Intellectual Disability Cohort Research Articles

ARID1B-related disorder in 87 adults: Natural history and self-sustainability

PurposeARID1Bis one of the most frequently mutated genes in intellectual disability cohorts. Thus, far few adult-aged patients with ARID1B-related disorder have been described, which limits our understanding of the disease’s natural history and our ability to counsel patients and their families. MethodsData on patients aged 18+ years with ARID1B-related disorder were collected through an online questionnaire completed by clinicians and parents. ResultsEighty-seven adult patients with ARID1B were included. Cognitive functioning ranged from borderline to severe intellectual disability. Patients identified through the genetic workup of their child were either mosaic or had a variant in exon 1. New clinical features identified in this population are loss of skill (16/64, 25%) and recurrent patella luxation (12/45, 32%). Self-sustainability data showed that 88% (45/51) could eat independently, and 16% (7/45) could travel alone by public transport. Facial photo analysis showed that patients’ photographs taken at different ages clustered consistently, separate from matched controls. ConclusionThe ARID1B spectrum is broad, and as patients age, there is a significant shift in the medical aspects requiring attention. To address the changing medical needs with increasing age, we have formulated recommendations to promote timely intervention in an attempt to mitigate disease progression.

Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles

BackgroundWe previously described the KINSSHIP syndrome, an autosomal dominant disorder associated with intellectual disability (ID), mesomelic dysplasia and horseshoe kidney, caused by de novo variants in the degron of AFF3. Mouse knock-ins and overexpression in zebrafish provided evidence for a dominant-negative mode of action, wherein an increased level of AFF3 resulted in pathological effects.MethodsEvolutionary constraints suggest that other modes-of-inheritance could be at play. We challenged this hypothesis by screening ID cohorts for individuals with predicted-to-be damaging variants in AFF3. We used both animal and cellular models to assess the deleteriousness of the identified variants.ResultsWe identified an individual with a KINSSHIP-like phenotype carrying a de novo partial duplication of AFF3 further strengthening the hypothesis that an increased level of AFF3 is pathological. We also detected seventeen individuals displaying a milder syndrome with either heterozygous Loss-of-Function (LoF) or biallelic missense variants in AFF3. Consistent with semi-dominance, we discovered three patients with homozygous LoF and one compound heterozygote for a LoF and a missense variant, who presented more severe phenotypes than their heterozygous parents. Matching zebrafish knockdowns exhibit neurological defects that could be rescued by expressing human AFF3 mRNA, confirming their association with the ablation of aff3. Conversely, some of the human AFF3 mRNAs carrying missense variants identified in affected individuals did not rescue these phenotypes. Overexpression of mutated AFF3 mRNAs in zebrafish embryos produced a significant increase of abnormal larvae compared to wild-type overexpression further demonstrating deleteriousness.To further assess the effect of AFF3 variation, we profiled the transcriptome of fibroblasts from affected individuals and engineered isogenic cells harboring + / + , KINSSHIP/KINSSHIP, LoF/ + , LoF/LoF or KINSSHIP/LoF AFF3 genotypes. The expression of more than a third of the AFF3 bound loci is modified in either the KINSSHIP/KINSSHIP or the LoF/LoF lines. While the same pathways are affected, only about one third of the differentially expressed genes are common to the homozygote datasets, indicating that AFF3 LoF and KINSSHIP variants largely modulate transcriptomes differently, e.g. the DNA repair pathway displayed opposite modulation.ConclusionsOur results and the high pleiotropy shown by variation at this locus suggest that minute changes in AFF3 function are deleterious.

Evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability

Intellectual disability (ID) is a common disorder, yet there is a wide spectrum of impairment from mild to profoundly affected individuals. Mild ID is seen as the low extreme of the general distribution of intelligence, while severe ID is often seen as a monogenic disorder caused by rare, pathogenic, highly penetrant variants. To investigate the genetic factors influencing mild and severe ID, we evaluated rare and common variation in the Northern Finland Intellectual Disability cohort (n = 1096 ID patients), a cohort with a high percentage of mild ID (n = 550) and from a population bottleneck enriched in rare, damaging variation. Despite this enrichment, we found only a small percentage of ID was due to recessive Finnish-enriched variants (0.5%). A larger proportion was linked to dominant variation, with a significant burden of rare, damaging variation in both mild and severe ID. This rare variant burden was enriched in more severe ID (p = 2.4e-4), patients without a relative with ID (p = 4.76e-4), and in those with features associated with monogenic disorders. We also found a significant burden of common variants associated with decreased cognitive function, with no difference between mild and more severe ID. When we included common and rare variants in a joint model, the rare and common variants had additive effects in both mild and severe ID. A multimodel inference approach also found that common and rare variants together best explained ID status (ΔAIC = 16.8, ΔBIC = 10.2). Overall, we report evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability.

Narrowing the diagnostic gap: Genomes, episignatures, long-read sequencing, and health economic analyses in an exome-negative intellectual disability cohort

PurposeGenome sequencing (GS)–specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)–negative intellectual disability (ID) cohorts have not been reported extensively. MethodsES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID. ResultsThe ES diagnostic yield was 42 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8 of 9 single-nucleotide variations/copy-number variations undetected in older ES, confirming a GS-unique diagnostic rate of 1 in 32 (3%). Episignatures contributed diagnostic information in 9% with GS corroboration in 1 of 32 (3%) and diagnostic clues in 2 of 32 (6%). A genetic etiology for ID was detected in 51 of 74 (69%) families. Twelve candidate disease genes were identified. Contemporary ES followed by GS cost US$4976 (95% CI: $3704; $6969) per diagnosis and first-line GS at a cost of $7062 (95% CI: $6210; $8475) per diagnosis. ConclusionPerforming GS only in ID trios would be cost equivalent to ES if GS were available at $2435, about a 60% reduction from current prices. This study demonstrates that first-line GS achieves higher diagnostic rate than contemporary ES but at a higher cost.

Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort.

Intellectual disability (ID) is a genetically heterogeneous condition, and so far, 1679 human genes have been identified for this phenotype. Countries with a high rate of parental consanguinity, such as Iran, provide an excellent opportunity to identify the remaining novel ID genes, especially those with an autosomal recessive (AR) mode of inheritance. This study aimed to investigate the most prevalent ID genes identified via next-generation sequencing (NGS) in a large ID cohort at the Genetics Research Center (GRC) of the University of Social Welfare and Rehabilitation Sciences. First, we surveyed the epidemiological data of 619 of 1295 families in our ID cohort, who referred to the Genetics Research Center from all over the country between 2004 and 2021 for genetic investigation via the NGS pipeline. We then compared our data with those of several prominent studies conducted in consanguineous countries. Data analysis, including cohort data extraction, categorization, and comparison, was performed using the R program version 4.1.2. We categorized the most common ID genes that were mutated in more than two families into 17 categories. The most common syndromic ID in our cohort was AP4 deficiency syndrome, and the most common non-syndromic autosomal recessive intellectual disability (ARID) gene was ASPM. We identified two unrelated families for the 36 ID genes. We found 14 genes in common between our cohort and the Arab and Pakistani groups, of which three genes (AP4M1, AP4S1, and ADGRG1) were repeated more than once. To date, there has been no comprehensive targeted NGS platform for the detection of ID genes in our country. Due to the large sample size of our study, our data may provide the initial step toward designing an indigenously targeted NGS platform for the diagnosis of ID, especially common ARID in our population.

Autism spectrum disorder and brain volume link through a set of mTOR-related genes.

