To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite ...this, no genotype-phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull's-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes-intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date.
The genetics of mental retardation Raymond, F. Lucy; Tarpey, Patrick
Human molecular genetics,
10/2006, Letnik:
15, Številka:
suppl-2
Journal Article
Recenzirano
Odprti dostop
Genetic abnormalities frequently give rise to a mental retardation phenotype. Recent advances in resolution of comparative genomic hybridization and genomic sequence annotation has identified new ...syndromes at chromosome 3q29 and 9q34. The finding of a significant number of copy number polymorphisms in the genome in the normal population, means that assigning pathogenicity to deletions and duplications in patients with mental retardation can be difficult but has been identified for duplications of MECP2 and L1CAM. Novel autosomal genes that cause mental retardation have been identified recently including CC2D1A identified by homozygosity mapping. Several new genes and pathways have been identified in the field of X-linked mental retardation but many more still await identification. Analysis of families where only a single male is affected reveals that the chance of this being due to a single X-linked gene abnormality is significantly less than would be expected if the excess of males in the population is entirely due to X-linked disease. Recent identification of novel X-linked mental retardation genes has identified components of the post-synaptic density and multiple zinc finger transcription factors as disease causing suggesting new mechanisms of disease causation. The first therapeutic treatments of animal models of mental retardation have been reported, a Drosophila model of Fragile X syndrome has been treated with lithium or metabotropic glutamate receptor (mGluR) antagonists and a mouse model of NF1 has been treated with the HMG-CoA reductase inhibitor lavastatin, which improves the learning and memory skills in these models.
Baker, Gordon et al. present the first international case series describing the neurodevelopmental disorder associated with Synaptotagmin 1 (SYT1) de novo missense mutations. Key features include ...movement abnormalities, severe intellectual disability, and hallmark EEG alterations. Expression of patients' SYT1 mutations in mouse neurons disturbs presynaptic vesicle dynamics in a mutation-specific manner.
Abstract
Synaptotagmin 1 (SYT1) is a critical mediator of fast, synchronous, calcium-dependent neurotransmitter release and also modulates synaptic vesicle endocytosis. This paper describes 11 patients with de novo heterozygous missense mutations in SYT1. All mutations alter highly conserved residues, and cluster in two regions of the SYT1 C2B domain at positions Met303 (M303K), Asp304 (D304G), Asp366 (D366E), Ile368 (I368T) and Asn371 (N371K). Phenotypic features include infantile hypotonia, congenital ophthalmic abnormalities, childhood-onset hyperkinetic movement disorders, motor stereotypies, and developmental delay varying in severity from moderate to profound. Behavioural characteristics include sleep disturbance and episodic agitation. Absence of epileptic seizures and normal orbitofrontal head circumference are important negative features. Structural MRI is unremarkable but EEG disturbance is universal, characterized by intermittent low frequency high amplitude oscillations. The functional impact of these five de novo SYT1 mutations has been assessed by expressing rat SYT1 protein containing the equivalent human variants in wild-type mouse primary hippocampal cultures. All mutant forms of SYT1 were expressed at levels approximately equal to endogenous wild-type protein, and correctly localized to nerve terminals at rest, except for SYT1M303K, which was expressed at a lower level and failed to localize at nerve terminals. Following stimulation, SYT1I368T and SYT1N371K relocalized to nerve terminals at least as efficiently as wild-type SYT1. However, SYT1D304G and SYT1D366E failed to relocalize to nerve terminals following stimulation, indicative of impairments in endocytic retrieval and trafficking of SYT1. In addition, the presence of SYT1 variants at nerve terminals induced a slowing of exocytic rate following sustained action potential stimulation. The extent of disturbance to synaptic vesicle kinetics is mirrored by the severity of the affected individuals' phenotypes, suggesting that the efficiency of SYT1-mediated neurotransmitter release is critical to cognitive development. In summary, de novo dominant SYT1 missense mutations are associated with a recognizable neurodevelopmental syndrome, and further cases can now be diagnosed based on clinical features, electrophysiological signature and mutation characteristics. Variation in phenotype severity may reflect mutation-specific impact on the diverse physiological functions of SYT1.
To describe better the motor phenotype, molecular genetic features, and clinical course of
-related disease.
