Further insights into the allan-herndon-dudley syndrome: Clinical and functional characterization of a novel MCT8 mutation

Background. Mutations in the thyroid hormone (TH) transporter MCT8 have been identified as the cause for Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and altered TH serum levels. Here we report a novel MCT8 mutation identified in 4 generations of one family, and its functional characterization. Methods. Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter. Results. The proband and a male cousin demonstrated clinical findings characteristic of AHDS. Serum analysis showed high T3, low rT3, and normal T4 and TSH levels in the proband. A MCT8 mutation (c.869C>T; p.S290F) was identified in the proband, his cousin, and several female carriers. Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect. Interestingly, both uptake and efflux of T3 and T4 was impaired in fibroblasts of the proband, compared to his healthy brother. However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells. Immunocytochemistry showed plasma membrane localization of wild-type MCT8 and the S290A and S290F mutants in JEG3 cells. Conclusions. We describe a novel MCT8 mutation (S290F) in 4 generations of a family with Allan-Herndon-Dudley Syndrome. Functional analysis demonstrates loss-of-function of the MCT8 transporter. Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context. Comparison of the S290F and S290A mutants indicates that it is not the loss of Ser but its substitution with Phe, which leads to S290F dysfunction

MetaCAM: Ensemble-Based Class Activation Map

The need for clear, trustworthy explanations of deep learning model predictions is essential for high-criticality fields, such as medicine and biometric identification. Class Activation Maps (CAMs) are an increasingly popular category of visual explanation methods for Convolutional Neural Networks (CNNs). However, the performance of individual CAMs depends largely on experimental parameters such as the selected image, target class, and model. Here, we propose MetaCAM, an ensemble-based method for combining multiple existing CAM methods based on the consensus of the top-k% most highly activated pixels across component CAMs. We perform experiments to quantifiably determine the optimal combination of 11 CAMs for a given MetaCAM experiment. A new method denoted Cumulative Residual Effect (CRE) is proposed to summarize large-scale ensemble-based experiments. We also present adaptive thresholding and demonstrate how it can be applied to individual CAMs to improve their performance, measured using pixel perturbation method Remove and Debias (ROAD). Lastly, we show that MetaCAM outperforms existing CAMs and refines the most salient regions of images used for model predictions. In a specific example, MetaCAM improved ROAD performance to 0.393 compared to 11 individual CAMs with ranges from -0.101-0.172, demonstrating the importance of combining CAMs through an ensembling method and adaptive thresholding.Comment: 9 page

The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position statement of the Canadian College of medical geneticists

Purpose and scope: The aim of this Position Statement is to provide recommendations for Canadian medical geneticists, clinical laboratory geneticists, genetic counsellors and other physicians regarding the use of genome-wide sequencing of germline DNA in the context of clinical genetic diagnosis. This statement has been developed to facilitate the clinical translation and development of best practices for clinical genome-wide sequencing for genetic diagnosis of monogenic diseases in Canada; it does not address the clinical application of this technology in other fields such as molecular investigation of cancer or for population screening of healthy individuals. Methods of statement development: Two multidisciplinary groups consisting of medical geneticists, clinical laboratory geneticists, genetic counsellors, ethicists, lawyers and genetic researchers were assembled to review existing literature and guidelines on genome-wide sequencing for clinical genetic diagnosis in the context of monogenic diseases, and to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. Results and conclusions: Recommendations include (1) clinical genome-wide sequencing is an appropriate approach in the diagnostic assessment of a patient for whom there is suspicion of a significant monogenic disease that is associated with a high degree of genetic heterogeneity, or where specific genetic tests have failed to provide a diagnosis; (2) until the benefits of reporting incidental findings are established, we do not endorse the intentional clinical analysis of disease-associated genes other than those linked to the primary indication; and (3) clinicians should provide genetic counselling and obtain informed consent prior to undertaking clinical genome-wide sequencing. Counselling should include discussion of the limitations of testing, likelihood and implications of diagnosis and incidental findings, and the potential need for further analysis to facilitate clinical interpretation, including studies performed in a research setting. These recommendations will be routinely reevaluated as knowledge of diagnostic and clinical utility of clinical genome-wide sequencing improves. While the document was developed to direct practice in Canada, the applicability of the statement is broader and will be of interest to clinicians and health jurisdictions internationally

Molecular Characterization of NRXN1 Deletions from 19,263 Clinical Microarray Cases Identifies Exons Important for Neurodevelopmental Disease Expression