Larger than average head and brain sizes are often observed in individuals with autism spectrum disorders (ASDs). ASD and brain volume are both highly heritable, with multiple genetic variants contributing. However, it is unclear whether ASD and brain volume share any genetic mechanisms. Genes from the mammalian target of rapamycin (mTOR) pathway influence brain volume, and variants are found in rare genetic syndromes that include ASD features. Here we investigated whether variants in mTOR-related genes are also associated with ASD and if they constitute a genetic link between large brains and ASD. We extended our analyses between large heads (macrocephaly) and rare de novo mTOR-related variants in an intellectual disability cohort (N=2,258). Subsequently using Fisher's exact tests we investigated the co-occurrence of mTOR-related de novo variants and ASD in the de-novo-db database (N=23,098). We next selected common genetic variants within a set of 96 mTOR-related genes in genome-wide genetic association data of ASD (N=46,350) to test gene-set association using MAGMA. Lastly, we tested genetic correlation between genome-wide genetic association data of ASD (N=46,350) and intracranial volume (N=25,974) globally using linkage disequilibrium score regression as well as mTOR specific by restricting the genetic correlation to the mTOR-related genes using GNOVA. Our results show that both macrocephaly and ASD occur above chance level in individuals carrying rare de novo variants in mTOR-related genes. We found a significant mTOR gene-set association with ASD (p=.0029) and an mTOR-stratified positive genetic correlation between ASD and intracranial volume (p=.027), despite the absence of a significant genome-wide correlation (p=.81). This work indicates that both rare and common variants in mTOR-related genes are associated with brain volume and ASD and genetically correlate them in the expected direction. We demonstrate that genes involved in mTOR signalling are potential mediators of the relationship between having a large brain and having ASD.

A Tiered Genetic Screening Strategy for the Molecular Diagnosis of Intellectual Disability in Chinese Patients.

Objective: Intellectual disability (ID) is one of the most common developmental disabilities. To identify the genetic etiology of IDs in Chongqing, we conducted a multistage study in Chinese Han patients. Methods: We collected the clinical and etiological data of 1665 ID patients, including 1,604 from the disabled children evaluation center and 61 from the pediatric rehabilitation unit. Routine genetic screening results were obtained, including karyotype and candidate gene analysis. Then 105 idiopathic cases with syndromic and severe ID/developmental delay (DD) were selected and tested by chromosomal microarray (CMA) and whole exome sequencing (WES) sequentially. The pathogenicity of the CNVs and SNVs were evaluated according to ACMG guidelines. Results: Molecular diagnosis was made by routine genetic screening in 216 patients, including 196 chromosomal syndromes. Among the 105 idiopathic patients, 49 patients with pathogenic/likely pathogenic CNVs and 21 patients with VUS were identified by CMA. Twenty-six pathogenic CNVs underlying well-known syndromic cases, such as Williams-Beuren syndrome, were confirmed by multiplex ligation-dependent probe amplification (MLPA). Nine novel mutations were identified by WES in thirty-fix CNV-negative ID cases. Conclusions: The study illustrated the genetic aberrations distribution of a large ID cohort in Chongqing. Compared with conventional or single methods, a tiered high-throughput diagnostic strategy was developed to greatly improve the diagnostic yields and extend the variation spectrum for idiopathic syndromic ID cases.

CARDIAC AUTONOMIC NEUROPATHY RISK ESTIMATED BY SUDOMOTOR FUNCTION IN YOUNG ADULTS WITH INTELLECTUAL DISABILITY

Objective: Young adults with Intellectual Disability (ID) are at higher risk of premature death, and present with increased prevalence of cardiovascular disease (CVD) than the general population. Cardiac autonomic neuropathy (CAN) is often associated with CVD risk factors including diabetes mellitus, metabolic syndrome and hypertension. Hence, it may be a predictor for cardiovascular morbidity and mortality. Screening for CAN risk through assessment of sudomotor function has been introduced as a method for early detection of autonomic dysfunction. Design and method: Adults with ID aged 18–45 years (n = 31) were compared to the general population (GP) (n = 29). Seated blood pressure, arterial stiffness (Pulse Wave Velocity [m/s] measured with Sphygmacor) and sudomotor function (measured with SUDOSCAN) were assessed. Results: Hand and feet electrical skin conductance (ESC) were lower in adults with ID ([Feet] ID = 72.8 microsiemens, GP = 80.4 microsiemens; p = 0.021 [Hands] ID = 65.6 microsiemens, GP = 76.8 microsiemens; p = 0.013) indicating elevated risk for CAN in the ID cohort. ESC in the ID population did not correlate with arterial stiffness, blood pressure nor body mass index (BMI), with both groups showing similar mean systolic blood pressures (ID = 127mmHg, GP = 122mmHg; p = 0.10) and PWV (ID = 8.0m/s, GP = 7.8m/s; p = 0.81), despite elevated BMI in the ID cohort (ID = 31.4 kg/m2, GP = 25.9 kg/m2; p = 0.002). However, ESC was related to Hb1Ac concentration, which was elevated in those with ID (ID = 34.4mmol/mol, GP = 29.7mmol/mol; p = 0.002). Conclusions: Our data indicates that sudomotor dysfunction is present in adults with ID and this was associated with impaired glucose metabolism. This suggest that CAN may play a role in the early development of CVD in young adults with ID. Given the increasing urgency to provide young individuals living with ID with the means to improve their health and wellbeing, screening for CAN could prove a useful tool in early detection of CVD risk, before the development of other typical risk factors including arterial stiffness and hypertension.

