Lafora disease (LD) is a severe form of progressive myoclonus epilepsy inherited in an autosomal recessive fashion. It is associated with biallelic pathogenic variations in EPM2A or NHLRC1, which ...encode laforin and malin, respectively. The disease usually starts with adolescent onset seizures followed by progressive dementia, refractory status epilepticus and eventually death within 10 years of onset. LD is generally accepted as having a homogenous clinical course with no considerable differences between EPM2A or NHLRC1 associated forms. Nevertheless, late-onset and slow progressing forms of the disease have also been reported. Herein, we have performed clinical and genetic analyses of 14 LD patients from 12 different families and identified 8 distinct biallelic variations in these patients. Five of these variations were novel and/or associated with the LD phenotype for the first time. Interestingly, almost half of the cases were homozygous for the rare rs769301934 (NM_198586.3(NHLRC1): c.436 G > A; p.(Asp146Asn)) allele in NHLRC1. A less severe phenotype with an onset at a later age may be the reason for the biased inflation of this variant, which is already present in the human gene pool and can hence arise in the homozygous form in populations with increased parental consanguinity.
Background
Syndromic intellectual disability (ID) with accompanying primary microcephaly is a group of rare neurodevelopmental disorders exhibiting extreme genetic and clinical heterogeneity. This ...layered heterogeneity can partially be resolved by unbiased genetic approaches targeting the genome with next generation sequencing (NGS) technologies, including exome sequencing (ES).
Objective
This study was performed to dissect the clinical and genetic features in five distinct IDM cases.
Methods
Singleton or trio ES approach followed by in-depth variant analysis using alternative inheritance models was performed.
Results
We have identified biallelic loss of function variants in genes
WDR62
and
AP4M1
in three families, together with de novo missense variants in genes
SOX11
and
TRIO
in two families. ES based haplotype analysis in two cases upon identification of an identical
WDR62
variant in the homozygous state in two cases was suggestive of a small shared haplotype of 0.1 Mb. Additionally, we have shown a paternal origin for the de novo variant in
TRIO
via a polymorphic tag SNP, which enlightens the mutational mechanism for this variant.
Conclusion
In populations with high parental consanguinity, an autosomal recessive inheritance pattern for data analysis is usually the most obvious choice. Therefore, heterozygous variants may be overlooked in standard NGS analyses in consanguineous families. Our findings underlie the importance of using multiple inheritance models in NGS data analysis.
Connectivity is key in this new era of smart infrastructure. Smart airports utilize new connected technologies to improve end-user experience while ensuring operational feasibility in aeronautical ...and non-aeronautical segments. The increasing need for digitizing the design-build-operate life cycles of airports can be met by implementing building information modeling (BIM) that enables accessing, managing, utilizing, and connecting physical and operational data in a digital collaborative environment. This study investigates the current state of practice in airport BIM (ABIM) and the use of ABIM processes in digital airport operations and maintenance by connecting existing data sources and integrating smart airport systems. The study proposes a comprehensive and adaptive ABIM management framework that depicts the alignment and connectivity of ABIM processes, resources and stakeholders with airport operational requirements by identifying gaps in the industry and literature, and developing a global understanding in ABIM visions. Research data are collected through literature and industry review, online surveys, and semi-structured interviews with aviation professionals. Mixed methods including non-parametric statistical analysis and qualitative analysis are used to determine the elements of the framework. Model-based systems engineering (MBSE) principles and language are used to generate the framework. For framework validation, a proof of concept (POC) is conducted by development and deployment of a web-based application. The developed ABIM framework is expected to guide major airport stakeholders in their BIM implementation processes to enhance airport operational efficiencies and in strategizing digital initiatives on a connected-BIM platform.
Purpose>Pavement deterioration prediction models play a crucial role in determining maintenance strategies and future funding needs. While deterioration prediction models have been studied ...extensively in the past, applications of these models to local street networks have been limited. This study aims to address this gap by sharing the results of network level deterioration prediction models developed at a local level.Design/methodology/approach>Network level pavement deterioration prediction models are developed using Markov chains for the local street network in Syracuse, New York, based on pavement condition rating data collected over a 15-year time period. Transition probability matrices are generated by calculating the percentage of street sections that transition from one state to another within one duty cycle. Bootstrap sampling with replacement is used to numerically generate 95% confidence intervals around the transition probability values.Findings>The overall local street network is divided into three cohorts based on street type (i.e. avenues, streets and roads) and two cohorts based on pavement type. All cohorts demonstrated very similar deterioration trends, indicating the existence of a fast-paced deterioration mechanism for the local street network of Syracuse.Originality/value>This study contributes to the body of knowledge in deterioration modeling of local street networks, especially in the absence of key predictor variables. Furthermore, this study introduces the use of bootstrap sampling with replacement method in generating confidence intervals for transition probability values.
