Structural variants (SVs) can affect protein-coding sequences as well as gene regulatory elements. However, SVs disrupting protein-coding sequences that also function as
cis
-regulatory elements ...remain largely uncharacterized. Here, we show that craniosynostosis patients with SVs containing the histone deacetylase 9
(HDAC9
) protein-coding sequence are associated with disruption of
TWIST1
regulatory elements that reside within the
HDAC9
sequence. Based on SVs within the
HDAC9
‐
TWIST1
locus, we defined the 3′-
HDAC9
sequence as a critical
TWIST1
regulatory region, encompassing craniofacial
TWIST1
enhancers and CTCF sites. Deletions of either
Twist1
enhancers (eTw5-7
Δ/Δ
) or CTCF site (CTCF-5
Δ/Δ
) within the
Hdac9
protein-coding sequence led to decreased
Twist1
expression and altered anterior/posterior limb expression patterns of SHH pathway genes. This decreased
Twist1
expression results in a smaller sized and asymmetric skull and polydactyly that resembles
Twist1
+/−
mouse phenotype. Chromatin conformation analysis revealed that the
Twist1
promoter interacts with
Hdac9
sequences that encompass
Twist1
enhancers and a CTCF site, and that interactions depended on the presence of both regulatory regions. Finally, a large inversion of the entire
Hdac9
sequence (
Hdac9
INV/+
) in mice that does not disrupt
Hdac9
expression but repositions
Twist1
regulatory elements showed decreased
Twist1
expression and led to a craniosynostosis-like phenotype and polydactyly. Thus, our study elucidates essential components of
TWIST1
transcriptional machinery that reside within the
HDAC9
sequence. It suggests that SVs encompassing protein-coding sequences could lead to a phenotype that is not attributed to its protein function but rather to a disruption of the transcriptional regulation of a nearby gene.
•We investigated the electrophysiological and behavioral correlates of emotional distraction in ADHD.•Emotional distracters disrupted patient’s performance on a cognitive task.•Patients displayed ...larger anterior N2 amplitudes to emotional distracters compared to controls.•Results suggest that patients with ADHD were more susceptible to emotional distraction than controls.
Although, in everyday life, patients with attention deficit hyperactivity disorder (ADHD) are frequently distracted by goal-irrelevant affective stimuli, little is known about the neural and behavioral substrates underlying this emotional distractibility. Because some of the most important brain responses associated with the sudden onset of an emotional distracter are characterized by their early latency onset and short duration, we addressed this issue by using a temporally agile neural signal capable of detecting and distinguishing them. Specifically, scalp event-related potentials (ERPs) were recorded while 20 boys with ADHD combined type and 20 healthy comparison subjects performed a digit categorization task during the presentation of three types of irrelevant, distracting stimuli: arousing negative (A−), neutral (N) and arousing positive (A+). Behavioral data showed that emotional distracters (both A− and A+) were associated with longer reaction times than neutral ones in the ADHD group, whereas no differences were found in the control group. ERP data revealed that, compared with control subjects, boys with ADHD showed larger anterior N2 amplitudes for emotional than for neutral distracters. Furthermore, regression analyses between ERP data and subjects’ emotional ratings of distracting stimuli showed that only in the ADHD group, emotional arousal (ranging from calming to arousing) was associated with anterior N2: its amplitude increased as the arousal content of the visual distracter increased. These results suggest that boys with ADHD are more vulnerable to the distracting effects of irrelevant emotional stimuli than control subjects. The present study provides first data on the neural substrates underlying emotional distractibility in ADHD.
To describe the clinical and genetic findings in a cohort of individuals with bathing epilepsy, a rare form of reflex epilepsy.
We investigated by Sanger and targeted resequencing the
gene in 12 ...individuals from 10 different families presenting with seizures triggered primarily by bathing or showering. An additional 12 individuals with hot-water epilepsy were also screened.
In all families with bathing epilepsy, we identified 8 distinct pathogenic or likely pathogenic variants and 2 variants of unknown significance in
, 9 of which are novel. Conversely, none of the individuals with hot-water epilepsy displayed
variants. In mutated individuals, seizures were typically triggered by showering or bathing regardless of the water temperature. Additional triggers included fingernail clipping, haircutting, or watching someone take a shower. Unprovoked seizures and a variable degree of developmental delay were also common.
Bathing epilepsy is genetically distinct reflex epilepsy caused mainly by
mutations.
ANO3 and early-onset dyskinetic encephalopathy Jiménez de Domingo, Ana; Lopez-Martín, Sara; Albert, Jacobo ...
European journal of medical genetics,
December 2020, 2020-Dec, 2020-12-00, 20201201, Volume:
63, Issue:
12
Journal Article
Peer reviewed
Mutations in the ANO3 gene have been associated with autosomal dominant craniocervical dystonia. However, little else is known about the genotype-phenotype characteristics of this disorder. Here we ...describe a 3 years-old girl with distal myoclonic dystonia. Whole exome sequencing in trio revealed a de novo missense ANO3 variant not previously described in international databases. A global psychomotor regression was observed once dystonia was present. Brain MRI changes paralleled these findings: whereas MRI at the age of 18 months was normal, mild brain and cerebellar atrophy was observed 18 months later. These results suggest that missense mutations in ANO3 may underlie complex disorders particularly characterized by early psychomotor regression and dystonia.
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition in childhood (5.3% to 7.1% worldwide prevalence), with substantial overall financial burden to ...children/adolescents, their families, and society. The aims of this study were to describe the clinical characteristics of children and adolescents with ADHD in Spain, estimate the associated direct/indirect costs of the disorder, and assess whether the characteristics and financial costs differed between children/adolescents adequately responding to currently available pharmacotherapies compared with children/adolescents for whom pharmacotherapies failed.
