Anxiety in Angelman Syndrome Grebe, Stacey C; Limon, Danica L; McNeel, Morgan M ...
American journal on intellectual and developmental disabilities,
01/2022, Volume:
127, Issue:
1
Journal Article
Peer reviewed
Open access
Angelman Syndrome (AS) is a neurodevelopmental disorder most commonly caused by the impaired expression of the maternal UBE3A gene on chromosome 15. Though anxiety has been identified as a frequently ...present characteristic in AS, there are limited studies examining anxiety in this population. Studies of anxiety in other neurodevelopmental disorders have found disorder specific symptoms of anxiety and age specific displays of anxiety symptoms. However, there is a consistent challenge in identifying anxiety in people with neurodevelopmental disorders given the lack of measurement instruments specifically designed for this population. Given the limited information about AS and anxiety, the aims of the current project were to (a) examine symptoms of anxiety in children with AS and (b) determine the correlates of anxiety in children with AS. Participants included 42 adult caregivers of youth with AS in the AS Natural History study who completed the Developmental Behavior Checklist (DBC). The results found that 26% of the sample demonstrated elevated symptoms of anxiety and established a relationship between elevated anxiety in youth with AS and higher levels of irritability, hyperactivity, self-absorbed behaviors, and disruptive/antisocial behaviors. Findings from this research provide a foundation for tailoring evidence-based assessments and treatments for youth with AS and anxiety.
Co‐occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM ...251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < −3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier‐Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel‐like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral‐Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel‐like phenotype and FFS, the last of which has not been associated with any disease gene to date.
Angelman syndrome (AS) is a neurodevelopmental disorder caused by a deletion on chromosome 15, uniparental disomy, imprinting defect, or UBE3A mutation. It is characterized by intellectual disability ...with minimal speech and certain behavioral characteristics. We used standardized measures to characterize the developmental profile and to analyze genotype-phenotype correlations in AS.
The study population consisted of 92 children, between 5 months and 5 years of age, enrolled in a Natural History Study. Each participant was evaluated using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), the Vineland Adaptive Behavior Scales, Second Edition (VABS-II), and the Aberrant Behavior Checklist.
Seventy-four percent had a deletion and 26% had uniparental disomy, an imprinting defect or a UBE3A mutation ("non-deletion"). The mean +/- standard deviation BSID-III cognitive scale developmental quotient (DQ) was 40.5 +/- 15.5. Participants with deletions were more developmentally delayed than the non-deletion participants in all BSID-III domains except in expressive language skills. The cognitive DQ was higher than the DQ in each of the other domains, and the receptive language DQ was higher than the expressive language DQ. In the corrected VABS-II, deletion participants had weaker motor and language skills than the non-deletion participants.
Children with AS have a distinct developmental and behavioral profile; their cognitive skills are stronger than their language and motor skills, and their receptive language skills are stronger than expressive language skills. Developmental outcomes are associated with genotype, with deletion patients having worse outcomes than non-deletion patients.
Chromosomal microarray analysis enables the detection of microdeletions/duplications and has become the standard in clinical diagnostic testing for individuals with congenital anomalies and ...developmental disabilities. In the era of genomic arrays, the value of traditional chromosome analysis needs to be reassessed.
We studied 3,710 unrelated patients by chromosomal microarray analysis and chromosome analysis simultaneously and compared the results.
We found that chromosomal microarray analysis detected the chromosomal imbalances that were identified by chromosome analysis with the exception of six cases (0.16%) that had mosaic abnormalities. Of note, one case showed mosaicism for two abnormal cell lines, resulting in a balanced net effect and a normal chromosomal microarray analysis. Further structural abnormalities such as unbalanced translocations, rings, and complex rearrangements were subsequently clarified by chromosome analysis in 18% of the cases with abnormal chromosomal microarray analysis results. Apparently balanced rearrangements were detected by chromosome analysis in 30 cases (0.8%).
Our data demonstrate that although chromosomal microarray analysis should be the first-tier test for clinical diagnosis of chromosome abnormalities, chromosome analysis remains valuable in the detection of mosaicism and delineation of chromosomal structural rearrangements.
