and evaluate a measure of child language, communication and related risks which can be used by community health nurses to accurately identify children with low language aged 24-30 months. METHODS: The Early Language Identification Measure (ELIM) was developed and comprised five measurement sections, each measuring different aspects of development combined into a single measure. This was tested blind against a reference standard language measure, the Preschool Language Scale-5 (PLS-5), at the universal 24-30-month health visitor review in England. The threshold for likely low language was the tenth centile or below on the PLS-5. The aim was to ascertain the performance of the five individual sections in the scale, and consider the optimum combination of sections, for predicting low language ability. Specificity, sensitivity, and positive and negative predictive values were reported for each of the five sections of the ELIM alone and in conjunction with each other. The performance for children from monolingual English-speaking families and those who spoke languages other than English were also considered separately. RESULTS: Three hundred and seventy-six children were assessed on both the ELIM identification measure and the PLS-5 with 362 providing complete data. While each section of the ELIM predicted low language ability, the optimal combination for predicting language outcome was the parent reported vocabulary checklist coupled with the practitioner observation of the child's communication and related behaviours. This gave a sensitivity of 0·98 with a specificity of 0·63. CONCLUSIONS: A novel measure has been developed which accurately identifies children at risk of low language, allowing clinicians to target resources efficiently and intervene early.

Heterogeneity of autism symptoms in community-referred infants and toddlers at elevated or low familial likelihood of autism.

Evidence suggests autistic individuals at elevated familial likelihood of autism spectrum disorder (by virtue of having an autistic sibling) have stronger cognitive abilities on average than autistic individuals with no family history of the condition, who have a low familial likelihood of autism. Investigating phenotypic differences between community-referred infants and toddlers with autism symptoms at elevated or low familial likelihood of autism may provide important insight into heterogeneity in the emerging autism phenotype. This study compared behavioral, cognitive, and language abilities of community-referred infants and toddlers with confirmed autism symptoms at elevated (EL) or low familial likelihood of autism (LL). Participants were 121 children aged 12 to 36 months who participated in two larger randomized trials of parent-mediated interventions for children with autism symptoms. Behavioral phenotypes were compared across three groups: children with at least one autistic sibling (EL-Sibs, n = 30), those with at least one older, non-autistic sibling and no family history of autism (LL-Sibs, n = 40), and first-born children with no family history of autism (LL-FB, n = 51). EL-Sibs had less severe autism symptoms and stronger cognitive abilities than children in LL groups. While the rate of receptive language delay was similar across groups, the rate of expressive language delay was markedly lower among EL-Sibs. After controlling for age and nonverbal cognitive ability, EL-Sibs were significantly less likely to present with expressive language delay than LL-Sibs. Familial likelihood of autism may play an important role in shaping the emerging autism phenotype in infancy and toddlerhood.

A Developmental Surveillance Score for Quantitative Monitoring of Early Childhood Milestone Attainment: Algorithm Development and Validation.

BACKGROUND: Developmental surveillance, conducted routinely worldwide, is fundamental for timely identification of children at risk of developmental delays. It is typically executed by assessing age-appropriate milestone attainment and applying clinical judgment during health supervision visits. Unlike developmental screening and evaluation tools, surveillance typically lacks standardized quantitative measures, and consequently, its interpretation is often qualitative and subjective. OBJECTIVE: Herein, we suggested a novel method for aggregating developmental surveillance assessments into a single score that coherently depicts and monitors child development. We described the procedure for calculating the score and demonstrated its ability to effectively capture known population-level associations. Additionally, we showed that the score can be used to describe longitudinal patterns of development that may facilitate tracking and classifying developmental trajectories of children. METHODS: We described the Developmental Surveillance Score (DSS), a simple-to-use tool that quantifies the age-dependent severity level of a failure at attaining developmental milestones based on the recently introduced Israeli developmental surveillance program. We evaluated the DSS using a nationwide cohort of >1 million Israeli children from birth to 36 months of age, assessed between July 1, 2014, and September 1, 2021. We measured the score's ability to capture known associations between developmental delays and characteristics of the mother and child. Additionally, we computed series of the DSS in consecutive visits to describe a child's longitudinal development and applied cluster analysis to identify distinct patterns of these developmental trajectories. RESULTS: The analyzed cohort included 1,130,005 children. The evaluation of the DSS on subpopulations of the cohort, stratified by known risk factors of developmental delays, revealed expected relations between developmental delay and characteristics of the child and mother, including demographics and obstetrics-related variables. On average, the score was worse for preterm children compared to full-term children and for male children compared to female children, and it was correspondingly worse for lower levels of maternal education. The trajectories of scores in 6 consecutive visits were available for 294,000 children. The clustering of these trajectories revealed 3 main types of developmental patterns that are consistent with clinical experience: children who successfully attain milestones, children who initially tend to fail but improve over time, and children whose failures tend to increase over time. CONCLUSIONS: The suggested score is straightforward to compute in its basic form and can be easily implemented as a web-based tool in its more elaborate form. It highlights known and novel relations between developmental delay and characteristics of the mother and child, demonstrating its potential usefulness for surveillance and research. Additionally, it can monitor the developmental trajectory of a child and characterize it. Future work is needed to calibrate the score vis-a-vis other screening tools, validate it worldwide, and integrate it into the clinical workflow of developmental surveillance.

A randomised controlled feasibility trial of an early years language development intervention: results of the 'outcomes of Talking Together evaluation and results' (oTTer) project.

