Novel EED mutation in patient with Weaver syndrome.

Weaver syndrome is a rare condition characterized by overgrowth, macrocephaly, accelerated osseous maturation, variable intellectual disability, and characteristic facial features. Pathogenic variants in EZH2, a histone methyltransferase, have previously been identified as a cause of Weaver syndrome. However, the underlying molecular cause in many patients remains unknown. We report a patient with a clinical diagnosis of Weaver syndrome whose exome was initially non-diagnostic. Reports in the medical literature of EED associated overgrowth prompted re-analysis of the patient's original exome data. The patient was found to have a likely pathogenic variant in EED. These findings support that Weaver syndrome is a disorder with locus heterogeneity and can be due to pathogenic variants in either EZH2 or EED. This case highlights the utility of exome sequencing as a clinical diagnostic tool for novel gene discovery as well as the importance of re-examination of exome data as new information about gene-disease associations becomes available. © 2016 Wiley Periodicals, Inc.

Small rare recurrent deletions and reciprocal duplications in 2q21.1, including brain-specific ARHGEF4 and GPR148.

We have identified a rare small (~450 kb unique sequence) recurrent deletion in a previously linked attention-deficit hyperactivity disorder (ADHD) locus at 2q21.1 in five unrelated families with developmental delay (DD)/intellectual disability (ID), ADHD, epilepsy and other neurobehavioral abnormalities from 17 035 samples referred for clinical chromosomal microarray analysis. Additionally, a DECIPHER (http://decipher.sanger.ac.uk) patient 2311 was found to have the same deletion and presented with aggressive behavior. The deletion was not found in either six control groups consisting of 13 999 healthy individuals or in the DGV database. We have also identified reciprocal duplications in five unrelated families with autism, developmental delay (DD), seizures and ADHD. This genomic region is flanked by large, complex low-copy repeats (LCRs) with directly oriented subunits of ~109 kb in size that have 97.7% DNA sequence identity. We sequenced the deletion breakpoints within the directly oriented paralogous subunits of the flanking LCR clusters, demonstrating non-allelic homologous recombination as a mechanism of formation. The rearranged segment harbors five genes: GPR148, FAM123C, ARHGEF4, FAM168B and PLEKHB2. Expression of ARHGEF4 (Rho guanine nucleotide exchange factor 4) is restricted to the brain and may regulate the actin cytoskeletal network, cell morphology and migration, and neuronal function. GPR148 encodes a G-protein-coupled receptor protein expressed in the brain and testes. We suggest that small rare recurrent deletion of 2q21.1 is pathogenic for DD/ID, ADHD, epilepsy and other neurobehavioral abnormalities and, because of its small size, low frequency and more severe phenotype might have been missed in other previous genome-wide screening studies using single-nucleotide polymorphism analyses.

Inattention and Hyperactivity in Children with Symptomatic and Asymptomatic Congenital Cytomegalovirus.

OBJECTIVES: To explore the relationship between congenital cytomegalovirus (CMV) and inattention and hyperactivity among school-aged children. METHODS: The Behavior Assessment System for Children, Second Edition, parent- and self-report, was completed among children with symptomatic congenital CMV (ScCMV) (n = 36), asymptomatic congenital CMV (AcCMV) (n = 76), and controls (n = 29) enrolled in a longitudinal cohort. The proportions of children with ScCMV, AcCMV, and controls with Attention Problems or Hyperactivity T-scores ever ≥ 65 were compared. Mean T-scores in these domains were also compared and adjusted for IQ. RESULTS: Children with AcCMV did not differ from controls in the proportion of children with elevated Attention Problems or Hyperactivity T-scores or in mean Attention Problems or Hyperactivity T-scores. Children with ScCMV had a higher proportion of elevated Attention Problems T-scores compared with the AcCMV group but not controls. There were no differences in the proportions of children with elevated Hyperactivity T-scores between ScCMV and AcCMV or control groups. Children with ScCMV had higher mean Attention Problems T-scores versus those with AcCMV and controls and higher mean Hyperactivity T-scores versus those with AcCMV but not controls. After adjustment for IQ, differences in mean Attention Problems or Hyperactivity T-scores were no longer significant. CONCLUSION: Children with AcCMV are not at increased risk of inattention or hyperactivity compared with controls. However, our study suggests an increased prevalence of inattention and hyperactivity among children with ScCMV. Differences in IQ were confirmed to have a confounding effect. Evaluation for attention-deficit/hyperactivity disorder may be warranted in this population.

Phenotypic characterization of individuals with SYNGAP1 pathogenic variants reveals a potential correlation between posterior dominant rhythm and developmental progression.