Cancer diagnoses among older people with intellectual disability compared with the general population: a national register study.

Cancer occurrence among older people with intellectual disability (ID) is poorly documented, so we investigated the frequency and distribution of cancer in older people with ID compared with the general population. People with ID who were ≥55years old and alive at the end of 2012 (n=7936; ID cohort) were identified through a national register of people with ID who received social services in Sweden to optimise the individual's opportunity for good living conditions in daily life. An equally large reference cohort from the general population (gPop cohort) was matched by year of birth and sex. Cancer diagnoses registered in inpatient and outpatient specialist care were collected for 2002-2012 from the ID cohort and compared with diagnoses in the gPop cohort. A lower total cancer frequency was observed in the ID cohort, which contained 555 cancers, compared with 877 cancers in the gPop cohort [odds ratio (OR): 0.63; 95% confidence interval (CI): 0.57-0.70]. Women accounted for 60% of cancers in the ID cohort. Breast and gynaecological organ cancers had similar or slightly lower frequencies in the ID cohort than in the general population, with breast OR of 0.95, uterine corpus OR of 1.00 and ovary OR of 0.73. Surprisingly, cancer frequency of the digestive organs (OR: 0.67), including the colon (OR: 0.82), was lower than in the general population. Cancers of the prostate (OR: 0.25), urinary tract (OR: 0.42) and lung were less frequent than in the general population. Cancer was diagnosed less frequently in the ID cohort than in the gPop cohort. However, cancers of the breast and colon-rectum remain frequent in people with ID and therefore warrant prevention policies, monitoring and screening similar to those of the general population.

Specialist psychiatric health care utilization among older people with intellectual disability \u2013 predictors and comparisons with the general population: a national register study

BackgroundPeople with intellectual disability (ID) face considerable barriers to accessing psychiatric health care, thus there is a risk for health disparity. The aims of the present study were 1) to compare specialist psychiatric health care utilization among older people with ID to that with their age peers in the general population, taking into account demographic factors and co-morbidities associated with specialist psychiatric health care utilization and 2) to determine a model for prediction of specialist psychiatric health care utilization among older people with ID.Material and methodsWe identified a national cohort of people with ID (ID cohort), aged 55+ years and alive at the end of 2012 (n = 7936), and a referent cohort from the general population (gPop cohort) one-to-one matched by year of birth and sex. Data on utilization of inpatient and outpatient specialist psychiatric health care, as well as on co-morbidities identified in either psychiatric or somatic specialist health care, were collected from the National Patient Register for the time period 2002–2012.ResultsAfter adjusting for sex, age, specialist psychiatric health care utilization the previous year, and co-morbidities, people in the ID cohort still had an increased risk of visits to unplanned inpatient (relative risk [RR] 1.95), unplanned outpatient (RR 1.59), planned inpatient (RR 2.02), and planned outpatient (RR 1.93) specialist psychiatric health care compared with the general population. Within the ID cohort, increasing age was a predictor for less health care, whereas psychiatric health care the previous year predicted increased risk of health care utilization the current year. As expected, mental and behavioral disorders predicted increased risk for psychiatric health care. Furthermore, episodic and paroxysmal disorders increased the risk of planned psychiatric health care.ConclusionsOlder people with ID have a high need for psychiatric specialist health care due to a complex pattern of diagnoses. Further research needs to investigate the conditions that can explain the lesser psychiatric care in higher age groups. There is also a need of research on health care utilization among people with ID in the primary health care context. This knowledge is critical for policymakers’ plans of resources to meet the needs of these people.