BACKGROUND: Early language difficulties are associated with poor school readiness and can impact lifelong attainment. The quality of the early home language environment is linked to language outcomes. However, few home-based language interventions have sufficient evidence of effectiveness in improving preschool children's language abilities. This study reports the first stage in the evaluation of a theory-based programme, Talking Together (developed and delivered by BHT Early Education and Training) given over 6 weeks to families in the home setting. We aimed to test the feasibility and acceptability of delivering Talking Together in the Better Start Bradford community prior to a definitive trial, using a two-armed randomised controlled feasibility study. METHODS: Families from a single site within the Better Start Bradford reach area were randomly allocated (1:1) to the Talking Together intervention or a wait list control group. Child language and parent-level outcome measures were administered before randomisation (baseline), pre-intervention (pre-test), 2 months post-intervention start (post-test), and 6 months post-intervention start (follow-up). Routine monitoring data from families and practitioners were also collected for eligibility, consent, protocol adherence, and attrition rates. Descriptive statistics on the feasibility and reliability of potential outcome measures were analysed alongside qualitative feedback on trial design acceptability. Pre-defined progression-to-trial criteria using a traffic light system were assessed using routine monitoring data. RESULTS: Two-hundred and twenty-two families were assessed for eligibility; of these, 164 were eligible. A total of 102 families consented and were randomised (intervention: 52, waitlist control: 50); 68% of families completed outcome measures at 6-month follow-up. Recruitment (eligibility and consent) reached 'green' progression criteria; however, adherence reached 'amber' and attrition reached 'red' criteria. Child- and parent-level data were successfully measured, and the Oxford-CDI was identified as a suitable primary outcome measure for a definitive trial. Qualitative data not only indicated that the procedures were largely acceptable to practitioners and families but also identified areas for improvement in adherence and attrition rates. CONCLUSIONS: Referral rates indicate that Talking Together is a much-needed service and was positively received by the community. A full trial is feasible with adaptations to improve adherence and reduce attrition. TRIAL REGISTRATION: ISRCTN registry ISRCTN13251954. Retrospectively registered 21 February 2019.

Clinical case report: mosaic ANK3 pathogenic variant in a patient with autism spectrum disorder and neurodevelopmental delay.

Ankyrins are a family of proteins that link integral membrane proteins to the underlying spectrin-actin cytoskeleton and play a key role in activities such as cell motility, activation, proliferation, cell-cell contact, and the maintenance of specialized membrane domains. Ankyrin 3 (ANK3) is one of the three major subtypes of the ankyrin protein family. Ankryin genes are ubiquitously expressed, but their expression is highest in the brain. In the central nervous system, ankyrins have critical roles at the axonal initial segment, the nodes of Ranvier, and at synapses. To date, pathogenic variants in ANK3 have been reported in individuals with neuropsychiatric, cognitive, and neurodevelopmental disorders. The clinical severity is variable in these individuals with both autosomal recessive and autosomal dominant patterns of inheritance observed. These findings have suggested genotype-phenotype correlations and even isoform-specific implications for individuals with ANK3 pathogenic variants. Here, we report a patient with speech delay, autism spectrum disorder, and a language disorder in which a de novo nonsense ANK3 alteration was discovered by exome sequencing. Interestingly, the next-generation sequencing data suggested the change was mosaic in the affected child, and it was confirmed by digital polymerase chain reaction (dPCR) at 22% allelic fraction. To our knowledge, this is the first case of an individual with a pathogenic mosaic ANK3 variant. This finding expands upon the existing genotype-phenotype information available for the ANK3 gene while also highlighting potential gene expression correlations with phenotype.

Does maternal genetic liability to folate deficiency influence the risk of antiseizure medication-associated language impairment and autistic traits in children of women with epilepsy?

BACKGROUND: Prenatal exposure to antiseizure medication (ASM) may lead to low plasma folate concentrations and is associated with impaired neurodevelopment. OBJECTIVES: To examine whether maternal genetic liability to folate deficiency interacts with ASM-associated risk of language impairment and autistic traits in children of women with epilepsy. METHODS: We included children of women with and without epilepsy and with available genetic data enrolled in the Norwegian Mother, Father, and Child Cohort Study. Information on ASM use, folic acid supplement use and dose, dietary folate intake, child autistic traits, and child language impairment was obtained from parent-reported questionnaires. Using logistic regression, we examined the interaction between prenatal ASM exposure and maternal genetic liability to folate deficiency expressed as polygenic risk score of low folate concentrations or maternal rs1801133 genotype (CC or CT/TT) on risk of language impairment or autistic traits. RESULTS: We included 96 children of women with ASM-treated epilepsy, 131 children of women with ASM-untreated epilepsy, and 37,249 children of women without epilepsy. The polygenic risk score of low folate concentrations did not interact with the ASM-associated risk of language impairment or autistic traits in ASM-exposed children of women with epilepsy compared with ASM-unexposed children aged 1.5-8 y. ASM-exposed children had increased risk of adverse neurodevelopment regardless of maternal rs1801133 genotype {adjusted odds ratio [aOR] for language impairment aged 8 y was 2.88 [95% confidence interval (CI): 1.00, 8.26] if CC and aOR 2.88 [95% CI: 1.10, 7.53] if CT/TT genotypes}. In children of women without epilepsy aged 3 y, those with maternal rs1801133 CT/TT compared with CC genotype had increased risk of language impairment (aOR: 1.18; 95% CI: 1.05, 1.34). CONCLUSIONS: In this cohort of pregnant women reporting widespread use of folic acid supplements, maternal genetic liability to folate deficiency did not significantly influence the ASM-associated risk of impaired neurodevelopment.