BACKGROUND: The SYNGAP1 gene encodes for a small GTPase-regulating protein critical to dendritic spine maturation and synaptic plasticity. Mutations have recently been identified to cause a breadth of neurodevelopmental disorders including autism, intellectual disability, and epilepsy. The purpose of this work is to define the phenotypic spectrum of SYNGAP1 gene mutations and identify potential biomarkers of clinical severity and developmental progression. METHODS: A retrospective clinical data analysis of individuals with SYNGAP1 mutations was conducted. Data included genetic diagnosis, clinical history and examinations, neurophysiologic data, neuroimaging, and serial neurodevelopmental/behavioral assessments. All patients were seen longitudinally within a 6-year period; data analysis was completed on June 30, 2018. Records for all individuals diagnosed with deleterious SYNGAP1 variants (by clinical sequencing or exome sequencing panels) were reviewed. RESULTS: Fifteen individuals (53% male) with seventeen unique SYNGAP1 mutations are reported. Mean age at genetic diagnosis was 65.9 months (28-174 months). All individuals had epilepsy, with atypical absence seizures being the most common semiology (60%). EEG abnormalities included intermittent rhythmic delta activity (60%), slow or absent posterior dominant rhythm (87%), and epileptiform activity (93%), with generalized discharges being more common than focal. Neuroimaging revealed nonspecific abnormalities (53%). Neurodevelopmental evaluation revealed impairment in all individuals, with gross motor function being the least affected. Autism spectrum disorder was diagnosed in 73% and aggression in 60% of cases. Analysis of biomarkers revealed a trend toward a moderate positive correlation between visual-perceptual/fine motor/adaptive skills and language development, with posterior dominant rhythm on electroencephalogram (EEG), independent of age. No other neurophysiology-development associations or correlations were identified. CONCLUSIONS: A broad spectrum of neurologic and neurodevelopmental features are found with pathogenic variants of SYNGAP1. An abnormal posterior dominant rhythm on EEG correlated with abnormal developmental progression, providing a possible prognostic biomarker.

Intelligence and Academic Achievement With Asymptomatic Congenital Cytomegalovirus Infection.

OBJECTIVES: To examine intelligence, language, and academic achievement through 18 years of age among children with congenital cytomegalovirus infection identified through hospital-based newborn screening who were asymptomatic at birth compared with uninfected infants. METHODS: We used growth curve modeling to analyze trends in IQ (full-scale, verbal, and nonverbal intelligence), receptive and expressive vocabulary, and academic achievement in math and reading. Separate models were fit for each outcome, modeling the change in overall scores with increasing age for patients with normal hearing (n = 78) or with sensorineural hearing loss (SNHL) diagnosed by 2 years of age (n = 11) and controls (n = 40). RESULTS: Patients with SNHL had full-scale intelligence and receptive vocabulary scores that were 7.0 and 13.1 points lower, respectively, compared with controls, but no significant differences were noted in these scores among patients with normal hearing and controls. No significant differences were noted in scores for verbal and nonverbal intelligence, expressive vocabulary, and academic achievement in math and reading among patients with normal hearing or with SNHL and controls. CONCLUSIONS: Infants with asymptomatic congenital cytomegalovirus infection identified through newborn screening with normal hearing by age 2 years do not appear to have differences in IQ, vocabulary or academic achievement scores during childhood, or adolescence compared with uninfected children.

Prevalence of Autism Spectrum Disorder in Children Referred for Diagnostic Autism Evaluation.

Increased public awareness of autism spectrum disorders (ASD) and routine screening in primary care have contributed to increased requests for diagnostic ASD evaluations. However, given the scarcity of subspecialty autism diagnostic resources, overreferral of children suspected of having ASD may be contributing to long waiting lists at tertiary care autism centers and delaying diagnosis for those children who truly have ASD. To determine whether children are being excessively referred to ASD-specific diagnostic clinics, our objective was to determine the prevalence of true ASD diagnoses in children referred for diagnostic ASD evaluation. Charts of all patients referred to a regional autism center between April 2011 and August 2012 for suspicion of a possible ASD were retrospectively reviewed and demographic and clinical diagnoses abstracted. Only 214 of 348 patients evaluated (61%) received an ASD diagnosis. Thus, concerns about autism are not confirmed by an ASD diagnosis in a significant number of children.

Neurodevelopmental disabilities in children with intermediate and premutation range fragile X cytosine-guanine-guanine expansions.

To determine the range of neurodevelopmental diagnoses associated with intermediate (45-54 repeats) and premutation (55-200 repeats) range cytosine-guanine-guanine fragile X expansions, the medical records of children with intermediate or premutation range expansions were retrospectively reviewed, and all neurodevelopmental diagnoses were abstracted. Twenty-nine children (9 female, 20 male; age, 13 months to 17 years) with intermediate (n = 25) or premutation (n = 4) range expansions were identified with neurodevelopmental diagnoses, including global developmental delay/intellectual disability (n = 15), language and learning disorders (n = 9), attention-deficit hyperactivity disorder (n = 5), epilepsy (n = 5), and motor disorders (n = 12), including 2 boys younger than 4 years of age with tremor and ataxia. Thus, children with intermediate or premutation range fragile X cytosine-guanine-guanine expansions may be more susceptible than children without such expansions to other processes, both genetic and environmental, that contribute to neurodevelopmental disability.