Microdeletions including 5q31 have been reported in only few patients to date. Apart from intellectual disability/developmental delay (ID/DD) of varying degrees, which is common to all reported patients, the clinical spectrum is wide and includes short stature, failure to thrive, congenital heart defects, encephalopathies, and dysmorphic features. We report a patient with a 0.9-Mb de novo deletion in 5q31.2, the smallest microdeletion in 5q31 reported thus far. His clinical presentation includes mild DD, borderline short stature, postnatal microcephaly, and mild dysmorphic signs including microretrognathia. Together with data from 7 reported overlapping microdeletions, analysis of our patient enabled the tentative delineation of a phenotype map for 5q31 deletions. In contrast to the mild phenotype of small microdeletions affecting only 5q31.2, carriers of larger microdeletions which also include subbands 5q31.1 and/or 5q31.3 seem to be more severely affected with congenital malformations, growth anomalies, and severe encephalopathies. A 240-kb smallest region of overlap in 5q31.2 is delineated which contains only 2 genes, CTNNA1 and LRRTM2. We propose LRRTM2 as the most promising candidate gene for ID/DD due to its expression pattern...
Intellectual disability (ID) with autosomal recessive (AR) inheritance is believed to be
common; however, very little is known about causative genes and genotype–phenotype
correlations. The broad genetic heterogeneity of AR-ID, and its usually nonsyndromic
nature make it difficult to pool multiple pedigrees with the same underlying genetic
defect to achieve consistent nosology. Nearly all autosomal genes responsible for
recessive cognitive disorders have been identified in large consanguineous families from
the Middle East, and nonsense mutations in TRAPPC9 have been reported in a total
of 5. Although several recurrent phenotypic abnormalities are described in some of these
patients, the associated phenotype is usually referred to as nonsyndromic. By means of
single-nucleotide polymorphism-array first and then by exome sequencing, we identified a
new pathogenic mutation in TRAPPC9 in two Italian sisters born to healthy and
apparently nonconsanguineous parents. It consists of a homozygous splice site mutation
causing exon skipping with frameshift and premature termination, as confirmed by mRNA
sequencing. By detailed phenotypic analysis of our patients, and by critical literature
review, we found that homozygous TRAPPC9 loss-of-function mutations cause a
Objective. To investigate the antenatal health and demographic factors as well as pregnancy and delivery outcomes in women with intellectual disability (ID) in Sweden. Design. A population-based register study. Setting. The National Patient Register (NPR) linked to the Medical Birth Register (MBR). Sample. Women with ID classified as International Classification of Diseases (ICD) 8–10 who gave birth in 1999–2007 (n = 326), identified from the NPR linked to the MBR, were compared with all first-time, singleton mothers without ID or any other psychiatric diagnoses during this period in Sweden (n = 340 624). Methods. Population-based data were extracted from the NPR and the MBR. Main outcome measures. Health and socio-demography at first antenatal visit, mode of delivery, pain relief during labor, preterm birth and discharge from hospital. Results. A higher proportion of women with ID were teenagers (18.4 vs. 3.3%), obese (20.1 vs. 8.6%) and single (36.6 vs. 6.2%) compared with women without ID, and women with ID smoked more often (27.9 vs. 7.9%). Women with ID had more often a preterm birth (12.2 vs. 6.1%), a cesarean section (CS) (24.5 vs. 17.7%) and used less nitrous oxide as pain relief during labor (59.5 vs. 75.8%). Women with ID had a higher risk for preterm birth [odds ratio (OR) 1.68]...
Objective. To study mode of birth, perinatal health and death in children born to mothers with intellectual disability (ID) in Sweden. Design. Population-based register study. Setting. National registers; the National Patient Register linked to the Medical Birth Register. Sample. Children of first-time mothers with ID (n = 326; classified in the International Classification of Diseases 8–10) were identified and compared with 340 624 children of first-time mothers without ID or any other psychiatric diagnosis between 1999 and 2007. Methods. Population-based data were extracted from the National Patient Register and the Medical Birth Register. Main outcome measures. Mode of birth, preterm birth, small for gestational age, Apgar score, stillbirth and perinatal death. Results. Children born to mothers with ID were more often stillborn (1.2 vs. 0.3%) or died perinatally (1.8 vs. 0.4%) than children born to mothers without ID. They had a higher proportion of cesarean section birth (24.5 vs. 17.7%) and preterm birth (12.2 vs. 6.1%), were small for gestational age (8.4 vs. 3.1%) and had lower Apgar scores (<7 points at five minutes; 3.7 vs 1.5%) compared with children born to mothers without ID. Logistic regression adjusted for maternal characteristics confirmed an increased risk of small for gestational age (odds ratio 2.25)...
