Intellectual disability associated with craniofacial dysmorphism, cleft palate, and congenital heart defect due to a de novo MEIS2 mutation: A clinical longitudinal study
Andrea GangfußGökhan YigitJanine AltmüllerPeter NürnbergJohanna Christina CzeschikBernd WollnikNina BögershausenPeter BurfeindDagmar WieczorekFrank J. KaiserAndreas RoosHeike KölbelUlrike Schara–SchmidtAlma Kuechler
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Abstract Intellectual disability (ID) has an estimated prevalence of 1.5%–2%. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that sporadic ID cases result from de novo mutations in genes associated with ID. Here, we report on a 10‐year‐old girl, who has been regularly presented in our neuropediatric and genetic outpatient clinic. A median cleft palate and a heart defect were surgically corrected in infancy. Apart from ID, she has behavioral anomalies, muscular hypotonia, scoliosis, and hypermobile joints. The facial phenotype is characterized by arched eyebrows, mildly upslanting long palpebral fissures, prominent nasal tip, and large, protruding ears. Trio WES revealed a de novo missense variant in MEIS2 (c.998G>A; p.Arg333Lys). Haploinsufficiency of MEIS2 had been discussed as the most likely mechanism of the microdeletion 5q14‐associated complex phenotype with ID, cleft palate, and heart defect. Recently, four studies including in total 17 individuals with intragenic MEIS2 variants were reported. Here we present the evolution of the clinical phenotype and compare with the data of known individuals.Keywords:
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Intellectual disability (ID) represents a neurodevelopmental disorder, which is characterized by marked defects in the intellectual function and adaptive behavior, with an onset during the developmental period. ID is mainly caused by genetic factors, and it is extremely genetically heterogeneous. This study aims to identify the genetic cause of ID using trio-WES analysis.We recruited four pediatric patients with unexplained ID from non-consanguineous families, who presented at the Department of Pediatrics, Guizhou Provincial People's Hospital. Whole-exome sequencing (WES) and Sanger sequencing validation were performed in the patients and their unaffected parents. Furthermore, conservative analysis and protein structural and functional prediction were performed on the identified pathogenic variants.We identified five novel de novo mutations from four known ID-causing genes in the four included patients, namely COL4A1 (c.2786T>A, p.V929D and c.2797G>A, p.G933S), TBR1 (c.1639_1640insCCCGCAGTCC, p.Y553Sfs*124), CHD7 (c.7013A>T, p.Q2338L), and TUBA1A (c.1350del, p.E450Dfs*34). These mutations were all predicted to be deleterious and were located at highly conserved domains that might affect the structure and function of these proteins.Our findings contribute to expanding the mutational spectrum of ID-related genes and help to deepen the understanding of the genetic causes and heterogeneity of ID.
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Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.
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Exome sequencing has greatly impacted the speed at which new disease genes are identified. In the last year alone, six studies have used exome sequencing to identify new genes involved in intellectual disability, a genetically heterogeneous condition affecting 1-3% of the population. These studies encompass the full gamut of modes of inheritance and phenotypic presentation, including syndromic and non-syndromic conditions, sporadic and familial cases, and dominant and recessive inheritance patterns. Because different disease presentations require different approaches to gene discovery, studies of intellectual disability provide a nearly comprehensive showcase of strategies for exome-driven gene discovery. Despite these successes, the etiology of ~60% of cases of intellectual disability remains unknown. The application of exome sequencing to the clinical diagnosis of intellectual disability in the near future will ultimately reduce the number of idiopathic cases and provide a rich source of sequence variation for the identification of new intellectual disability genes.
