Samantha Maguire | Brown University (original) (raw)

Papers by Samantha Maguire

PLOS Genetics, Jan 20, 2022

To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most ... more To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most common neurodevelopmental disorder, a high throughput Massively Parallel Splicing Assay (MaPSY) was employed and identified 42 exonic splicing mutants out of 725 coding de novo variants discovered in the sequencing of ASD families. A redesign of the minigene constructs in MaPSY revealed that upstream exons with strong 5' splice sites increase the magnitude of skipping phenotypes observed in downstream exons. Select hits were validated by RT-PCR and amplicon sequencing in patient cell lines. Exonic splicing mutants were enriched in probands relative to unaffected siblings-especially synonymous variants (7.5% vs 3.5%, respectively). Of the 26 genes disrupted by exonic splicing mutations, 6 were in known ASD genes and 3 were in paralogs of known ASD genes. Of particular interest was a synonymous variant in TNRC6C-an ASD gene paralog with interactions with other ASD genes. Clinical records of 3 ASD patients with TNRC6C variant revealed respiratory issues consistent with phenotypes observed in TNRC6 depleted mice. Overall, this study highlights the need for splicing analysis in determining variant pathogenicity, especially as it relates to ASD.

Medical Devices: Evidence and Research

Over 400,000 Americans are intubated in emergency settings annually, with indications ranging fro... more Over 400,000 Americans are intubated in emergency settings annually, with indications ranging from respiratory failure to airway obstructions to anaphylaxis. About 12.7% of emergency intubations are unsuccessful on the first attempt. Failure to intubate on the first attempt is associated with a higher likelihood of adverse events, including oxygen desaturation, aspiration, trauma to soft tissue, dysrhythmia, hypotension, and cardiac arrest. Difficult airways, as classified on an established clinical scale, are found in up to 30% of emergency department (ED) patients and are a significant contributor to failure to intubate. Difficult intubations have been associated with longer lengths of stay and significantly greater costs than standard intubations. There exists a wide range of airway management devices, both invasive and noninvasive, which are available in the emergency setting to accommodate difficult airways. Yet, first-pass success rates remain variable and leave room for improvement. In this article, we review the disease states most correlated with intubation, the current landscape of emergency airway management technologies, and the market potential for innovation. The aim of this review is to inspire new technologies to assist difficult airway management, given the substantial opportunity for translation due to two key-value signposts of medical innovation: the potential to decrease cost and the potential to improve clinical outcomes.

Zenodo (CERN European Organization for Nuclear Research), Sep 19, 2022

Humans co-existed and interbred with other hominins which later became extinct. These archaic hom... more Humans co-existed and interbred with other hominins which later became extinct. These archaic hominins are known to us only through fossil records and for two cases, genome sequences. Here we engineer Neanderthal and Denisovan sequences into thousands of artificial genes to reconstruct the pre-mRNA processing patterns of these extinct populations. Of the 5,224 alleles tested in this massively parallel splicing reporter assay (MaPSy), we report 969 exonic splicing mutations (ESMs) that correspond to differences in exon recognition between extant and extinct hominins. Using MaPSy splicing variants, predicted splicing variants, and splicing quantitative trait loci, we show that splice-disrupting variants experienced greater purifying selection in anatomically modern humans than in Neanderthals. Adaptively introgressed variants were enriched for moderate effect splicing variants, consistent with positive selection for alternative spliced alleles following introgression. As particularly ...

A. SSM versus all exonic mutations in the HGMD with regions of 99.9% ... more A. SSM versus all exonic mutations in the HGMD with regions of 99.9% confidence interval shown in gray. COSMIC cancer genes are highlighted in Red. MLH1, BRCA1, BRCA2, and NF1 are highlighted and labeled. B-C. Average percent of SSM or ESM in cancer genes versus non-cancer genes reported in HGMD. D. Average HI score of cancer genes in Upper, Expected, and Lower categories of genes.</p

A. SSM versus all exonic mutations in the HGMD with regions of 99.9% ... more A. SSM versus all exonic mutations in the HGMD with regions of 99.9% confidence interval shown in gray. Genes with more, expected, and less SSM are shown in red (Upper), blue (Expected), and green (Lower), respectively. Location of MLH1, MSH2, and PMS2 are highlighted and labeled. B. Percent ESM of total mutations tested using MaPSy in each category. C. Due to the inability of MaPSy to observe mutant-specific exon skipping events (as a result of the identical flanking exons), ESMs found in MLH1, BRCA1, and OPA1 were validated as individual wildtype and mutant minigene constructs. All three mutant constructs showed exon skipping events, which were not shown in wildtype constructs.</p

CERN European Organization for Nuclear Research - Zenodo, Sep 19, 2022

A. The order of variable importance by mean decease in accuracy for S... more A. The order of variable importance by mean decease in accuracy for SSM-prone genes versus genes with an expected number of SSM. The directions that associate with SSM-prone genes are indicated, positive directions are green, and negative directions are red. B. Classification performance of the random forest models and the logistic regression models was calculated as the area under the curve (AUC) in receiver operating characteristic (ROC) analysis. C. Scheme of random forest classification on all genomic genes. D. Average proportion of low frequency ExAC splice-site variants per splice-site in predicted SSM-prone genes (probability: 0.60–0.86) versus genes not predicted to be SSM-prone (P = 6.1043e-18, Mann-Whitney). E. Common variants are depleted from the category of variants that cause loss of splice-site signal at the 5′ splice-site (upper plot). Rare variants are enriched in the range of the splice site signal scores that abolish 5′ splice-site recognition (lower plot).</p

