Catalogue Search | MBRL
Are you sure you want to remove the book from the shelf?
{{itemTitle}}
107
result(s) for
"Kingston, Helen"
Sort by:
ألف باء الوراثة الإكلينيكية
يتناول الكتاب عدة موضوعات تدور في إطار موضوع الوراثة الإكلينيكية فيبدأ بموضوع خدمة الوراثة الإكلينيكية ثم قوانين مندل الوراثية الوراثة اللامندلية دراسة صبغيات الإنسان وراثة الأمراض الشائعة التشوهات الخلقية التعرف على الأشخاص حاملي الأمراض الوراثية تشخيص الأمراض الوراثية وسائل علاج الأمراض الوراثية وأخيرا دراسة واستخدام الحامض النووي في الأمراض الوراثية الشائعة.
Book
Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders
PurposeThe increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.MethodsRetrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.ResultsAbnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.ConclusionsOur results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.
Journal Article
Embedding social relations into primary care: A population‐based approach. What matters most? Population practice of social ecology in medicine and communities
Background The importance of social connectedness has long been an area of research in medical research. The damaging impact of social isolation is recognised and proven. This article describes our experiences of embedding routine enquiry about networks of support into routine clinical care. Aims The majority of care happens through the strength of bonds and support between the network of immediate family and friends. Acknowledging these networks and actively working to support them is central to health and wellbeing. Results In parallel, working to improve professional networks builds trust, shared understanding and stronger relationships that benefit us all. The strengthening of bonds across and between teams delivering health care can benefit those working within them and lead to improved outcomes for both staff and patients. Conclusion Developing Frome as a compassionate community has enabled improved patient care, improved staff wellbeing and financial savings for the health community.
Journal Article
Prevalence and architecture of de novo mutations in developmental disorders
The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging
de novo
mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year.
Whole-exome analysis of individuals with developmental disorders shows that
de novo
mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described.
De novo
mutations in developmental disorders
Matthew Hurles, Jeremy McRae and colleagues from the Deciphering Developmental Disorders Study report exome sequencing of 4,293 families containing individuals with severe, undiagnosed developmental disorders. They find enrichment of damaging
de novo
mutations in 94 genes, implicating them in developmental disorders. They estimate that 42% of the cohort carry pathogenic
de novo
mutations in coding sequences resulting in disrupted or altered protein function.
Journal Article
CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in
CHD3
, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo
CHD3
mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo
CHD3
mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.
Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in
CHD3
that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.
Journal Article
Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism
Background Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. Methods We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. Results Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as ‘NIPBL-like’. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. Conclusions Future diagnostic testing in ‘mutation-negative’ CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.
Journal Article
Mutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathy
Centronuclear myopathies are characterized by muscle weakness and abnormal centralization of nuclei in muscle fibers not secondary to regeneration. The severe neonatal X-linked form (myotubular myopathy) is due to mutations in the phosphoinositide phosphatase myotubularin (
MTM1
)
1
, whereas mutations in dynamin 2 (
DNM2
) have been found in some autosomal dominant cases
2
. By direct sequencing of functional candidate genes, we identified homozygous mutations in amphiphysin 2 (
BIN1
) in three families with autosomal recessive inheritance. Two missense mutations affecting the BAR (Bin1/amphiphysin/RVS167) domain disrupt its membrane tubulation properties in transfected cells, and a partial truncation of the C-terminal SH3 domain abrogates the interaction with DNM2 and its recruitment to the membrane tubules. Our results suggest that mutations in
BIN1
cause centronuclear myopathy by interfering with remodeling of T tubules and/or endocytic membranes, and that the functional interaction between BIN1 and DNM2 is necessary for normal muscle function and positioning of nuclei.
Journal Article
Effectiveness of Structured Teacher Adaptations to an Evidence-Based Summer Literacy Program
The authors conducted a cluster-randomized trial to examine the effectiveness of structured teacher adaptations to the implementation of an evidence-based summer literacy program that provided students with (a) books matched to their reading level and interests and (b) teacher scaffolding for summer reading in the form of end-of-year comprehension lessons and materials sent to students' homes in the summer months. In this study, 27 high-poverty elementary schools (75-100% eligibility for free or reduced-price lunch) were matched by prior reading achievement and poverty level and randomly assigned to one of two implementation conditions: a core treatment condition that directly replicated implementation procedures used in previous experiments, or a core treatment with structured teacher adaptations condition. In the adaptations condition, teachers were organized into grade-level teams around a practical improvement goal and given structured opportunities to use their knowledge, experience, and local data to extend or modify program components for their students and local contexts. Students in the adaptations condition performed 0.12 standard deviation higher on a reading comprehension posttest than students in the core treatment. An implementation analysis suggests that fidelity to core program components was high in both conditions and that teachers in the adaptations condition primarily made changes that extended or modified program procedures and activities in acceptable ways. Adaptations primarily served to increase the level of family engagement and student engagement with summer books. These results suggest that structured teacher adaptations may enhance rather than diminish the effectiveness of an evidence-based summer literacy program.
Journal Article