Prescription of pain medication among older cancer patients with and without an intellectual disability: a national register study

BackgroundThe longevity for people with intellectual disability (ID) has significantly increased in developed countries during the past decades. Consequently, the incidence of cancer is expected to increase in this group. The aim of the present study was to investigate the prescription of pain medication in older cancer patients with intellectual disability (ID) compared to older patients in the general population, surviving or living with a cancer diagnosis.MethodsThis Swedish national registry-based study, included people with ID aged 55 years or older in 2012, and alive at the end of that year (ID cohort, n = 7936). For comparisons, we used a referent cohort, one-to-one matched with the general population by year of birth and sex (gPop cohort, n = 7936). People with at least one diagnosis of cancer during 2002–2012 were identified using the Swedish National Patient Register, resulting in 555 cancer patients with ID and 877 cancer patients from the general population. These two cohorts of cancer patients were compared with respect to prescription of pain medication for the period 2006–2012. Outcome data were aggregated so that each patient was categorized as either having or not having at least one prescription of each investigated drug group during the study period, and relative risks (RRs) for prescription were estimated for prescription in the ID cohort vs the gPop cohort.ResultsCancer patients with ID were less likely than cancer patients in the gPop cohort to have at least one prescription of COX inhibitors (RR 0.61) and weak opioids (RR 0.63). They were, however, more likely to be prescribed paracetamol (RR 1.16), antidepressants (RR 2.09), anxiolytics (RR 2.84), and “other hypnotics, sedatives, and neuroleptics” (RR 1.39). No statistically significant differences between the two cohorts were found for strong opioids, antiepileptics, tricyclic antidepressants, or hypnotics and sedatives.ConclusionIn the studied cohort of older people surviving or living with cancer, prescriptions for pain-treatment was less common in patients with ID compared to the general population. These results may suggest that pain is not sufficiently treated among cancer patients with ID, a situation that most likely would compromise the quality of life in this group.

Pharmacotherapy for mood and anxiety disorders in older people with intellectual disability in comparison with the general population

BackgroundPeople with intellectual disability (ID) have high prevalence of psychiatric disorders, but even higher rates of prescription of psychotropic drugs.MethodsUsing Swedish national registers, we identified a group of older people with ID and diagnosis of mood disorders (ICD-10 codes F32-F39) and/or anxiety (ICD-10 code F4) during 2006–2012 (n = 587) and a referent group of people from the general population with the same diagnoses during the same time period (n = 434). For both groups, we collected information on prescription of anxiolytics, hypnotics and sedatives, antidepressants, and GABA-agonists.ResultsAmong those with a diagnosis of anxiety, people with ID were more likely than those in the general population to be prescribed anxiolytics (Relative Risk 1.32 [95% Confidence Interval 1.19–1.46]) and GABA-agonists (1.10 [1.08–1.31]). Moreover, among those with anxiety but without mood disorders, ID was associated with increased prescription of antidepressants (1.20 [1.03–1.39]). Within the ID cohort, behaviour impairment and MSP (i.e. moderate, severe, or profound) ID was associated with increased prescription of anxiolytics, both among those with anxiety (1.15 [1.03–1.30] for behaviour impairment and 1.23 [1.10–1.38] for MSP ID) and among those with mood disorders (1.14 [0.97–1.35] for behaviour impairment and 1.26 [1.04–1.52] for MSP ID). Moreover, MSP ID was associated with increased prescription of GABA-agonists among those with anxiety (1.23 [1.10–1.38]).ConclusionsThe excess prescription of anxiolytics but not antidepressants may suggest shortages in the psychiatric health care of older people with intellectual disability and mood and anxiety disorders.