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Abstract Background Intellectual disability is a prevalent neurodevelopmental disorder, with the majority of affected children exhibiting global developmental delay before the age of 5 years. In recent years, certain children have been found to carry homozygous variations of the EEF1D gene, leading to autosomal recessive intellectual disability. However, the pathogenicity of compound heterozygous variations in this gene remains largely unknown. Methods Trio whole‐exome sequencing and copy number variation sequencing were done for the genetic etiological diagnosis of a 3‐year and 11‐month‐old Chinese boy who presented with brachycephaly, severe to profound global developmental delay, and hypotonia in the lower limbs. Results In this case, compound heterozygous variants of the EEF1D gene were found in the child through trio whole‐exome sequencing; one was a splice variant (NM_032378.6:c.1905+1G>A) inherited from his father, and the other was a nonsense variant (NM_032378.6:c.676C>T) inherited from his mother. The nonsense variant leads to the production of a premature termination (p.Gln226*). These variations have the ability to explain the clinical phenotypes of the child. Conclusions Our study expands the variation spectrum and provides compelling evidence for EEF1D as a candidate gene for autosomal recessive intellectual disability. However, due to the deficient number of reported cases, researchers need to further study EEF1D and supplement the clinical phenotypes and treatment measures.
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Investigating novel genetic variants involved in intellectual disability (ID) development is essential. X-linked intellectual disability (XLID) accounts for over 10% of all cases of ID in males. XLID genes are involved in many cellular pathways and processes. Some of them are not specific to the development and functioning of the neural system. The implementation of exome sequencing simplifies the search for novel variants, especially those less expected. Here, we describe a nonsense variant of the XLID gene, WDR13. The mutation c.757C>T (p.Arg253Ter) was uncovered by X-chromosome exome sequencing in males with a familial form of intellectual disability. Quantitative PCR (qPCR) analysis showed that variant c.757C>T caused a significant decrease in WDR13 expression in the patient's fibroblast. Moreover, it dysregulated other genes linked to intellectual disability, such as FMR1, SYN1, CAMK2A, and THOC2. The obtained results indicate the pathogenic nature of the detected variant and suggest that the WDR13 gene interacts with other genes essential for the functioning of the nervous system, especially the synaptic plasticity process.
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Here, we report on a male patient with developmental delay, speech impairment, mild dysmorphic features, and borderline intellectual disability, bearing a de novo balanced t(5;6)(q11;q25.3). By combining FISH and long distance inverse PCR, we identified two genes, ADAMTS6 and ARID1B , which were disrupted at the translocation breakpoints. Due to the opposing transcriptional directions of the two genes, no fusion transcripts could be formed. ADAMTS6 on chromosome 5 encodes a zinc metalloprotease. To date, there has been no information about the substrates and the exact role of this enzyme protein. ARID1B on chromosome 6 is involved in chromatin remodeling and transcriptional activation and is known to play a role in neural development. To our knowledge, this is the fourth translocation involving ARID1B reported in association with intellectual disability. ARID1B haploinsufficiency has already been described in patients with intellectual disabilities with or without corpus callosum abnormalities, Coffin–Siris syndrome and autism (OMIM 614562 and OMIM 614556). A review of patients with ARID1B mutations reveals their broad phenotypic variability. The phenotype of the present patient is of the mildest described to date and further underscores this observation. We conclude that the most prominent and consistent clinical findings in patients with ARID1B haploinsufficiency are developmental delay, speech impairment and intellectual disability and propose that patients with unresolved genetic background and these clinical findings should be considered for ARID1B mutation screening. © 2014 Wiley Periodicals, Inc.
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The recent advent of exome sequencing has allowed for the identification of pathogenic gene variants responsible for a variety of diseases that were previously clinically diagnosed, with no underlying molecular etiology.Among these conditions, intellectual disability is a prevalent heterogeneous condition, presenting itself in a large spectrum of intensity, in some cases associated with congenital malformations, behavioral and various other intellectual development alterations.Here we report on a 36-year-old male patient, with a mild intellectual disability that remained undiagnosed at the molecular level for all his life.Using Nextera Exome Sequencing, a Chr3:9.517.294A>AC (c.3848_3849insC) SETD5 gene insertion was found.This rare variant was classified as likely pathogenic due to its frameshift nature in the gene, in which loss-of-function mutations have been previously reported to cause intellectual disability, as well as a 3p25.3microdeletion phenotype.It is possible that this variant shows partial activity, due to its gene localization, which would explain the patient's mild phenotype when compared with other reports.
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