Baratela-Scott syndrome (BSS) is a rare, autosomal-recessive disorder characterized by short stature, facial dysmorphisms, developmental delay, and skeletal dysplasia caused by pathogenic variants in ...XYLT1. We report clinical and molecular investigation of 10 families (12 individuals) with BSS. Standard sequencing methods identified biallelic pathogenic variants in XYLT1 in only two families. Of the remaining cohort, two probands had no variants and six probands had only a single variant, including four with a heterozygous 3.1 Mb 16p13 deletion encompassing XYLT1 and two with a heterozygous truncating variant. Bisulfite sequencing revealed aberrant hypermethylation in exon 1 of XYLT1, always in trans with the sequence variant or deletion when present; both alleles were methylated in those with no identified variant. Expression of the methylated XYLT1 allele was severely reduced in fibroblasts from two probands. Southern blot studies combined with repeat expansion analysis of genome sequence data showed that the hypermethylation is associated with expansion of a GGC repeat in the XYLT1 promoter region that is not present in the reference genome, confirming that BSS is a trinucleotide repeat expansion disorder. The hypermethylated allele accounts for 50% of disease alleles in our cohort and is not present in 130 control subjects. Our study highlights the importance of investigating non-sequence-based alterations, including epigenetic changes, to identify the missing heritability in genetic disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In the past two decades, genetic testing for cancer risk assessment has entered mainstream clinical practice due to the availability of low-cost panels of multiple cancer-associated genes. However, ...the clinical value of multiple-gene panels for cancer susceptibility is not well established, especially in cases where panel testing identifies more than one pathogenic variant. The risk for specific malignancies as a result of a mutated gene is complex and likely influenced by superimposed modifier variants and/or environmental effects. Recent data suggests that the combination of multiple pathogenic variants may be fewer than reported by chance, suggesting that some mutation combinations may be detrimental. Management of patients with "incidentally" discovered mutations can be particularly challenging, especially when established guidelines call for radical procedures (e.g. total gastrectomy in CDH1) in patients and families without a classic clinical history concerning for that cancer predisposition syndrome.
We present two cases, one of an individual and one of a family, with multiple pathogenic mutations detected by multi-gene panel testing to highlight challenges practitioners face in counseling patients about pathogenic variants and determining preventive and therapeutic interventions.
Ongoing investigation is needed to improve our understanding of inherited susceptibility to disease in general and cancer predisposition syndromes, as this information has the potential to lead to the development of more precise and patient-specific counseling and surveillance strategies. The real-world adoption of new or improved technologies into clinical practice frequently requires medical decision-making in the absence of established understanding of gene-gene interactions. In the meantime, practitioners must be prepared to apply a rationale based on currently available knowledge to clinical decision-making. Current practice is evolving to rely heavily on clinical concordance with personal and family history in making specific therapeutic decisions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Many Semantic Web problems are difficult to solve through common divide-and-conquer strategies, since they are hard to partition. We present
Marvin, a parallel and distributed platform for processing ...large amounts of RDF data, on a network of loosely coupled peers. We present our
divide-conquer-swap strategy and show that this model converges towards completeness.
Within this strategy, we address the problem of making distributed reasoning scalable and load-balanced. We present
SpeedDate, a routing strategy that combines data clustering with random exchanges. The random exchanges ensure load balancing, while the data clustering attempts to maximise efficiency.
SpeedDate is compared against random and deterministic (DHT-like) approaches, on performance and load-balancing. We simulate parameters such as system size, data distribution, churn rate, and network topology. The results indicate that
SpeedDate is near-optimally balanced, performs in the same order of magnitude as a DHT-like approach, and has an average throughput per node that scales with
i
for
i items in the system. We evaluate our overall
Marvin system for performance, scalability, load balancing and efficiency.