PURPOSE: The purpose of the current study was to assess the penetrance of NRXN1 deletions. METHODS: We compared the prevalence and genomic extent of NRXN1 deletions identified among 19,263 clinically referred cases to that of 15,264 controls. The burden of additional clinically relevant copy-number variations (CNVs) was used as a proxy to estimate the relative penetrance of NRXN1 deletions. RESULTS: We identified 41 (0.21%) previously unreported exonic NRXN1 deletions ascertained for developmental delay/intellectual disability that were significantly greater than in controls (odds ratio (OR) = 8.14; 95% confidence interval (CI): 2.91-22.72; P \u3c 0.0001). Ten (22.7%) of these had a second clinically relevant CNV. Subjects with a deletion near the 3\u27 end of NRXN1 were significantly more likely to have a second rare CNV than subjects with a 5\u27 NRXN1 deletion (OR = 7.47; 95% CI: 2.36-23.61; P = 0.0006). The prevalence of intronic NRXN1 deletions was not statistically different between cases and controls (P = 0.618). The majority (63.2%) of intronic NRXN1 deletion cases had a second rare CNV at a prevalence twice as high as that for exonic NRXN1 deletion cases (P = 0.0035). CONCLUSIONS: The results support the importance of exons near the 5\u27 end of NRXN1 in the expression of neurodevelopmental disorders. Intronic NRXN1 deletions do not appear to substantially increase the risk for clinical phenotypes.Genet Med 19 1, 53-61

The Lantern, 2021-2022

No More Buses through El Paso • A Woman\u27s World • The Angel of Tragedy • A Victim of Circumstance • Ace of Hearts • Ghost Light • Missing Diamonds • The Upside-Down House: A Dialogue with the Self • What is Chronic Pain? • A Sunny Day in Sinkhole • Extra Marshmallows • Fourth Wall Broken • Hemlock • In the Comfort of Others • Lasting Impressions • Let\u27s Do the Time Warp Again • One Last Afternoon • Space Invaders • The Dogwood Tree • An Ode to Poppies • Charlotte\u27s Web • Crab • Crossing • Dandelions • Dandelion Sandwich • Grizzly Hood • Help Wanted • I Gave Way • I\u27m not who you wanted but maybe one day I can be • Kneeling • Lemon Cookies • Lies • Method Acting • Moment of Tranquility • Our Home • Overthinking • Sea Glass • Seasonal • Thirty-Two (No Spares) • The Autumn Beast • The Miller\u27s Daughter • Theodore • To the Earring I Left Behind in Your Carpet • Virginia • Waltzing • Yellow House • 1/25 British Monarch • Cracked • In the Shadows • Jewelwing • Life on the Wing • O\u27 Captain my Captain • Stars Above the Bay • The Common Fall • Tom • Cats + Crowshttps://digitalcommons.ursinus.edu/lantern/1190/thumbnail.jp

Fitzsimmons Syndrome: Spastic Paraplegia, Brachydactyly, and Cognitive Impairment

Fitzsimmons syndrome is an infrequently described entity comprising slowly progressive spastic paraplegia, brachydactyly, and cone-shaped epiphyses, dysarthria, and low-normal intelligence. Five patients with this syndrome have been reported. The cause remains unknown. Here we describe a 16-year-old boy with Fitzsimmons syndrome. He was noted to toe-walk at age 18 months and spasticity progressed slowly into a spastic gait with contractures. He has mild dysarthria. and hypernasal speech. Brachydactyly is notable but cannot be classified into one of the recognized types. A cone-shaped epiphysis was apparent on the only available childhood radiograph. He has moderate cognitive handicap and pervasive developmental delay. A detailed comparison of this patient with the earlier described cases is presented to further delineate the condition and increase awareness of this syndrome. (C) 2009 Wiley-Liss, In

Pedigree of the family with AHDS.

<p>The black squares reflect affected males. Circles with a dot represent unaffected heterozygous female carriers. Diamond indicates a pregnancy. Slashed symbols indicate deceased individuals.</p

Brain MRI of the index patient.

<p>T2-weighted axial images at 23 months, 3 years and 2 months showing delayed myelination, and at 10 years and 10 months myelination has normalized.</p

Thyroid hormone serum levels in proband and family.

<p>The dashed lines reflect the boundaries of the normal range for adults of the respective test. P = patient, C = carrier and N = unaffected family members.</p

Metabolism of [¹²⁵I]T3 and [¹²⁵I]T4 by D3 and T3 uptake saturation in MCT8 expressing cells.

<p>Metabolism of [¹²⁵I]T3 (A) and [¹²⁵I]T4 (B) after 4 hours in COS1 and JEG3 cells co-transfected with pCIneo-hD3 and empty vector, WT or mutant MCT8. Metabolism is shown as % of radioactivity in the incubation medium. <b>C</b> Inhibition of [¹²⁵I]T3 uptake by WT and mutated MCT8 by increasing concentrations of unlabelled T3. Results are presented as mean ± SEM (n = 3). Significance is indicated for D3 co-transfected with WT or mutant MCT8 <i>vs</i>. D3 alone. *P <0.05; **P <0.01; ***P <0.001.</p