Beunders, Gea; Voorhoeve, Els; Golzio, Christelle; Pardo, Luba M.; Rosenfeld, Jill A.; Talkowski, Michael E.; Simonic, Ingrid; Lionel, Anath C.; Vergult, Sarah; Pyatt, Robert E.; van de Kamp, Jiddeke; Nieuwint, Aggie; Weiss, Marjan M.; Rizzu, Patr
Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3′ AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.
We report a case of an interstitial chromosome 20q11.21 microdeletion in a 7-year-old male child presenting with mild intellectual disability and facial dysmorphisms. Array comparative genomic hybridization (CGH) has shown that the deletion resulted in the loss of 68 genes, among which 5 genes (COX4I2, MYLK2, ASXL1, DNMT3B, and SNTA1) are disease causing. The size of the deletion was estimated to span 2.6 Mb. Only three cases of deletions encompassing this chromosomal region have been reported. The phenotype of the index patient was found to resemble the mildest cases of Bohring-Opitz syndrome that is caused by ASXL1 mutations. An in silico evaluation of the deleted genomic region has shown that benign genomic variations have never been observed to affect the ASXL1 gene, in contrast to the other disease-causing genes. As a result, it was suggested that ASXL1 loss is likely to be the main cause of the phenotypic manifestations. The present case report indicates that a loss of the disease-causing gene can produce a milder phenotype of a single gene condition.
Down syndrome is the most common cause of intellectual disability. In the United States, it is recommended that prenatal testing for Down syndrome be offered to all women. Because of this policy and consequent public perception, having Down syndrome has become a disadvantage in the prenatal period. However, in the postnatal period, there may be some advantage to having Down syndrome. In order to help parents make informed decisions about screening and testing, it is crucial to reconcile divergent prenatal and postnatal perspectives. Advancements in genetic technologies will also impact the informed consent process and need to be considered.
Intellectual disability (ID) is one of the many features manifested in various genetic syndromes leading to deficits in cognitive function among affected individuals. ID is a feature affected by polygenes and multiple environmental factors. It leads to a broad spectrum of affected clinical and behavioral characteristics among patients. Until now, the causative mechanism of ID is unknown and the progression of the condition is poorly understood. Advancement in technology and research had identified various genetic abnormalities and defects as the potential cause of ID. However, the link between these abnormalities with ID is remained inconclusive and the roles of many newly discovered genetic components such as non-coding RNAs have not been thoroughly investigated. In this review, we aim to consolidate and assimilate the latest development and findings on a class of small non-coding RNAs known as microRNAs (miRNAs) involvement in ID development and progression with special focus on Down syndrome (DS) and X-linked ID (XLID) [including Fragile X syndrome (FXS)].
Arthrogryposis multiplex congenita (AMC) is caused by heterogeneous pathologies leading to multiple antenatal joint contractures through fetal akinesia. Understanding the pathophysiology of this disorder is important for clinical care of the affected individuals and genetic counseling of the families. We thus aimed to establish the genetic basis of an AMC subtype that is associated with multiple dysmorphic features and intellectual disability (ID). We used haplotype analysis, next-generation sequencing, array comparative genomic hybridization, and chromosome breakpoint mapping to identify the pathogenic mutations in families and simplex cases. Suspected disease variants were verified by cosegregation analysis. We identified disease-causing mutations in the zinc-finger gene ZC4H2 in four families affected by X-linked AMC plus ID and one family affected by cerebral palsy. Several heterozygous females were also affected, but to a lesser degree. Furthermore, we found two ZC4H2 deletions and one rearrangement in two female and one male unrelated simplex cases, respectively. In mouse primary hippocampal neurons, transiently produced ZC4H2 localized to the postsynaptic compartment of excitatory synapses, and the altered protein influenced dendritic spine density. In zebrafish...
Members of the Nuclear eXport Factor (NXF) family are involved in the export of mRNA from the nucleus to the cytoplasm, or hypothesized to play a role in transport of cytoplasmic mRNA. We previously reported on the loss of NXF5 in a male patient with a syndromic form of intellectual disability. To study the functional role of NXF5 we identified the mouse counterpart. Based on synteny, mouse Nxf2 is the ortholog of human NXF5. However, we provide several lines of evidence that mouse Nxf7 is the actual functional equivalent of NXF5. Both Nxf7 and NXF5 are predominantly expressed in the brain, show cytoplasmic localization, and present as granules in neuronal dendrites suggesting a role in cytoplasmic mRNA metabolism in neurons. Nxf7 was primarily detected in the pyramidal cells of the hippocampus and in layer V of the cortex. Similar to human NXF2, mouse Nxf2 is highly expressed in testis and shows a nuclear localization. Interestingly, these findings point to a different evolutionary path for both NXF genes in human and mouse. We thus generated and validated Nxf7 knockout mice, which were fertile and did not present any gross anatomical or morphological abnormalities. Expression profiling in the hippocampus and the cortex did not reveal significant changes between wild-type and Nxf7 knockout mice. However...
