The Healthcare and Societal Costs of Familial Intellectual Disability

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

Expanding Clinical Presentations Due to Variations in THOC2 mRNA Nuclear Export Factor

Multiple TREX mRNA export complex subunits (e.g., THOC1, THOC2, THOC5, THOC6, THOC7) have now been implicated in neurodevelopmental disorders (NDDs), neurodegeneration and cancer. We previously implicated missense and splicing-defective THOC2 variants in NDDs and a broad range of other clinical features. Here we report 10 individuals from nine families with rare missense THOC2 variants including the first case of a recurrent variant (p.Arg77Cys), and an additional individual with an intragenic THOC2 microdeletion (Del-Ex37-38). Ex vivo missense variant testing and patient-derived cell line data from current and published studies show 9 of the 14 missense THOC2 variants result in

Expression and function of novel members of the MS4A family

The MS4A (membrane-spanning four-domains, subfamily A) family encompasses a group of genes (MS4A1 to MS4A15 and TMEM176A and B) primarily clustered to chromosome 11q12-13. To date, the majority of MS4A family members have been reported to be expressed in cells of haematopoietic origin and to function in multimeric complexes that regulate cell activation and proliferation. The pan B cell marker, CD20 (MS4A1), was the first isolated MS4A molecule and has been shown to interact with the B cell receptor (BCR) at the cell surface to regulate BCR-dependent cytoplasmic calcium mobilisation and signalling pathways, ultimately playing a role in cell survival and proliferation. Fc{u03B5}RI{u03B2} (MS4A2) shares high amino acid sequence identity to CD20, is expressed in mast cells and basophils as part of the high affinity IgE receptor complex (Fc{u03B5}RI) and regulates IgE-mediated signalling pathways. The main role of Fc{u03B5}RI{u03B2} is in the recruitment of src-family protein tyrosine kinase, lyn, ultimately leading to enhancement of down-stream effector functions mediated through IgE-antigen binding of Fc{u03B5}RI, such as mast cell degranulation. Fc{u03B5}RI{u03B2} has also been proposed as a candidate gene for an atopy susceptibility locus localised at chromosome 11q13 although no profound phenotypic differences have been identified between linked polymorphisms and the wild-type form of Fc{u03B5}RI{u03B2}. A limited number of other MS4A family members have been functionally characterised although far less extensively. These include the perinuclear-expressed HTm4 (MS4A3) that is involved in haematopoietic cell cycling and MS4A12 that has been shown to play a regulatory role in colon epithelial cell cycling and store operate calcium channel (SOCC) opening in an epidermal growth factor receptor (EGFR)-dependent manner. Beyond these reports, little is known about the majority of the MS4A family members and fundamental information is lacking including amino acid sequence characteristics, cellular and subcellular expression distribution and functional roles. In order to address some of these deficiencies in our understanding of the MS4A family, the aim of this thesis was to further characterise the expression distribution of MS4A family members, identify novel homologous genes and investigate the function of one specific family member, MS4A8B. The analysis of sequence databases using the basic local alignment search tool (BLAST), led to the identification of three novel MS4A members (MS4A13, MS4A14 and MS4A15) localised in the MS4A gene cluster on chromosome 11q12-13. MS4A13 encodes a putative transmembrane-four protein, while MS4A14 and MS4A15 were predicted to be transmembrane-three proteins with MS4A14 shown to have a highly divergent C-terminal domain that displayed significant similarity with a region of a Plasmodium falciparum heavy dynein chain. Comparative analysis of the translated amino acid sequences of these new MS4A members with CD20, Fc{u03B5}RI{u03B2}, HTm4 and MS4A5 showed high amino acid sequence identity between MS4A family members particularly within the transmembrane regions, with identity largely found in the first and second membrane-spanning domains. Further analysis suggested that many putative src-homology 2 (SH2) and 3 (SH3) binding domains and endosomal trafficking motifs were identified in MS4A family member amino acid sequences. Phylogenetic analysis showed that there is a clear distinction in sequence similarity between human MS4A members localised to chromosome 11q12-13 and the two distant relatives, TMEM176A and TMEM176B at chromosome 7q36.1. The mRNA distribution of the MS4A family in human tissues, primary cells (including the complete immune transcriptome) and transformed cell lines was investigated and indicated that MS4A genes are mostly found in the immune compartment and show differential expression within haematopoietic cell subsets. CD20, Fc{u03B5}RI{u03B2} and HTm4 showed haematopoietic cell expression distribution largely consistent with that previously described. MS4A4A, MS4A6A and MS4A7 were expressed across several subsets of haematopoietic cells, particularly in those that are involved in innate immunity including macrophages, neutrophils and dendritic cells. A subset of MS4A genes were found to be expressed in non-haematopoietic cells; MS4A5, MS4A13, MS4A14 and MS4A15 were all found in the testis and displayed differential distribution in cells that undergo spermatogenesis and those that are involved in homeostatic functions in the testis. Immunohistochemistry highlighted MS4A15 expression in the lung epithelium as well as cells of likely haematopoietic origins in the submucosal region of the lung. Within the airways, MS4A8B was identified predominantly at the apical surface of the tracheal and lung epithelium. MS4A8B was also found in cells of the subepithelium including cells with morphological similarities to mast cells. C-terminal tagging with enhanced green fluorescent protein (eGFP) and transient transfection into mammalian cell lines was undertaken for a number of MS4A members (MS4A4A, MS4A6A, MS4A7 and MS4A8B) in order to determine their subcellular localisation. MS4A4A and MS4A8B were expressed at the cell surface -a similar finding as previously reported for CD20, Fc{u03B5}RI{u03B2} and MS4A12. Intriguingly, MS4A6A and MS4A7 showed a distinctive pattern of localisation to that of other MS4A members, being identified near the cell surface in organelles juxtaposed to the plasma membrane. Further analysis of the specific subcellular localisation of MS4A4A, MS4A6A and MS4A7 suggested that they were differentially localised in the endocytic pathway. MS4A4A was localised to late and recycling endosomes (RE), MS4A6A appeared in clathrin coated pits and vesicles, early endosomes and RE and MS4A7 was present in RE. A truncated isoform of MS4A6A lacking a portion of the C-terminal domain was also identified and tagged with eGFP to determine its subcellular localisation. In contrast to the wild-type full-length form of MS4A6A, the truncated isoform was found to be expressed on the cell surface in a similar pattern as described for MS4A4A. Two putative tyrosine-based endosome sorting motifs were missing in the truncated isoform of MS4A6A, although mutation of the motifs in the wild-type form did not alter the subcellular localisation, suggesting these motifs were not responsible for the disparity in subcellular trafficking. The role of MS4A8B as a potential regulator of cell signalling was investigated. The stimulation of MS4A8B-transfected HMC-1 mast cells with IgE and antigen suggested that MS4A8B promoted the enhancement of tyrosine phosphorylation after high affinity IgE receptor engagement but inhibited degranulation. Similarly, the over expression of MS4A8B in BEAS2B bronchial epithelial cells was shown to enhance tyrosine phosphorylation after interleukin four treatment yet reduced the release of 15(S)-hydroxyeicosatetranoic acid (15(S)-HETE). In both of these systems, the mutation of the tyrosine residue in the C-terminal domain putative tyrosine-based signalling motif resulted in a reduction in tyrosine phosphorylation and enhanced inhibition of degranulation or 15(S)-HETE release, suggesting this is an activatory motif (ITAM). However, the results also suggest that MS4A8B is likely involved in inhibitory pathways. Finally, MS4A8B was studied as a promising potential candidate for the atopic asthma susceptibility gene localised at chromosome 11q13, due to its specific expression In the trachea and lung, in conjunction with the observed regulatory role in modifying Fc{u03B5}RI complex signalling in mast cells. Initial studies investigated whether there were any differences in the level or pattern of MS4A8B expression between lung biopsies from an asthmatic patient and a non-asthmatic control. No obvious expression changes were identified in the epithelium although expression of MS4A8B was not observed in the asthmatic subepithelium whereas it was noted in the non-asthmatic control. In conclusion, the data in this thesis adds to the information regarding the phylogeny, cellular and subcellular expression distribution and possible function for the MS4A family in signalling pathways. It also lays the foundation for the investigation of a possible novel atopy susceptibility gene at chromosome 11q13, in the form of MS4A8B