We reviewed clinical information, video recordings, and neuroimaging of a newly identified ...cohort of 7 patients with de novo missense and splice site
mutations, detected by next-generation sequencing techniques.
Patients first presented in early childhood (median age of presentation 10 months, range 0-48 months), with a wide range of clinical symptoms ranging from severe motor and cognitive impairment with marked choreoathetosis, self-injurious behavior, and epileptic encephalopathy to a milder phenotype, featuring moderate developmental delay associated with complex stereotypies, mainly facial dyskinesia and mild epilepsy. Hyperkinetic movements were often exacerbated by specific triggers, such as voluntary movement, intercurrent illnesses, emotion, and high ambient temperature, leading to hospital admissions. Most patients were resistant to drug intervention, although tetrabenazine was effective in partially controlling dyskinesia for 2/7 patients. Emergency deep brain stimulation (DBS) was life saving in 1 patient, resulting in immediate clinical benefit with complete cessation of violent hyperkinetic movements. Five patients had well-controlled epilepsy and 1 had drug-resistant seizures. Structural brain abnormalities, including mild cerebral atrophy and corpus callosum dysgenesis, were evident in 5 patients. One patient had a diffuse astrocytoma (WHO grade II), surgically removed at age 16.
Our findings support the causative role of
mutations in an expanded spectrum of early-onset epilepsy and movement disorders, frequently exacerbated by specific triggers and at times associated with self-injurious behavior. Tetrabenazine and DBS were the most useful treatments for dyskinesia.
The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ...ADP-ribosylation factor family of small GTPases, caused this disorder. In addition to MRX1, IQSEC2 mutations were identified in three other families with X-linked intellectual disability. This discovery was made possible by systematic and unbiased X chromosome exome resequencing.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Brown-Vialetto-Van Laere syndrome is a rare neurological disorder with a variable age at onset and clinical course. The key features are progressive ponto-bulbar palsy and bilateral sensorineural ...deafness. A complex neurological phenotype with a mixed picture of upper and lower motor neuron involvement reminiscent of amyotrophic lateral sclerosis evolves with disease progression. We identified a candidate gene,
C20orf54, by studying a consanguineous family with multiple affected individuals and subsequently demonstrated that mutations in this gene were the cause of disease in other, unrelated families.
Genomic conditions can be associated with developmental delay, intellectual disability, autism spectrum disorder, and physical and mental health symptoms. They are individually rare and highly ...variable in presentation, which limits the use of standard clinical guidelines for diagnosis and treatment. A simple screening tool to identify young people with genomic conditions associated with neurodevelopmental disorders (ND-GCs) who could benefit from further support would be of considerable value. We used machine learning approaches to address this question.
A total of 493 individuals were included: 389 with a ND-GC, mean age = 9.01, 66% male) and 104 siblings without known genomic conditions (controls, mean age = 10.23, 53% male). Primary carers completed assessments of behavioural, neurodevelopmental and psychiatric symptoms and physical health and development. Machine learning techniques (penalised logistic regression, random forests, support vector machines and artificial neural networks) were used to develop classifiers of ND-GC status and identified limited sets of variables that gave the best classification performance. Exploratory graph analysis was used to understand associations within the final variable set.
All machine learning methods identified variable sets giving high classification accuracy (AUROC between 0.883 and 0.915). We identified a subset of 30 variables best discriminating between individuals with ND-GCs and controls which formed 5 dimensions: conduct, separation anxiety, situational anxiety, communication and motor development.
This study used cross-sectional data from a cohort study which was imbalanced with respect to ND-GC status. Our model requires validation in independent datasets and with longitudinal follow-up data for validation before clinical application.
In this study, we developed models that identified a compact set of psychiatric and physical health measures that differentiate individuals with a ND-GC from controls and highlight higher-order structure within these measures. This work is a step towards developing a screening instrument to identify young people with ND-GCs who might benefit from further specialist assessment.
Several copy number variants (CNVs) are associated with a high risk of neurodevelopmental and psychiatric disorders (referred to as ND-CNVs). We aimed to characterise the effect of ND-CNVs on ...childhood development and investigate whether different ND-CNVs lead to distinct and specific patterns of cognitive and behavioural outcomes.