The occurrence of comorbidities with affective and anxiety disorders among older people with intellectual disability compared with the general population: a register study

BackgroundLittle is known regarding the burden of comorbidities among older people with intellectual disability (ID) who have affective and anxiety disorders. Therefore, we aimed to investigate the occurrence and risk of psychiatric and somatic comorbidities with affective and/or anxiety disorders in older people with ID compared to the general population.MethodsThis population study was based on three Swedish national registers over 11 years (2002–2012). The ID group was identified in the LSS register, which comprises of data on measures in accordance with the Act Concerning Support and Service for Persons with Certain Functional Impairments (n = 7936), and a same-sized reference cohort from the Total Population Register was matched by sex and year of birth. The study groups consisted of those with affective (n = 918) and anxiety (n = 825) disorder diagnoses. The information about diagnoses were collected from the National Patient Register based on ICD-10 codes.ResultsThe rate of psychiatric comorbidities with affective and anxiety disorders was approximately 11 times higher for people with ID compared to the general reference group. The two most common psychiatric comorbidities occurred with affective and anxiety disorders were Unspecified non-organic psychosis and Other mental disorders due to brain damage and dysfunction and to physical disease (8% for each with affective disorders and 7 and 6% with anxiety disorders, respectively). In contrast, somatic comorbidity comparisons showed that the general reference group was 20% less likely than the ID cohort to have comorbid somatic diagnoses. The most commonly occurring somatic comorbidities were Injury, poisoning and certain other consequences of external causes (49 and 47% with affective and anxiety disorders, respectively) and Signs and symptoms and abnormal clinical and laboratory findings not elsewhere classified (44 and 50% with affective and anxiety disorders, respectively).ConclusionOlder people with ID and with affective and anxiety diagnoses are more likely to be diagnosed with psychiatric comorbidities that are unspecified, which reflects the difficulty of diagnosis, and there is a need for further research to understand this vulnerable group. The low occurrence rate of somatic diagnoses may be a result of those conditions being overshadowed by the high degree of psychiatric comorbidities.

The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin–Siris syndrome

PurposePathogenic variants in ARID1B are one of the most frequent causes of intellectual disability (ID) as determined by large-scale exome sequencing studies. Most studies published thus far describe clinically diagnosed Coffin–Siris patients (ARID1B-CSS) and it is unclear whether these data are representative for patients identified through sequencing of unbiased ID cohorts (ARID1B-ID). We therefore sought to determine genotypic and phenotypic differences between ARID1B-ID and ARID1B-CSS. In parallel, we investigated the effect of different methods of phenotype reporting.MethodsClinicians entered clinical data in an extensive web-based survey.Results79 ARID1B-CSS and 64 ARID1B-ID patients were included. CSS-associated dysmorphic features, such as thick eyebrows, long eyelashes, thick alae nasi, long and/or broad philtrum, small nails and small or absent fifth distal phalanx and hypertrichosis, were observed significantly more often (p < 0.001) in ARID1B-CSS patients. No other significant differences were identified.ConclusionThere are only minor differences between ARID1B-ID and ARID1B-CSS patients. ARID1B-related disorders seem to consist of a spectrum, and patients should be managed similarly. We demonstrated that data collection methods without an explicit option to report the absence of a feature (such as most Human Phenotype Ontology-based methods) tended to underestimate gene-related features.

Ambulatory Care Sensitive Admissions in Individuals With Autism Spectrum Disorder, Intellectual Disability, and Population Controls.

Ambulatory care sensitive (ACS) admissions are those for which effective primary care can prevent the need for emergency department (ED) visits and inpatient hospitalizations, and are an indicator of primary care access. Individuals with autism spectrum disorder (ASD) and/or intellectual disability (ID) may be at higher risk for ACS admissions than individuals in the general population due to difficulty accessing primary care. The objective of this study was to compare the incidence of ACS admissions among four cohorts of individuals aged 2-24 years: ASD without co-occurring ID (ASD-only), ASD with co-occurring ID (ASD + ID), ID without ASD (ID-only), and population controls (PC). Data from ED visits and inpatient hospitalizations occurring between January 1, 2000 and December 31, 2015 were examined to identify ACS admissions. Generalized linear models were used to examine differences between cohorts on the number of ACS ED visits and inpatient hospitalizations. Results revealed the ASD + ID and ID-only cohorts had significantly higher rates of ACS inpatient hospitalizations than the PC cohort. Additionally, the ID-only cohort had higher rates of ACS ED visits than the PC cohort. The ASD-only and PC cohorts did not differ on incidence of ACS admissions. These findings suggest that presence of an ID with or without co-occurring ASD increased the risk for ACS inpatient hospitalizations, and presence of ID-only increased the risk for ACS ED visits. Future work should examine trajectories of ACS admissions over time and consider inclusion of additional characteristics that may elucidate reasons for differences in ACS admissions among these groups. Autism Res 2019, 12: 295-302 © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Preventable hospitalizations are a common indicator of problems with access to quality primary healthcare. Findings of this study suggest that individuals with intellectual disability, with or without autism spectrum disorder, have higher rates of preventable hospitalizations than the general population. Further research is needed to understand how to improve access to primary care and reduce preventable hospitalizations for this vulnerable population.

