A new patient with a terminal de novo 2p25.3 deletion of 1.9 Mb associated with early-onset of obesity, intellectual disabilities and hyperkinetic disorder.
Ontology highlight
ABSTRACT:
SUBMITTER: Bonaglia MC
PROVIDER: S-EPMC4131807 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
Publications
A new patient with a terminal de novo 2p25.3 deletion of 1.9 Mb associated with early-onset of obesity, intellectual disabilities and hyperkinetic disorder.
Bonaglia Maria Clara MC Giorda Roberto R Zanini Sergio S
Molecular cytogenetics 20140805
Terminal and interstitial deletions of 2p25.3 (size < Mb), detected by array-CGH analysis, have been reported in about 18 patients sharing common clinical features represented by early-onset obesity/ overweightness associated with intellectual disabilities (ID) and behavioural troubles. This observations led to hypothesize that 2p subtelomeric deletion should be associated with syndromic obesity and MYT1L became the main candidate gene for ID and obesity since it is deleted or disrupted in all h ...[more]
Similar Datasets
Project description:BackgroundIntellectual disability (ID) is a complex condition that can impact multiple domains of development. The genetic contribution to ID's etiology is significant, with more than 100 implicated genes and loci currently identified. The majority of such variants are rare and de novo genetic mutations.MethodsWe have applied whole-genome microarray to identify large, rare, clinically relevant copy number variants (CNVs). We have applied well-established algorithms for variants call. Quantitative polymerase chain reaction (qPCR) was applied to validate the variants using three technical replicates for each family member. To assess whether the copy number variation was due to balanced translocation or mosaicism, we further conducted droplet digital PCR (ddPCR) on the whole family. We have, as well, applied "critical-exon" mapping, human developmental brain transcriptome, and a database of known associated neurodevelopmental disorder variants to identify candidate genes.ResultsHere we present two siblings who are both impacted by a large terminal duplication and a deletion. Whole-genome microarray revealed an 18.82 megabase (MB) duplication at terminal locus (7q34-q36.3) of chromosome 7 and a 3.90 MB deletion impacting the terminal locus (15q26.3) of chromosome 15. qPCR and ddPCR experiments confirmed the de novo origin of the variants and the co-occurrence of these two de novo events among the siblings, but their absence in both parents, implicates an unbalanced translocation that could have mal-segregated among the siblings or a possible germline mosaicism. These terminal events impact IGF1R, CNTNAP2, and DPP6, shown to be strongly associated with neurodevelopmental disorders. Detailed clinical examination of the siblings revealed the presence of both shared and distinct phenotypic features.ConclusionsThis study identified two large rare terminal de novo events impacting two siblings. Further phenotypic investigation highlights that even in the presence of identical large high penetrant variants, spectrum of clinical features can be different between the siblings.
| S-EPMC6785528 | biostudies-literature
Project description:Calcium/calmodulin-dependent protein kinases (CaMKs) are key mediators of calcium signaling and underpin neuronal health. Although widely studied, the contribution of CaMKs to Mendelian disease is rather enigmatic. Here, we describe an unusual neurodevelopmental phenotype, characterized by milestone delay, intellectual disability, autism, ataxia, and mixed hyperkinetic movement disorder including severe generalized dystonia, in a proband who remained etiologically undiagnosed despite exhaustive testing. We performed trio whole-exome sequencing to identify a de novo essential splice-site variant (c.981+1G>A) in CAMK4, encoding CaMKIV. Through in silico evaluation and cDNA analyses, we demonstrated that c.981+1G>A alters CAMK4 pre-mRNA processing and results in a stable mRNA transcript containing a 77-nt out-of-frame deletion and a premature termination codon within the last exon. The expected protein, p.Lys303Serfs*28, exhibits selective loss of the carboxy-terminal regulatory domain of CaMKIV and bears striking structural resemblance to previously reported synthetic mutants that confer constitutive CaMKIV activity. Biochemical studies in proband-derived cells confirmed an activating effect of c.981+1G>A and indicated that variant-induced excessive CaMKIV signaling is sensitive to pharmacological manipulation. Additionally, we found that variants predicted to cause selective depletion of CaMKIV's regulatory domain are unobserved in diverse catalogs of human variation, thus revealing that c.981+1G>A is a unique molecular event. We propose that our proband's phenotype is explainable by a dominant CAMK4 splice-disrupting mutation that acts through a gain-of-function mechanism. Our findings highlight the importance of CAMK4 in human neurodevelopment, provide a foundation for future clinical research of CAMK4, and suggest the CaMKIV signaling pathway as a potential drug target in neurological disease.
| S-EPMC6318768 | biostudies-literature
Project description:We describe a case of a 34-year-old male presenting with oligospermia and an otherwise normal phenotype. Investigation with array-based comparative genomic hybridization (aCGH) revealed an interstitial deletion of about 15.5 Mb in chromosome 5p13.3p14.3. We compared the phenotype of our patient with recently reported patients studied by aCGH, who show an overlapping deletion. We also analyzed the gene content of the deleted region in order to propose a possible involvement of specific genes in the clinical phenotype.
