Mutation analysis in Bardet-Biedl syndrome by DNA pooling and massively parallel resequencing in 105 individuals

Bardet–Biedl syndrome (BBS) is a rare, primarily autosomal-recessive ciliopathy. The phenotype of this pleiotropic disease includes retinitis pigmentosa, postaxial polydactyly, truncal obesity, learning disabilities, hypogonadism and renal anomalies, among others. To date, mutations in 15 genes (BBS1–BBS14, SDCCAG8) have been described to cause BBS. The broad genetic locus heterogeneity renders mutation screening time-consuming and expensive. We applied a strategy of DNA pooling and subsequent massively parallel resequencing (MPR) to screen individuals affected with BBS from 105 families for mutations in 12 known BBS genes. DNA was pooled in 5 pools of 21 individuals each. All 132 coding exons of BBS1–BBS12 were amplified by conventional PCR. Subsequent MPR was performed on an Illumina Genome Analyzer II(™) platform. Following mutation identification, the mutation carrier was assigned by CEL I endonuclease heteroduplex screening and confirmed by Sanger sequencing. In 29 out of 105 individuals (28%), both mutated alleles were identified in 10 different BBS genes. A total of 35 different disease-causing mutations were confirmed, of which 18 mutations were novel. In 12 additional families, a total of 12 different single heterozygous changes of uncertain pathogenicity were found. Thus, DNA pooling combined with MPR offers a valuable strategy for mutation analysis of large patient cohorts, especially in genetically heterogeneous diseases such as BBS

Specifying the nature of the vocabulary gap through children’s word learning skills

Currently, a serious gap in vocabulary development and knowledge exists between children of higher socioeconomic status (SES) and their less advantaged peers. An important finding highlighted that children of higher SES know 600 more words on average than children form lower SES backgrounds. This disparity in vocabulary knowledge puts children from low SES backgrounds at a significant disadvantage when entering school because vocabulary is an essential tool for later school success. However, this ‘gap’ has only been described in terms of the number of words known by children. This is unlikely to wholly reflect their vocabulary knowledge and potential for learning. We looked to word learning strategies as way to further explore the nature of this ‘vocabulary gap’ as word-learning skills have been implicated as a significant factor in mediating the relationship between early experiences and vocabulary knowledge. The goal of this study was to examine the relationship between significant SES factors on children’s word learning skills. Such information could significantly contribute to creating better vocabulary intervention approaches for at-risk children and further inform our understanding of the ‘vocabulary gap’. Research goals were explored by having 145 2 ½ to 3 ½ year old subjects participate in 3 different word learning tasks. We selected particular tasks that were well documented in the literature, could be easily implemented within our target age range, had strong face validity, reflected a variety of types of information that children might use in word learning, and were relevant to the core challenges children face as they develop vocabulary. Results indicated that performance on one word-learning task, Mutual Exclusivity, was significantly associated with both of our indicators of SES, maternal education (r = .33, p < .001) and income (r = .30, p < .01). Children’s performance on the Gaze following task was only significantly associated with maternal education (r = .27, p < .01). These results indicate that the ‘vocabulary gap’ can be further specified by some, but not all, children’s word-learning skills. Future research should include studies of intervention based in word-learning skills like Mutual Exclusivity to help children further generalize vocabulary development.Communication Sciences and Disorder

Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines

© 2019 Steunstichting ESOT Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer

Protein Phosphatases and Alzheimer's Disease

Alzheimer’s Disease (AD) is characterized by progressive loss of cognitive function, linked to marked neuronal loss. Pathological hallmarks of the disease are the accumulation of the amyloid-β (Aβ) peptide in the form of amyloid plaques and the intracellular formation of neurofibrillary tangles (NFTs). Accumulating evidence supports a key role for protein phosphorylation in both the normal and pathological actions of Aβ as well as the formation of NFTs. NFTs contain hyperphosphorylated forms of the microtubule-binding protein tau, and phosphorylation of tau by several different kinases leads to its aggregation. The protein kinases involved in the generation and/or actions of tau or Aβ are viable drug targets to prevent or alleviate AD pathology. However, it has also been recognized that the protein phosphatases that reverse the actions of these protein kinases are equally important. Here, we review recent advances in our understanding of serine/threonine and tyrosine protein phosphatases in the pathology of AD