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.publisher: Elsevier articletitle: THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability journaltitle: The American Journal of Human Genetics articlelink: http://dx.doi.org/10.1016/j.ajhg.2015.05.021 content_type: article copyright: Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.status: publishe

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities

Gonadal mosaicism of a novel IQSEC2 variant causing female limited intellectual disability and epilepsy

We report a family with four girls with moderate to severe intellectual disability and epilepsy. Two girls showed regression in adolescence and died of presumed sudden unexpected death in epilepsy at 16 and 22 years. Whole exome sequencing identified a truncating pathogenic variant in IQSEC2 at NM_001111125.2: c.2679_2680insA, p.(D894fs*10), a recently identified cause of epileptic encephalopathy in females (MIM 300522). The IQSEC2 variant was identified in both surviving affected sisters but in neither parent. We describe the phenotypic spectrum associated with IQSEC2 variants, highlighting how IQSEC2 is adding to a growing list of X-linked genes that have a female-specific phenotype typically associated with de novo mutations. This report illustrates the need for careful review of all whole exome data, incorporating all possible modes of inheritance including that suggested by the family history.Lisa J Ewans, Michael Field, Ying Zhu, Gillian Turner, Melanie Leffler, Marcel E Dinger, Mark J Cowley, Michael F Buckley, Ingrid E Scheffer, Matilda R Jackson, Tony Roscioli and Cheryl Shoubridg