In this case-control study, we used data from the Intellectual Disability and Mental Health: Assessing the Genomic Impact on Neurodevelopment (IMAGINE-ID) study. Children aged 4 years and older with pathogenic CNV or single nucleotide variants were recruited via the UK National Health Service (NHS) medical genetic clinic network and via patient support groups to complete broad online phenotyping, from whom children aged 6-19 years with at least one of a specific group of ND-CNVs (1q21.1 proximal duplication, and distal deletion and duplication, 2p16.3 deletion, 9q34.3 deletion, 15q11.2 deletion, 15q13.3 deletion and duplication, 16p11.2 proximal deletion and duplication, and distal deletion, and 22q11.2 deletion and duplication) and their families were approached for a deep phenotyping, home-based assessment, and we report on this sample here. We invited siblings of index children to participate as controls, for whom the presence of ND-CNVs was excluded by use of microarray results and also medical records where possible. We systematically assessed the children for psychiatric disorders and broader traits of neurodevelopmental, cognitive, and psychopathological origin and compared results of ND-CNV carriers with control siblings to test the hypothesis that phenotypes would differ by genotype, both quantitatively in terms of severity and qualitatively in the pattern of associated impairments.
Between Oct 1, 2014, and Dec 31, 2018, of 2819 children recruited, 258 (9%) had one ND-CNV of interest, with 13 CNVs across nine loci, and underwent a home-based assessment. 106 control siblings were enrolled. 186 (80%) of ND-CNV carriers met criteria for one or more psychiatric disorder (odds ratio OR 13·8, 95% CI 7·2-26·3, compared with controls). The risk of attention-deficit hyperactivity disorder (OR 6·9, 3·2-15·1), oppositional defiant disorder (OR 3·6, 1·4-9·4), any anxiety disorder (OR 2·9, 1·2-6·7), and autism spectrum disorder traits (OR 44·1, 15·3-127·5) was particularly high compared with controls. ND-CNV carriers were impaired across all neurodevelopmental, cognitive, and psychopathological traits compared with controls. Only moderate quantitative and qualitative differences in phenotypic profile were found between genotypes. Overall, the range of phenotypes was broadly similar for all ND-CNV genotypes. Traits did show some evidence of genotypic specificity, with rank-based analyses showing moderate qualitative and quantitative profile differences between ND-CNVs; however, the specific genotype accounted for a low proportion of variance in cognitive and behavioural outcomes (approximately 5-20% depending on the trait).
The 13 ND-CNVs studied have a similar range of adverse effects on childhood neurodevelopment, despite subtle quantitative and qualitative differences. Genomic risk for neuropsychiatric disorder has pleiotropic effects on multiple processes and neural circuits and indicates that future research should avoid being narrowly focused on single phenotypes.
UK Medical Research Council and Medical Research Foundation.
Copy number variants are amongst the most highly penetrant risk factors for psychopathology and neurodevelopmental deficits, but little information about the detailed clinical phenotype associated ...with particular variants is available. We present the largest study of the microdeletion and -duplication at the distal 1q21 locus, which has been associated with schizophrenia and intellectual disability, in order to investigate the range of psychiatric phenotypes. Clinical and cognitive data from 68 deletion and 55 duplication carriers were analysed with logistic regression analysis to compare frequencies of mental disorders between carrier groups and controls, and linear mixed models to compare quantitative phenotypes. Both children and adults with copy number variants at 1q21 had high frequencies of psychopathology. In the children, neurodevelopmental disorders were most prominent (56% for deletion, 68% for duplication carriers). Adults had increased prevalence of mood (35% for deletion OR = 6.6 (95% CI: 1.4-40.1), 55% for duplication carriers 8.3 (1.4-55.5)) and anxiety disorders (24% 1.8 (0.4-8.4) and 55% 10.0 (1.9-71.2)). The adult group, which included mainly genetically affected parents of probands, had an IQ in the normal range. These results confirm high prevalence of neurodevelopmental disorders associated with CNVs at 1q21 but also reveal high prevalence of mood and anxiety disorders in a high-functioning adult group with these CNVs. Because carriers of neurodevelopmental CNVs who show relevant psychopathology but no major cognitive impairment are not currently routinely receiving clinical genetic services widening of genetic testing in psychiatry may be considered.
PDF