Background. The coexistence of psychiatric disorders in people with intellectual disability (ID) is common. This study determined the prevalence of psychiatric disorders in children with ID in Barwani, India. Method. A total of 262 children with ID were evaluated for psychiatric disorders using the diagnostic criteria outlined in the International Classification of Diseases (ICD-10). Results. Psychiatric disorders appeared in study participants at the following rates: attention deficit hyperactivity disorder (ADHD), 6.5%; autism, 4.2%; anxiety, 2.7%; bipolar disorder, 1.1%; delusional disorder, 0.8%; depression, 2.3%; obsessive-compulsive disorder, 0.8%; schizophrenia, 1.9%; enuresis, 10.3%; epilepsy, 23.7%; and behavioral problems, 80.9%. The prevalence of psychiatric disorders was statistically higher in severely intellectually disabled children (IQ ≤ 49) than mildly intellectually disabled children (IQ ≥ 50). Conclusions. There is a higher prevalence of psychiatric disorders in children with ID when their IQ ≤ 49 compared with ID children whose IQ ≥ 50.
TCF4 (transcription factor 4; E2-2, ITF2) is a transcription factor that when haplo-insufficient causes Pitt–Hopkins Syndrome (PTHS), an autism-spectrum disorder that is associated with pervasive developmental delay and severe intellectual disability. The TCF4 gene is also a risk factor with highly significant linkage to schizophrenia, presumably via overexpression of the TCF4 gene product in the central nervous system. This review will present an overview of the clinical manifestations of PTHS and relate those clinical attributes to the underlying molecular genetics of TCF4. In order to provide a molecular biological context for the loss of function of TCF4 in PTHS, the review will also present a brief overview of the basic biochemistry of TCF4-mediated regulation of cellular and neuronal gene expression. In the final section of this review, I will discuss and speculate upon possible roles for the TCF4 transcription factor in neuronal function and comment upon how understanding these roles may give new insights into the molecular neurobiology of human cognition.
PQBP1 is a nuclear-cytoplasmic shuttling protein that is engaged in RNA metabolism and transcription. In mouse embryonic brain, our previous in situ hybridization study revealed that PQBP1 mRNA was dominantly expressed in the periventricular zone region where neural stem progenitor cells (NSPCs) are located. Because the expression patterns in NSPCs are related to the symptoms of intellectual disability and microcephaly in PQBP1 gene-mutated patients, we investigated the transcriptional regulation of PQBP1 by NSPC-specific transcription factors. We selected 132 genome sequences that matched the consensus sequence for the binding of Sox2 and POU transcription factors upstream and downstream of the mouse PQBP1 gene. We then screened the binding affinity of these sequences to Sox2-Pax6 or Sox2-Brn2 with gel mobility shift assays and found 18 genome sequences that interacted with the NSPC-specific transcription factors. Some of these sequences had cis-regulatory activities in Luciferase assays and in utero electroporation into NSPCs. Furthermore we found decreased levels of expression of PQBP1 protein in NSPCs of heterozygous Sox2-knockout mice in vivo by immunohistochemistry and western blot analysis. Collectively, these results indicated that Sox2 regulated the transcription of PQBP1 in NSPCs.
A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome. Using high resolution molecular karyotyping, we identified two intragenic de novo frameshift deletions, likely resulting in haploinsufficiency, in two patients with a similar phenotype of hypotonia, moderate ID, conotruncal heart defect and facial anomalies. In both, Sanger sequencing of MED13L did not reveal any pathogenic mutation and exome sequencing in one patient showed no evidence for a non-allelic second hit. A further patient with hypotonia, learning difficulties and perimembranous VSD showed a 1 Mb de novo triplication in 12q24.2, including MED13L and MAP1LC3B2. Our findings show that MED13L haploinsufficiency in contrast to the previously observed missense mutations cause a distinct syndromic phenotype. Additionally...