A. Disease coding mutations in exons 4, 5, 7, 8 and 15 of ML... more A. Disease coding mutations in exons 4, 5, 7, 8 and 15 of MLH1 were analyzed with MaPSy. While none of the mutations in exons 4, 5 and 7 (blue bars) were found to disrupt splicing, almost all of the mutations tested in exons 8 and 15 (red bars) significantly altered splicing (100% and 71%, respectively). B. Splicing efficiency of wildtype (blue) and mutant (red) alleles that were tested with MaPSy in exons 8 and 15 of MLH1.</p

The percentages of mutant mRNA retained in each stage of the assembly relative to wildty... more The percentages of mutant mRNA retained in each stage of the assembly relative to wildtype mRNA are shown for all ESM that were identified in MLH1 exon 8 and 15. The majority of ESM were blocked in the transition from A and B complex. Two of the ESM (CM082944 and CM04546) in exon 8 also slowed down the final transesterification reactions to yield spliced mRNA and the lariat.</p

CERN European Organization for Nuclear Research - Zenodo, Oct 7, 2022

PLoS genetics, Mar 1, 2018

Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 1... more Substitutions that disrupt pre-mRNA splicing are a common cause of genetic disease. On average, 13.4% of all hereditary disease alleles are classified as splicing mutations mapping to the canonical 5' and 3' splice sites. However, splicing mutations present in exons and deeper intronic positions are vastly underreported. A recent re-analysis of coding mutations in exon 10 of the Lynch Syndrome gene, MLH1, revealed an extremely high rate (77%) of mutations that lead to defective splicing. This finding is confirmed by extending the sampling to five other exons in the MLH1 gene. Further analysis suggests a more general phenomenon of defective splicing driving Lynch Syndrome. Of the 36 mutations tested, 11 disrupted splicing. Furthermore, analyzing past reports suggest that MLH1 mutations in canonical splice sites also occupy a much higher fraction (36%) of total mutations than expected. When performing a comprehensive analysis of splicing mutations in human disease genes, we fo...

PLOS Genetics

To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most ... more To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most common neurodevelopmental disorder, a high throughput Massively Parallel Splicing Assay (MaPSY) was employed and identified 42 exonic splicing mutants out of 725 coding de novo variants discovered in the sequencing of ASD families. A redesign of the minigene constructs in MaPSY revealed that upstream exons with strong 5’ splice sites increase the magnitude of skipping phenotypes observed in downstream exons. Select hits were validated by RT-PCR and amplicon sequencing in patient cell lines. Exonic splicing mutants were enriched in probands relative to unaffected siblings -especially synonymous variants (7.5% vs 3.5%, respectively). Of the 26 genes disrupted by exonic splicing mutations, 6 were in known ASD genes and 3 were in paralogs of known ASD genes. Of particular interest was a synonymous variant in TNRC6C - an ASD gene paralog with interactions with other ASD genes. Clinical record...

PLOS Genetics, Jan 20, 2022

Medical Devices: Evidence and Research

Zenodo (CERN European Organization for Nuclear Research), Sep 19, 2022

A. SSM versus all exonic mutations in the HGMD with regions of 99.9% ... more A. SSM versus all exonic mutations in the HGMD with regions of 99.9% confidence interval shown in gray. COSMIC cancer genes are highlighted in Red. MLH1, BRCA1, BRCA2, and NF1 are highlighted and labeled. B-C. Average percent of SSM or ESM in cancer genes versus non-cancer genes reported in HGMD. D. Average HI score of cancer genes in Upper, Expected, and Lower categories of genes.</p

A. SSM versus all exonic mutations in the HGMD with regions of 99.9% ... more A. SSM versus all exonic mutations in the HGMD with regions of 99.9% confidence interval shown in gray. Genes with more, expected, and less SSM are shown in red (Upper), blue (Expected), and green (Lower), respectively. Location of MLH1, MSH2, and PMS2 are highlighted and labeled. B. Percent ESM of total mutations tested using MaPSy in each category. C. Due to the inability of MaPSy to observe mutant-specific exon skipping events (as a result of the identical flanking exons), ESMs found in MLH1, BRCA1, and OPA1 were validated as individual wildtype and mutant minigene constructs. All three mutant constructs showed exon skipping events, which were not shown in wildtype constructs.</p

CERN European Organization for Nuclear Research - Zenodo, Sep 19, 2022

CERN European Organization for Nuclear Research - Zenodo, Oct 7, 2022

PLoS genetics, Mar 1, 2018

PLOS Genetics

To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most ... more To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most common neurodevelopmental disorder, a high throughput Massively Parallel Splicing Assay (MaPSY) was employed and identified 42 exonic splicing mutants out of 725 coding de novo variants discovered in the sequencing of ASD families. A redesign of the minigene constructs in MaPSY revealed that upstream exons with strong 5’ splice sites increase the magnitude of skipping phenotypes observed in downstream exons. Select hits were validated by RT-PCR and amplicon sequencing in patient cell lines. Exonic splicing mutants were enriched in probands relative to unaffected siblings -especially synonymous variants (7.5% vs 3.5%, respectively). Of the 26 genes disrupted by exonic splicing mutations, 6 were in known ASD genes and 3 were in paralogs of known ASD genes. Of particular interest was a synonymous variant in TNRC6C - an ASD gene paralog with interactions with other ASD genes. Clinical record...