Falls resulting in health care among older people with intellectual disability in comparison with the general population.

BackgroundFalls are common among older people with intellectual disability (ID) and are also a major contributor to injuries in this population. Yet, fall characteristics have only been sparsely studied, and the results are inconsistent. The aim of the present study was to investigate type of falls, places where they occurred and activities that caused them, as well as health outcomes and health utilisation patterns after falls, among older people with ID in comparison with their age peers in the general population.MethodsWe established an administrative cohort of people with ID aged 55 years, or more, and alive at the end of 2012 (ID cohort; n = 7936). A cohort from the general population, one‐to‐one matched by sex and year of birth, was used as referents. Data regarding fall‐induced health care episodes in inpatient and outpatient specialist care were collected from the National Patient Register for the period 2002–2012.ResultsWith the exception of falls from one level to another (i.e. fall on and from stairs and steps, ladder and scaffolding; fall from, out of or through building or structure; fall from tree or cliff and diving or jumping into water; or other fall from one level to another), people in the ID cohort were more likely to fall and fall more often than those in the general population cohort. Falls during a vital activity (e.g. attending to personal hygiene or eating) were twice as common among people with ID compared with the general population. When falling, people with ID were more likely to injure their head and legs but less likely to sustain injuries to the thorax and elbow/forearm. They were more likely to have superficial injuries, open wounds and fractures but less likely to have dislocations, sprain and strains. Fall‐related health care visits among people with ID were more likely to be in inpatient care and be unplanned. People with ID were also more likely than those in the general population to have a readmission within 30 days.ConclusionsPeople with ID are more likely to require specialist care after a fall and also more likely to obtain injuries to the head, compared with the general population. This is important to consider when taking preventive measures to reduce falls and fall‐related injuries.

Novel MEF2C point mutations in Chinese patients with Rett (\u2212like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation

BackgroundMEF2C (Myocyte-specific enhancer factor 2C) has been associated with neurodevelopmental disorders. This study aimed at delineating the clinical profiles of MEF2C gene mutations.MethodsIn total, 112 Chinese patients with intellectual disability (ID) were recruited, including 44 patients presented with Rett syndrome (RTT) or RTT-like syndrome, and 68 patients with non-syndromic ID. Targeted next-generation sequencing (NGS) was performed. Detailed clinical information was collected.ResultsFive heterozygous MEF2C gene mutations were identified, of which three were novel. The MEF2C mutant rate was 4.5% (5/112) in total, and 6.8% (3/44) in the RTT (−like) cohort. All patients with MEF2C gene mutation presented with cognitive impairment, gross motor delay, speech disorder and autistic features. Four patients had epilepsy, which responded well to antiepileptic drugs. One female was diagnosed with classical RTT, two females with RTT-like syndrome, and two males with non-syndromic ID. Generally, the phenotype of two males with relatively downstream mutations (c.565C > T, p.Arg 189*; c.766C > T, p.Arg 256*) was milder than that of three females with upstream mutations (c.48C > G, p.Asn16Lys; c.334G > T, p.Glu112* and c.403-1G > T).ConclusionsOur findings expanded the current understanding of the consequences of MEF2C dysfunctions, especially MEF2C point mutations. MEF2C mutations are associated with a broad clinical spectrum, ranged from classical RTT to non-syndromic ID. Through our study, it can be inferred that there is correlation between the phenotype and MEF2C-genotype, the mutation site. Overall, the MEF2C gene mutational analysis should be performed in ID cohort, especially in patients with features overlapped with RTT.