Genet Med 2013:15(6):450–457
Fibrochondrogenesis is a severe, autosomal-recessive, short-limbed skeletal dysplasia. In a single case of fibrochondrogenesis, whole-genome SNP genotyping identified unknown ancestral consanguinity ...by detecting three autozygous regions. Because of the predominantly skeletal nature of the phenotype, the 389 genes localized to the autozygous intervals were prioritized for mutation analysis by correlation of their expression with known cartilage-selective genes via the UCLA Gene Expression Tool, UGET. The gene encoding the α1 chain of type XI collagen (
COL11A1) was the only cartilage-selective gene among the three candidate intervals. Sequence analysis of
COL11A1 in two genetically independent fibrochondrogenesis cases demonstrated that each was a compound heterozygote for a loss-of-function mutation on one allele and a mutation predicting substitution for a conserved triple-helical glycine residue on the other. The parents who were carriers of missense mutations had myopia. Early-onset hearing loss was noted in both parents who carried a loss-of-function allele, suggesting
COL11A1 as a locus for mild, dominantly inherited hearing loss. These findings identify
COL11A1 as a locus for fibrochondrogenesis and indicate that there might be phenotypic manifestations among carriers.
We studied seven children with CNS folate deficiency (CFD). All cases exhibited psychomotor retardation, regression, cognitive delay, and dyskinesia; six had seizures; four demonstrated neurological ...abnormalities in the neonatal period. Two subjects had profound neurological abnormalities that precluded formal behavioral testing. Five subjects received ADOS and ADI-R testing and met diagnostic criteria for autism or autism spectrum disorders. They exhibited difficulties with transitions, insistence on sameness, unusual sensory interests, and repetitive behaviors. Those with the best language skills largely used repetitive phrases. No mutations were found in folate transporter or folate enzyme genes. These findings demonstrate that autistic features are salient in CFD and suggest that a subset of children with developmental regression, mental retardation, seizures, dyskinesia, and autism may have CNS folate abnormalities.
Brain malformations caused by 17p13.3 deletions include lissencephaly with deletions of the larger Miller–Dieker syndrome region or smaller deletions of only PAFAH1B1, white matter changes, and a ...distinct syndrome due to deletions including YWHAE and CRK but sparing PAFAH1B1. We sought to understand the significance of 17p13.3 deletions between the YWHAE/CRK and PAFAH1B1 loci.
We analyzed the clinical features of six individuals from five families with 17p13.3 deletions between and not including YWHAE/CRK and PAFAH1B1 identified among individuals undergoing clinical chromosomal microarray testing or research genome sequencing.
Five individuals from four families had multifocal white matter lesions while a sixth had a normal magnetic resonance image. A combination of our individuals and a review of those in the literature with white matter changes and deletions in this chromosomal region narrows the overlapping region for this brain phenotype to ~345kb, including 11 RefSeq genes, with RTN4RL1 haploinsufficiency as the best candidate for causing this phenotype.
While previous literature has hypothesized dysmorphic features and white matter changes related to YWHAE, our cohort contributes evidence to the presence of additional genetic changes within 17p13.3 required for proper brain development.
Point mutations and genomic deletions of the CDKL5 (STK9) gene on chromosome Xp22 have been reported in patients with severe neurodevelopmental abnormalities, including Rett-like disorders. To date, ...only larger-sized (8-21 Mb) duplications harboring CDKL5 have been described. We report seven females and four males from seven unrelated families with CDKL5 duplications 540-935 kb in size. Three families of different ethnicities had identical 667kb duplications containing only the shorter CDKL5 isoform. Four affected boys, 8-14 years of age, and three affected girls, 6-8 years of age, manifested autistic behavior, developmental delay, language impairment, and hyperactivity. Of note, two boys and one girl had macrocephaly. Two carrier mothers of the affected boys reported a history of problems with learning and mathematics while at school. None of the patients had epilepsy. Similarly to CDKL5 mutations and deletions, the X-inactivation pattern in all six studied females was random. We hypothesize that the increased dosage of CDKL5 might have affected interactions of this kinase with its substrates, leading to perturbation of synaptic plasticity and learning, and resulting in autistic behavior, developmental and speech delay, hyperactivity, and macrocephaly.
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