| S-EPMC3711483 | biostudies-literature
Project description:We report on a 29-year-old Greek-Cypriot female with a de novo 6.3?Mb distal 10q26.2q26.3 deletion. She had a very mild neurocognitive phenotype with near normal development and intellect. In addition, she had certain distinctive features and postural orthostatic tachycardia. We review the relevant literature and postulate that certain of her features can be diagnostically relevant. This report illustrates the powerful diagnostic ability of array-CGH in the elucidation of relatively mild phenotypes.
| S-EPMC4532806 | biostudies-literature
Project description:We describe a boy presenting with intellectual disability and dysmorphic features in whom a cryptic microdeletion in chromosome band 2q12.1 was identified with array CGH. The deletion results in a loss of the POU3F3 and MRPS9 genes. In this paper, we discuss the possible role of POU3F3 haploinsufficiency in relation to the boy's phenotype.
| S-EPMC3919428 | biostudies-literature
Project description:BackgroundMutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels.MethodsThe functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype-phenotype correlations of these and other cases were related to the functional analyses.ResultsThe first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel.ConclusionsComparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing.
| S-EPMC4413743 | biostudies-literature
Project description:We report a girl with a de novo distal deletion of 9p affected by idiopathic central precocious puberty and intellectual disability. Genome-wide array-CGH revealed a terminal deletion of about 11?Mb, allowing to define her karyotype as 46; XX, del(9)(p23-pter). To our knowledge, this is the second reported case of precocious puberty associated with 9p distal deletion. A third case associates precocious puberty with a more proximal 9p deletion del(9)(p12p13,3). In our case, more than 40 genes were encompassed in the deleted region, among which, DMRT1 which is gonad-specific and has a sexually dimorphic expression pattern and ERMP1 which is required in rats for the organization of somatic cells and oocytes into discrete follicular structures. Although we cannot exclude that precocious puberty in our del(9p) patient is a coincidental finding, the report of the other two patients with 9p deletions and precocious puberty indeed suggests a causative relationship.
| S-EPMC3747469 | biostudies-literature
Project description:BackgroundPathogenic PAK1 variants were described to be causative of neurodevelopmental disorder with macrocephaly, seizures, and speech delay. Herein, we present a de novo PAK1 variant combine with a de novo terminal 1q microdeletion in a Chinese pediatric patient, aiming to provide more insights into the underlying genotype-phenotype relationship.MethodsEnrolled in this study was a 6-year-old girl with clinical features of global developmental delay, severe intellectual disability, speech delay, and seizures from Quanzhou region of China. Karyotype and chromosomal microarray analysis (CMA) were performed to detect chromosome abnormalities in this family. Whole exome sequencing (WES) was performed to investigate additional genetic variants in this family.ResultsNo chromosomal abnormalities were elicited from the entire family by karyotype analysis. Further familial CMA results revealed that the patient had a de novo 2.7-Mb microdeletion (arr[GRCh37] 1q44(246,454,321_249,224,684) × 1]) in 1q44 region, which contains 14 OMIM genes, but did not overlap the reported smallest region of overlap (SRO) responsible for the clinical features in 1q43q44 deletion syndrome. In addition, WES result demonstrated a de novo NM_002576: c.251C > G (p.T84R) variant in PAK1 gene in the patient, which was interpreted as a likely pathogenic variant.ConclusionIn this study, we identify a novel PAK1 variant associated with a terminal 1q microdeletion in a patient with neurodevelopmental disorder. In addition, we believe that the main clinical features may ascribe to the pathogenic variant in PAK1 gene in the patient.
| S-EPMC9830755 | biostudies-literature
Project description:An IL-4 antagonist was designed based on structural and biochemical analysis of unbound IL-4 and IL-4 in complex with its high-affinity receptor (IL-4Ralpha). Our design strategy sought to capture a protein-protein interaction targeting the high affinity that IL-4 has for IL-4Ralpha. This strategy has impact due to the potential relevance of IL-4Ralpha as a drug target in the treatment of asthma. To mimic the IL-4 binding surface, critical side chains for receptor binding were identified, and these side chains were transplanted onto a previously characterized, de novo-designed four-helix protein called designed helical protein 1 (DHP-1). This first-generation design resolved the ambiguity previously described for the connectivity between helices in DHP-1 and resulted in a protein capable of binding to IL-4Ralpha. The second-generation antagonist was based upon further molecular modeling, and it succeeded in binding IL-4Ralpha better than the first-generation. This protein, termed DHP-14-AB, yielded a protein with a cooperative unfolding transition (DeltaGu0=8.1 kcal/mol) and an IC50 of 27 microM when in competition with IL-4 whereas DHP-1 had no affinity for IL-4Ralpha. The crystal structure of DHP-14-AB was determined to 1.9-A resolution and was compared with IL-4. This comparison revealed how design strategies targeting protein-protein interactions require high-resolution 3D data and the incorporation of orientation-specific information at the level of side-chains and secondary structure element interactions.
| S-EPMC548554 | biostudies-literature
Project description:Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.
| S-EPMC4214635 | biostudies-literature