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Genetics is believed to have an important role in intellectual disability (ID). Recent studies have emphasized the involvement of de novo mutations (DNMs) in ID but the extent to which they contribute to its pathogenesis and the identity of the corresponding genes remain largely unknown. Here, we report a screen for DNMs in subjects with moderate or severe ID. We sequenced the exomes of 41 probands and their parents, and confirmed 81 DNMs affecting the coding sequence or consensus splice sites (1.98 DNMs/proband). We observed a significant excess of de novo single nucleotide substitutions and loss-of-function mutations in these cases compared to control subjects, suggesting that at least a subset of these variations are pathogenic. A total of 12 likely pathogenic DNMs were identified in genes previously associated with ID (ARID1B, CHD2, FOXG1, GABRB3, GATAD2B, GRIN2B, MBD5, MED13L, SETBP1, TBR1, TCF4, WDR45), resulting in a diagnostic yield of ∼29%. We also identified 12 possibly pathogenic DNMs in genes (HNRNPU, WAC, RYR2, SET, EGR1, MYH10, EIF2C1, COL4A3BP, CHMP2A, PPP1CB, VPS4A, PPP2R2B) that have not previously been causally linked to ID. Interestingly, no case was explained by inherited mutations. Protein network analysis indicated that the products of many of these known and candidate genes interact with each other or with products of other ID-associated genes further supporting their involvement in ID. We conclude that DNMs represent a major cause of moderate or severe ID.

ABSTRACTBackgroundInuit children from Nunavut have been observed to have high rates of macrocephaly, which sometimes leads to burdensome travel for medical evaluation, often with no pathology identified upon assessment. Given reports that World Health Organization (WHO) growth charts may not reflect all populations, we sought to compare head circumference measurements in a cohort of Inuit children with the WHO charts. MethodsWe extracted head circumference data from a previous retrospective cohort study where, with Inuit partnership, we reviewed medical records of Inuit children (from birth to age 5 yr) born between Jan. 1, 2010, and Dec. 31, 2013, and residing in Nunavut. To create a cohort of Inuit children similar to the cohorts used in the development of the WHO growth charts, we excluded children with preterm birth, documented neurologic or genetic disease, and most congenital anomalies. We compared head circumference values with the 2007 WHO charts using centiles estimated with a generalized additive model. ResultsWe analyzed records of 1960 Inuit children (8866 data points), of whom 993 (50.8%) were female. Most data were from ages 0 to 36 months. At all age points, we found that the study cohort had statistically significantly larger head circumferences than WHO medians, with most z scores for head circumference measurements among Inuit children falling 0.5–1 standard deviations above the WHO reference ( p < 0.001). At age 12 months, median head circumferences were 1.3 cm and 1.5 cm larger for male and female Inuit children, respectively. Using WHO growth curves, macrocephaly was significantly overdiagnosed and microcephaly was underdiagnosed ( p < 0.001). InterpretationOur results support the observation that Inuit children from Nunavut have larger head circumferences than other populations, and use of the WHO charts may thus lead to overdiagnosis of macrocephaly and underdiagnosis of microcephaly. Population-specific growth curves for Inuit children should be considered to provide timely and appropriate diagnoses of microcephaly and avoid overinvestigation of macrocephaly.

Champlain BASE™ (Building Access to Specialists through eConsultation) is a web-based asynchronous electronic communication service that allows primary-care- practitioners (PCPs) to submit \"elective\" clinical questions to a specialist. For adults, PCPs have reported improved access and timeliness to specialist advice, averted face-to-face specialist referrals in up to 40% of cases and high provider satisfaction. To determine whether the expansion of eConsult to a pediatric setting would result in similar measures of improved healthcare system process and high provider acceptance reported in adults. Prospective observational cohort study. Single Canadian tertiary-care academic pediatric hospital (June 2014-16) servicing 1.2 million people. 1. PCPs already using eConsult. 2.Volunteer pediatric specialists provided services in addition to their regular workload. 3.Pediatric patients (< 18 years-old) referred for none-acute care conditions. Specialty service utilization and access, impact on PCP course-of-action and referral-patterns and survey-based provider satisfaction data were collected. 1064 eConsult requests from 367 PCPs were answered by 23 pediatric specialists representing 14 specialty-services. The top three specialties represented were: General Pediatrics 393 cases (36.9%), Orthopedics 162 (15.2%) and Psychiatry 123 (11.6%). Median specialist response time was 0.9 days (range <1 hour-27 days), most consults (63.2%) required <10minutes to complete and 21/21(100%) specialist survey-respondents reported minimal workload burden. For 515/1064(48.4%) referrals, PCPs received advice for a new or additional course of action; 391/1064(36.7%) referrals resulted in an averted face-to-face specialist visit. In 9 specialties with complete data, the median wait-time was significantly less (p<0.001) for an eConsult (1 day, 95%CI:0.9-1.2) compared with a face-to-face referral (132 days; 95%CI:127-136). The majority (>93.3%) of PCPs rated eConsult as very good/excellent value for both patients and themselves. All specialist survey-respondents indicated eConsult should be a continued service. Similar to adults, eConsult improves PCP access and timeliness to elective pediatric specialist advice and influences their care decisions, while reporting high end-user satisfaction. Further study is warranted to assess impact on resource utilization and clinical outcomes.

Introduction Spinal cord infarction is extremely rare in childhood and can result from a wide range of causes. Fibrocartilaginous embolism can give rise to spinal stroke and mimic non-vascular disease such as acute transverse myelitis. Case We report two children who suffered an asymmetrical spinal cord infarction due to fibrocartilaginous embolism. The clinical presentation, radiological findings, and pathophysiology of fibrocartilaginous embolism are described. Each patient demonstrated marked clinical improvement after receiving extensive physical therapy and rehabilitation. One child demonstrated complete clinical recovery. The other had persistent asymmetrical foot weakness and distal sensory deficits. Conclusion We outline the key clinical and radiographic features that enable spinal cord infarction to be differentiated from transverse myelitis. Prognosis depends on many factors such as extent and type of injury, level of the cord affected, and age at the time of spinal cord infarction.

ObjectiveTo determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms.MethodsChildren with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG- and AQP4-antibodies using live cell-based assays.Results45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016).Conclusions67% of all children presenting with NMO or limited forms tested positive for MOG- or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes.

Purpose Pathogenic 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. Methods Clinicians entered clinical data in an extensive web-based survey. Results 79 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. Conclusion There 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.