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This report presents the detection of a heterozygous deletion at chromosome 12q14 in three unrelated patients with a similar phenotype consisting of mild mental retardation, failure to thrive in ...infancy, proportionate short stature and osteopoikilosis as the most characteristic features. In each case, this interstitial deletion was found using molecular karyotyping. The deletion occurred as a de novo event and varied between 3.44 and 6 megabases (Mb) in size with a 3.44 Mb common deleted region. The deleted interval was not flanked by low-copy repeats or segmental duplications. It contains 13 RefSeq genes, including LEMD3, which was previously shown to be the causal gene for osteopoikilosis. The observation of osteopoikilosis lesions should facilitate recognition of this new microdeletion syndrome among children with failure to thrive, short stature and learning disabilities.
Abstract Characteristic features of the 12q14 microdeletion syndrome include low birth weight, failure to thrive, short stature, learning disabilities and Buschke–Ollendorff lesions in bone and skin. ...This report on two additional patients with this microdeletion syndrome emphasizes the rather constant and uniform phenotype encountered in this disorder and refines the critical region to a 2.61 Mb interval on 12q14.3, encompassing 10 RefSeq genes. We have previously shown that LEMD3 haploinsufficiency is responsible for the Buschke–Ollendorff lesions and now provide strong evidence that a heterozygous deletion of HMGA2 is causing the growth failure observed in this disorder. The identification of an intragenic HMGA2 deletion in a boy with proportionate short stature and the cosegregation of this deletion with reduced adult height in the extended family of the boy further underscore the role of HMGA2 in regulating human linear growth.
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Microsatellite instability (MSI) may be a molecular marker of colorectal tumor biology. We sought to evaluate the incidence and significance of MSI in an unselected colorectal cancer population.
...Colorectal cancer cases from a community health system were prospectively evaluated for MSI and patient outcomes monitored.
Of 240 eligible, 140 underwent testing; 43 (31%) had high-frequency MSI (MSI-H). Those with MSI-H tumors presented with earlier disease stage (
P = .014) and lymphocytic infiltration (
P < .001). Stage III MSI-H patients trended toward improved disease-free survival (
P = .065). MSI-H patients were more likely to have other primary malignancies.
Prevalence of MSI-H in the general colorectal cancer population is higher than previously reported. MSI testing of colorectal cancers is useful as part of a molecular profile to stratify patients for prognosis, treatment, and further study. Patients with MSI-H tumors are more likely to have other primary malignancies, suggesting a role for heightened screening.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
8.
Massively Scalable Web Service Discovery Anadiotis, G.; Kotoulas, S.; Lausen, H. ...
2009 International Conference on Advanced Information Networking and Applications
Conference Proceeding
The increasing popularity of Web services (WS) has exemplified the need for scalable and robust discovery mechanisms. Although decentralized solutions for discovering WS promise to fulfill these ...needs, most make limiting assumptions concerning the number of nodes and the topology of the network and rely on having information on the data a-priori (e.g. categorizations or popularity distributions). In addition, most systems are tested via simulations using artificial datasets. In this paper we introduce a lightweight, scalable and robust WSDL discovery mechanism based on real-time calculation of term popularity. In order to evaluate this mechanism, we have collected and analyzed real data from deployed WS and performed a large-scale emulation on the DAS-3 distributed supercomputer. Results show that we can achieve Web-scale service discovery based on term search and we also sketch an extension of this mechanism to support a fully-fledged WS query language.
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10.
Ornithine transcarbamylase deficiency and pancreatitis Anadiotis, George; Ierardi-Curto, Lynne; Kaplan, Paige B. ...
The Journal of pediatrics,
January 2001, 2001, 2001-Jan, 2001-1-00, 20010101, Volume:
138, Issue:
1
Journal Article
Peer reviewed
We describe a male patient with a Y202H ornithine transcarbamylase deficiency gene mutation who had pancreatitis while taking a low-protein diet, citrulline, and sodium phenylbutyrate. (J Pediatr ...2001;138:123-4)
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