This was a multicenter, cross-sectional, descriptive analysis conducted in 15 health units representative of the overall Spanish population. Data on demographic characteristics, socio-occupational status, social relationships, clinical variables of the disease, and pharmacological and non-pharmacological treatments received were collected in 321 children and adolescents with ADHD. Direct and indirect costs were estimated over one year from both a health care system and a societal perspective.
The estimated average cost of ADHD per year per child/adolescent was €5733 in 2012 prices; direct costs accounted for 60.2% of the total costs (€3450). Support from a psychologist/educational psychologist represented 45.2% of direct costs and 27.2% of total costs. Pharmacotherapy accounted for 25.8% of direct costs and 15.5% of total costs. Among indirect costs (€2283), 65.2% was due to caregiver expenses. The total annual costs were significantly higher for children/adolescents who responded poorly to pharmacological treatment (€7654 versus €5517; P = 0.024), the difference being mainly due to significantly higher direct costs, particularly with larger expenses for non-pharmacological treatment (P = 0.012).
ADHD has a significant personal, familial, and financial impact on the Spanish health system and society. Successful pharmacological intervention was associated with lower overall expenses in the management of the disorder.
Holoprosencephaly is a spectrum of developmental disorder of the embryonic forebrain in which there is failed or incomplete separation of the prosencephalon into two cerebral hemispheres. To date, ...dominant mutations in sonic hedgehog (SHH) pathway genes are the predominant Mendelian causes, and have marked interfamilial and intrafamilial phenotypical variabilities.
We describe two families in which offspring had holoprosencephaly spectrum and homozygous predicted-deleterious variants in phospholipase C eta-1 (
). Immunocytochemistry was used to examine the expression pattern of PLCH1 in human embryos. We used SHH as a marker of developmental stage and of early embryonic anatomy.
In the first family, two siblings had congenital hydrocephalus, significant developmental delay and a monoventricle or fused thalami with a homozygous
c.2065C>T, p.(Arg689*) variant. In the second family, two siblings had alobar holoprosencephaly and cyclopia with a homozygous
c.4235delA, p.(Cys1079ValfsTer16) variant. All parents were healthy carriers, with no holoprosencephaly spectrum features. We found that the subcellular localisation of PLCH1 is cytoplasmic, but the p.(Cys1079ValfsTer16) variant was predominantly nuclear. Human embryo immunohistochemistry showed PLCH1 to be expressed in the notorcord, developing spinal cord (in a ventral to dorsal gradient), dorsal root ganglia, cerebellum and dermatomyosome, all tissues producing or responding to SHH. Furthermore, the embryonic subcellular localisation of PLCH1 was exclusively cytoplasmic, supporting protein mislocalisation contributing to the pathogenicity of the p.(Cys1079ValfsTer16) variant.
Our data support the contention that PLCH1 has a role in prenatal mammalian neurodevelopment, and deleterious variants cause a clinically variable holoprosencephaly spectrum phenotype.
Utilizing trio whole-exome sequencing and a gene matching approach, we identified a cohort of 18 male individuals from 17 families with hemizygous variants in KCND1, including two de novo missense ...variants, three maternally inherited protein-truncating variants, and 12 maternally inherited missense variants. Affected subjects present with a neurodevelopmental disorder characterized by diverse neurological abnormalities, mostly delays in different developmental domains, but also distinct neuropsychiatric signs and epilepsy. Heterozygous carrier mothers are clinically unaffected. KCND1 encodes the α-subunit of Kv4.1 voltage-gated potassium channels. All variant-associated amino acid substitutions affect either the cytoplasmic N- or C-terminus of the channel protein except for two occurring in transmembrane segments 1 and 4. Kv4.1 channels were functionally characterized in the absence and presence of auxiliary β subunits. Variant-specific alterations of biophysical channel properties were diverse and varied in magnitude. Genetic data analysis in combination with our functional assessment shows that Kv4.1 channel dysfunction is involved in the pathogenesis of an X-linked neurodevelopmental disorder frequently associated with a variable neuropsychiatric clinical phenotype.
Hemizygous variants of KCND1 lead to alterations in the biophysical properties of the encoded ion channel, implicating dysfunction of Kv4.1 voltage-gated potassium channels in the etiology of an X-linked neurodevelopmental disorder with variable expressivity.
Autism spectrum disorder (ASD) is a group of neurological and developmental disabilities characterised by clinical and genetic heterogeneity. The current study aimed to expand ASD genotyping by ...investigating potential associations with
mutations. Specifically, the disease-causing variants of
in 410 trios manifesting neurodevelopmental disorders using whole-exome sequencing were explored. The consequences of the identified variants were studied at the transcript level using quantitative polymerase chain reaction (qPCR). For validation, immunofluorescence and immunoblotting were performed to analyse mutational effects at the protein level. The compound heterozygous variants of
(NM_182914.3:c.2483T>G; p.(Val828Gly) and NM_182914.3:c.2362G>A; p.(Glu788Lys)) were identified in a 4.5-year-old male, clinically diagnosed with autism spectrum disorder, developmental delay and intellectual disability. Both variants reside within the nesprin-2 giant spectrin repeat (SR5) domain and are predicted to be highly damaging using in silico tools. Specifically, a significant reduction of nesprin-2 giant protein levels is revealed in patient cells.
transcription and the nuclear envelope localisation of the mutant proteins was however unaffected as compared to parental control cells. Collectively, these data provide novel insights into the cardinal role of the nesprin-2 giant in neurodevelopment and suggest that the biallelic hypomorphic
mutations may be a new cause of intellectual disability and ASD.
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