Millions of human genomes and exomes have been sequenced, but their clinical applications remain limited due to the difficulty of distinguishing disease-causing mutations from benign genetic ...variation. Here we demonstrate that common missense variants in other primate species are largely clinically benign in human, enabling pathogenic mutations to be systematically identified by the process of elimination. Using hundreds of thousands of common variants from population sequencing of six non-human primate species, we train a deep neural network that identifies pathogenic mutations in rare disease patients with 88% accuracy and enables the discovery of 14 new candidate genes in intellectual disability at genome-wide significance. Cataloging common variation from additional primate species would improve interpretation for millions of variants of uncertain significance, further advancing the clinical utility of human genome sequencing.
CHD3 heterozygous variants are associated with Snijders Blok‐Campeau syndrome (SBCS) which consists of intellectual disability (ID), macrocephaly, and dysmorphic facies. Most reported variants are ...missense or loss of function clustered within the ATPase/helicase domain of the protein. We report a severe neurocognitive phenotype caused by biallelic CHD3 variants in two siblings, each inherited from a mildly affected parent. Male and female siblings were referred to the Genetics Clinic due to severe ID and profound dysmorphism. The parents are first cousins of Iranian descent with borderline intellectual abilities. Exome sequencing was performed for the affected female and her parents. A single homozygous candidate variant in the CHD3 gene was detected in the proband: c.5384_5389dup. p.Arg1796_Phe1797insTrpArg, resulting in an in‐frame insertion of 2 amino acids located outside the ATPase/helicase domain at the C‐terminal region of CHD3‐encoding residues. This variant is classified as likely pathogenic according to ACMG guidelines. The variant was detected in a heterozygous state in each parent. Both affected siblings were homozygous, while their unaffected brother did not carry the variant. Biallelic CHD3 variants cause a severe neurodevelopmental syndrome that is distinguishable from SBCS. We assume that the variant type (in‐frame insertion) and location may enable CHD3 biallelic variants.
Intellectual disability (ID) is a prevailing neurodevelopmental condition associated with impaired cognitive and adaptive behaviors. Many chromatin-modifying enzymes and other epigenetic regulators ...have been genetically associated with ID disorders (IDDs). Here we review how alterations in the function of histone modifiers, chromatin remodelers, and methyl-DNA binding proteins contribute to neurodevelopmental defects and altered brain plasticity. We also discuss how progress in human genetics has led to the generation of mouse models that unveil the molecular etiology of ID, and outline the direction in which this field is moving to identify therapeutic strategies for IDDs. Importantly, because the chromatin regulators linked to IDDs often target common downstream genes and cellular processes, the impact of research in individual syndromes goes well beyond each syndrome and can also contribute to the understanding and therapy of other IDDs. Furthermore, the investigation of these disorders helps us to understand the role of chromatin regulators in brain development, plasticity, and gene expression, thereby answering fundamental questions in neurobiology.
Summary
Objective
Epilepsy is highly prevalent among patients with intellectual disability (ID), and seizure control is often difficult. Identification of the underlying etiology in this patient ...group is important for daily clinical care. We assessed the diagnostic yield of whole exome sequencing (WES). In addition, we evaluated which clinical characteristics influence the likelihood of identifying a genetic cause and we assessed the potential impact of the genetic diagnosis on (antiepileptic) treatment strategy.
Methods
One hundred patients with both unexplained epilepsy and (borderline) ID (intelligence quotient ≤ 85) were included. All patients were evaluated by a clinical geneticist, a (pediatric) neurologist, and/or a specialist ID physician. WES analysis was performed in two steps. In step 1, analysis was restricted to the latest versions of ID and/or epilepsy gene panels. In step 2, exome analysis was extended to all genes (so‐called full exome analysis). The results were classified according to the American College of Medical Genetics and Genomics guidelines.
Results
In 58 patients, the diagnostic WES analysis reported one or more variant(s). In 25 of the 100 patients, these were classified as (likely) pathogenic, in 24 patients as variants of uncertain significance, and in the remaining patients the variant was most likely not related to the phenotype. In 10 of 25 patients (40%) with a (likely) pathogenic variant, the genetic diagnosis might have an impact on the treatment strategy in the future.
Significance
This study illustrates the clinical diagnostic relevance of WES for patients with both epilepsy and ID. It also demonstrates that implementing WES diagnostics might have impact on the (antiepileptic) treatment strategy in this population. Confirmation of variants of uncertain significance in (candidate) genes may further increase the yield.
Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, ...but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.