PurposeThe purpose of this paper is to systematically analyse how building information modelling (BIM) transforms complex infrastructure settings (i.e. airports) around digital technologies by ...enhancing connectivity and collaboration between major stakeholders and construction technology solutions. The objectives include understanding each project party's perspective for BIM implementation to align their motivations and connectivity along project's supply chain network and how BIM drives construction technology ecosystem uses for a more integrative and collaborative project delivery.Design/methodology/approachThe study adopts qualitative data collection and analysis methods comprising semi-structured interviews, thematic analysis and an explanatory case study of a large-hub airport project.FindingsThe study findings show that enabling BIM implementation leads to streamlining construction technology ecosystem uses that increase connectivity within project parties' processes. Airports – as hosting high-value assets – can fast realize value of synergistic activities throughout project delivery by harnessing significant amount of siloed data created by each major party.Originality/valueThe study provides a structured analysis of how complex project settings leverage construction technology uses through their core BIM processes by highlighting multi-party approaches from an ecosystem perspective. This study also contributes to the body of knowledge and practice by presenting a transferrable and scalable approach for leveraging connected construction technology in a large-scale project involving fragmented processes managed by a large number of stakeholders.
Triggering or modulation of seizures and rhythmic EEG patterns by external stimuli are well-known with the most common clinical appearance of stimulus induced periodic discharges (SI- PDs) patterns ...which are elicited by physical or auditory stimulation. However, stimulus terminated periodic discharges (ST-PDs), in other words, the periodic discharges stopped by external stimuli is an extremely rare electroencephalographic (EEG) finding. We report a 20-year-old woman with a marked psychomotor developmental delay of unknown cause, with frequent EEG patterns of long-lasting (10–60 s) bilateral paroxysmal high-voltage slow waves with occasional spikes, misdiagnosed as non-convulsive status epilepticus. However, no apparent clinical change was noted by the technician, physician, and her mother during these subclinical ictal EEG recordings. Interestingly, however, these epileptic discharges were abruptly interrupted by sudden verbal stimuli on the EEG, repeatedly. Whole exome sequencing and genotyping were performed to investigate possible genetic etiology that revealed two sequence variants, a frameshift variant of CACNA1H NM_021098.3:c.1701del;p.Asp568ThrfsTer15 and a missense variant of GRIN2D NM_000836.4:c.1783A>T;p.Thr595Ser as well as a copy number variant part deletion of ATP6V1A gene arr hg193q13.31(113,499,698_113,543,081)x1 as possible pathogenic candidates. The subclinical periodic discharges terminated by verbal stimuli, is a very rare manifestation and needs particular attention. External modulation of ictal-appearing EEG patterns is important to identify stimulus terminated EEG patterns.
Approximately a quarter of the bridges in the United States are classified as either functionally obsolete or structurally deficient by the United States Department of Transportation (USDOT). As ...such, transportation agencies are challenged to handle the increasing need of upgrades with limited resources. Accelerated Bridge Construction (ABC) can reduce the construction duration and can decrease the environmental and socio-economic impacts of repair and upgrade activities by minimizing traffic disruptions. As several states are using accelerated construction techniques, a standard guideline would be highly beneficial for these agencies in developing or improving the ABC decision-making process. As problems are often project specific, a decision tool can assist in determining the viability of ABC over traditional construction methods and in selecting appropriate construction and contracting strategies on a case-by-case basis. This paper presents findings of a recent survey with regards to utilization of ABC strategies by state Departments of Transportation (DOTs), and a decision support framework which consists of three models: (1) Analytical Hierarchy Process (AHP) based ABC vs. traditional construction decision-making model; (2) ABC alternatives selection model; and (3) procurement method and contract selection model. The paper also discusses the use of ABC in New York State and describes a New York State bridge project to validate the AHP model.
Developmental and Epileptic Encephalopathies (DEEs) are a group of early-onset syndromic disorders characterized by varying degree of intellectual disability, autism spectrum, seizures, and ...developmental delay. Herein, we have clinically and genetically dissected three siblings from Turkey with DEE born to first cousin unaffected parents. We identified a homozygous pathogenic variant in
(ENST00000358232.11:c.1385G>A; p.(Arg462Gln)). Our results, together with in depth literature review, underlie the importance of codon encoding the arginine at position 462 as a hotspot for
related neurological phenotypes.
Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies ...and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10-15; Cleveland: P = 2.85×10-4; Finnish-ancestry Epi25: P = 1.80×10-4) or population controls (Epi25: P = 2.35×10-70; Cleveland: P = 1.43×10-7; Finnish-ancestry Epi25: P = 3.11×10-4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10-4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10-19; Cleveland: P = 1.69×10-6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10-15; Cleveland: P = 1.39×10-2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls-in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.
Objective: To explore the underlying genetic variations and
mechanisms in a family affected by isolated dystonia.
Material and Method: We employed whole genome Single Nucleotide
Polymorphism (SNP) ...based linkage analysis along with
whole exome sequencing (WES) in a consanguineous family presenting
with isolated dystonia. An in-house pipeline compiled
for WES analysis along with in-depth in silico prediction algorithms
were used to assess the associated data produced in this
study. Sanger sequencing was used for variant confirmation and
segregation.
Results: Data analysis included locus oriented WES variant prioritization
and cryptic splicing predictions. We detected a homozygous
and synonymous variation rs748449895 (NM_015125.4:
c.4143C>T; p.(Thr1381=)) in the capicua transcriptional repressor,
CIC. This variation disrupts the YB-1 RNA recognition motif
and creates an alternative SRp20 RNA recognition motif.
Conclusion: The resulting variant might cause the dystonia phenotype
by affecting the alternative splicing of CIC transcript and
altering the exon inclusion motif which may disrupt the ATXN1–
CIC complex.
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