Genome-wide investigation of an ID cohort reveals de novo 3\u2032UTR variants affecting gene expression

Intellectual disability (ID) is a severe neurodevelopmental disorder with genetically heterogeneous causes. Large-scale sequencing has led to the identification of many gene-disrupting mutations; however, a substantial proportion of cases lack a molecular diagnosis. As such, there remains much to uncover for a complete understanding of the genetic underpinnings of ID. Genetic variants present in non-coding regions of the genome have been highlighted as potential contributors to neurodevelopmental disorders given their role in regulating gene expression. Nevertheless the functional characterization of non-coding variants remains challenging. We describe the identification and characterization of de novo non-coding variation in 3′UTR regulatory regions within an ID cohort of 50 patients. This cohort was previously screened for structural and coding pathogenic variants via CNV, whole exome and whole genome analysis. We identified 44 high-confidence single nucleotide non-coding variants within the 3′UTR regions of these 50 genomes. Four of these variants were located within predicted miRNA binding sites and were thus hypothesised to have regulatory consequences. Functional testing showed that two of the variants interfered with miRNA-mediated regulation of their target genes, AMD1 and FAIM. Both these variants were found in the same individual and their functional consequences may point to a potential role for such variants in intellectual disability.

Whole-exome sequencing reanalysis at 12 months boosts diagnosis and is cost-effective when applied early in Mendelian disorders.

Whole-exome sequencing (WES) has revolutionized Mendelian diagnostics, however, there is no consensus on the timing of data review in undiagnosed individuals and only preliminary data on the cost-effectiveness of this technology. We aimed to assess the utility of WES data reanalysis for diagnosis in Mendelian disorders and to analyze the cost-effectiveness of this technology compared with a traditional diagnostic pathway. WES was applied to a cohort of 54 patients from 37 families with a variety of Mendelian disorders to identify the genetic etiology. Reanalysis was performed after 12 months with an improved WES diagnostic pipeline. A comparison was made between costs of a modeled WES pathway and a traditional diagnostic pathway in a cohort with intellectual disability (ID). Reanalysis of WES data at 12 months improved diagnostic success from 30 to 41% due to interim publication of disease genes, expanded phenotype data from referrer, and an improved bioinformatics pipeline. Cost analysis on the ID cohort showed average cost savings of US$586 (AU$782) for each additional diagnosis. Early application of WES in Mendelian disorders is cost-effective and reanalysis of an undiagnosed individual at a 12-month time point increases total diagnoses by 11%.

Prescription of potentially inappropriate medications among older people with intellectual disability: a register study

BackgroundOlder people have a greater disease burden and are more likely than younger to be prescribed medications. They are also more sensitive to adverse effects. With this in mind, a range of medications have been suggested inappropriate in this population. People with intellectual disability (ID) have a higher disease burden than the general population, putting them at even greater risk of prescription of such medications. The aim of this study was to describe prescription of potentially inappropriate medications among older people with ID in relation to prescriptions among their age peers in the general population.MethodsWe established an administrative cohort of people with ID (ID cohort; n = 7936), using a Swedish national register. A referent cohort from the general population (gPop) was matched one-to-one by sex and year of birth. Data regarding prescription of potentially inappropriate medications were collected from the Swedish prescribed drug register for the years 2006–2012.ResultsPeople with ID were more likely than the general population to be prescribed medications with anticholinergic effects, intermediate- or long-acting benzodiazepines, and antipsychotics at least once during the study period, and also had more number of years with prescription. Except for benzodiazepines, those in the ID cohort with at least one prescription had larger amounts prescribed than those in the gPop cohort. People in the ID cohort were less likely than the general population to be prescribed non-steroidal anti-inflammatory drugs (NSAIDs). Among those with at least one prescription of NSAIDs, those in the ID cohort had prescriptions during fewer years and in lower amounts than those in the gPop cohort.ConclusionsAlthough prescription of potentially inappropriate medications overall is more common among people with ID than in the general population, the opposite pattern is found for medications for pain management. This may be a result of pain being under-recognized and under-treated in this population. Thus, there is a need for training as well as increased knowledge and awareness among care and health care professionals regarding signs of adverse effects and the need of continuous evaluation of treatment in this vulnerable group.