Most of the studies on the cost of intellectual disability are limited to a healthcare perspective or cohorts composed of individuals where the etiology of the condition is a mixture of genetic and ...non-genetic factors. When used in policy development, these can impact the decisions made on the optimal allocation of resources. In our study, we have developed a static microsimulation model to estimate the healthcare, societal, and lifetime cost of individuals with familial intellectual disability, an inheritable form of the condition, to families and government. The results from our modeling show that the societal costs outweighed the health costs (approximately 89.2% and 10.8%, respectively). The lifetime cost of familial intellectual disability is approximately AUD 7 million per person and AUD 10.8 million per household. The lifetime costs to families are second to those of the Australian Commonwealth government (AUD 4.2 million and AUD 9.3 million per household, respectively). These findings suggest that familial intellectual disability is a very expensive condition, representing a significant cost to families and government. Understanding the drivers of familial intellectual disability, especially societal, can assist us in the development of policies aimed at improving health outcomes and greater access to social care for affected individuals and their families.
Inhibitory interneurons are essential for proper brain development and function. Dysfunction of interneurons is implicated in several neurodevelopmental disorders, including autism spectrum disorder ...(ASD) and intellectual disability (ID). We have previously shown that Arid1b haploinsufficiency interferes with interneuron development and leads to social, cognitive, and emotional impairments consistent with ASD and ID. It is unclear, however, whether interneurons play a major role for the behavioral deficits in Arid1b haploinsufficiency. Furthermore, it is critical to determine which interneuron subtypes contribute to distinct behavioral phenotypes. In the present study, we generated Arid1b haploinsufficient mice in which a copy of the Arid1b gene is deleted in either parvalbumin (PV) or somatostatin (SST) interneurons, and examined their ASD- and ID-like behaviors. We found that Arid1b haploinsufficiency in PV or SST interneurons resulted in distinct features that do not overlap with one another. Arid1b haploinsufficiency in PV neurons contributed to social and emotional impairments, while the gene deletion in the SST population caused stereotypies as well as learning and memory dysfunction. These findings demonstrate a critical role of interneurons in Arid1b haploinsufficient pathology and suggest that PV and SST interneurons may have distinct roles in modulating neurological phenotypes in Arid1b haploinsufficiency-induced ASD and ID.
Summary
De novo mutations of the neuronal sodium channel SCN8A have been identified in approximately 2% of individuals with epileptic encephalopathy. These missense mutations alter the biophysical ...properties of sodium channel Nav1.6 in ways that lead to neuronal hyperexcitability. We generated two mouse models carrying patient mutations N1768D and R1872W to examine the effects on neuronal function in vivo. The conditional R1872W mutation is activated by expression of CRE recombinase, permitting characterization of the effects of the mutation on different classes of neurons and at different points in postnatal development. Preclinical drug testing in these mouse models provides support for several new therapies for this devastating disorder. In contrast with the gain‐of‐function mutations in epilepsy, mutations of SCN8A that result in partial or complete loss of function are associated with intellectual disability and other disorders.
Patients with mutations in Cyclin M2 (CNNM2) suffer from hypomagnesaemia, seizures, and intellectual disability. Although the molecular function of CNNM2 is under debate, the protein is considered ...essential for renal Mg
reabsorption. Here, we used a Cnnm2 knock out mouse model, generated by CRISPR/Cas9 technology, to assess the role of CNNM2 in Mg
homeostasis. Breeding Cnnm2
mice resulted in a Mendelian distribution at embryonic day 18. Nevertheless, only four Cnnm2
pups were born alive. The Cnnm2
pups had a significantly lower serum Mg
concentration compared to wildtype littermates. Subsequently, adult Cnnm2
mice were fed with low, control, or high Mg
diets for two weeks. Adult Cnnm2
mice showed mild hypomagnesaemia compared to Cnnm2
mice and increased serum Ca
levels, independent of dietary Mg
intake. Faecal analysis displayed increased Mg
and Ca
excretion in the Cnnm2
mice. Transcriptional profiling of Trpm6, Trpm7, and Slc41a1 in kidneys and colon did not reveal effects based on genotype. Microcomputed tomography analysis of the femurs demonstrated equal bone morphology and density. In conclusion, CNNM2 is vital for embryonic development and Mg
homeostasis. Our data suggest a previously undescribed role of CNNM2 in the intestine, which may contribute to the Mg
deficiency in mice and patients.
Antiseizure medications (ASMs) are the second most widely prescribed psychotropic for people with intellectual disabilities in England. Multiple psychotropic prescribing is prevalent in almost half ...of people with intellectual disabilities on ASMs. This analysis identifies limited evidence of ASM benefit in challenging behaviour management and suggests improvements needed to inform clinical practice.
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