Brain function and behavior undergo significant plasticity and refinement, particularly during specific critical and sensitive periods. In autistic and intellectual disability (ID) neurodevelopmental disorders (NDDs) and their corresponding genetic mouse models, impairments in many neuronal and behavioral phenotypes are temporally regulated and in some cases, transient. However, the links between neurobiological mechanisms governing typically normal brain and behavioral development (referred to also as “neurotypical” development) and timing of NDD impairments are not fully investigated. This perspective highlights temporal patterns of synaptic and neuronal impairment, with a restricted focus on autism and ID types of NDDs. Given the varying known genetic and environmental causes for NDDs, this perspective proposes two strategies for investigation: (1) a focus on neurobiological mechanisms underlying known critical periods in the (typically) normal-developing brain; (2) investigation of spatio-temporal expression profiles of genes implicated in monogenic syndromes throughout affected brain regions. This approach may help explain why many NDDs with differing genetic causes can result in overlapping phenotypes at similar developmental stages and better predict vulnerable periods within these disorders...
Intellectual Disability (ID) disorders, defined by an IQ below 70, are genetically and phenotypically highly heterogeneous. Identification of common molecular pathways underlying these disorders is crucial for understanding the molecular basis of cognition and for the development of therapeutic intervention strategies. To systematically establish their functional connectivity, we used transgenic RNAi to target 270 ID gene orthologs in the Drosophila eye. Assessment of neuronal function in behavioral and electrophysiological assays and multiparametric morphological analysis identified phenotypes associated with knockdown of 180 ID gene orthologs. Most of these genotype-phenotype associations were novel. For example, we uncovered 16 genes that are required for basal neurotransmission and have not previously been implicated in this process in any system or organism. ID gene orthologs with morphological eye phenotypes, in contrast to genes without phenotypes, are relatively highly expressed in the human nervous system and are enriched for neuronal functions, suggesting that eye phenotyping can distinguish different classes of ID genes. Indeed, grouping genes by Drosophila phenotype uncovered 26 connected functional modules. Novel links between ID genes successfully predicted that MYCN...
People with intellectual disability (ID) are living longer than ever before, raising concerns about old-age associated disorders. Dementia is among the most serious of these disorders, and theories relating cognitive reserve to risk predict that older adults with ID should be particularly vulnerable. Previous estimates of relative risk for dementia associated with ID have been inconsistent, and the present analyses examined the possible influence of variation in diagnostic criteria on findings. As expected, relaxation in the stringency of case definition for adults with ID increased relative risk, underscoring the importance of developing valid criteria for defining mild cognitive impairment, early dementia, and distinguishing between the two in adults with ID. Once available, these standards will contribute to more effective evidence-based planning.
Little is known about the relationships between phonological processing, language, and reading in children with intellectual disability (ID). We examined the structure of phonological processing in 294 school-aged children with mild ID and the relationships between its components and expressive and receptive language and reading skills using structural equation modeling. Phonological processing consisted of two distinct but correlated latent abilities: phonological awareness and naming speed. Phonological awareness had strong relationships with expressive and receptive language and reading skills. Naming speed had moderate relationships with these variables. Results suggest that children with ID bring the same skills to the task of learning to read as children with typical development, highlighting that phonologically based reading instruction should be considered a viable approach.
We recently reported that duplication of the E3 ubiquitin ligase HUWE1 results in intellectual disability (ID) in male patients. However, the underlying molecular mechanism remains unknown. We used Drosophila melanogaster as a model to investigate the effect of increased HUWE1 levels on the developing nervous system. Similar to the observed levels in patients we overexpressed the HUWE1 mRNA about 2-fold in the fly. The development of the mushroom body and neuromuscular junctions were not altered, and basal neurotransmission was unaffected. These data are in agreement with normal learning and memory in the courtship conditioning paradigm. However, a disturbed branching phenotype at the axon terminals of the dorsal cluster neurons (DCN) was detected. Interestingly, overexpression of HUWE1 was found to decrease the protein levels of dishevelled (dsh) by 50%. As dsh as well as Fz2 mutant flies showed the same disturbed DCN branching phenotype, and the constitutive active homolog of β-catenin, armadillo, could partially rescue this phenotype, our data strongly suggest that increased dosage of HUWE1 compromises the Wnt/β-catenin pathway possibly by enhancing the degradation of dsh.
To assess and manage pain in children and adolescents with mild to moderate intellectual disability, healthcare providers need access to updated tools and current knowledge. Recent studies show that these children can verbally express pain and use self-assessment tools accurately. Moreover, they know pain coping strategies. Finally, they show mental imaging skills and are able to recall autobiographical memories. These new data suggest that such children and adolescents could be candidates to for hypno-analgesia protocols and behavioral relaxation.