More Like this

1. Influence of age at seizure onset on the acquisition of neurodevelopmental skills in an SCN8A cohort

   https://doi.org/10.1111/epi.16288  

   Encinas, Alejandra C.; Moore, Ida; Watkins, Joseph C.; Hammer, Michael F. (July 2019, Epilepsia)

   Abstract ObjectiveTo characterize a cohort of patients withSCN8A‐related epilepsy and to perform analyses to identify correlations involving the acquisition of neurodevelopmental skills. MethodsWe analyzed patient data (n = 91) submitted to an online registry tailored to characteristics of children withSCN8Avariants. Participants provided information on the history of their child's seizures, medications, comorbidities, and developmental skills based on the DenverIIitems. Spearman rank tests were utilized to test for correlations among a variety of aspects of seizures, medications, and neurodevelopmental progression. ResultsThe 91 participants carried 71 missense variants (41 newly reported) and three truncating variants. Ages at seizure onset ranged from birth to >12 months of age (mean ± SD = 5 months 21 days ± 7 months 14 days). Multiple seizure types with multimodal onset times and developmental delay were observed as general features of this cohort. We found a positive correlation between a developmental score based upon percentage of acquired skills and the age at seizure onset, current seizure freedom, and initial febrile seizures. Analyses of cohort subgroups revealed clear distinctions between patients who had a single reported variant inSCN8Aand those with an additional variant reported in a gene other thanSCN8A, as well as between patients with different patterns of regression before and at seizure onset. SignificanceThis is the first study of anSCN8A patient cohort of this size and for which correlations between age at seizure onset and neurodevelopment were investigated. Our correlation studies suggest that variants of uncertain significance should be considered in assessing children withSCN8A‐related disorders. This study substantially improves the characterization of this patient population and our understanding of the neurodevelopmental effects associated with seizures forSCN8A patients, and provides a clinical context at initial presentation that may be prognostic for developmental outcome. 

   more » « less
2. From buds to shoots: insights into grapevine development from the Witch’s Broom bud sport

   https://doi.org/10.1186/s12870-024-04992-y  

   Ritter, Eleanore J.; Cousins, Peter; Quigley, Michelle; Kile, Aidan; Kenchanmane Raju, Sunil K.; Chitwood, Daniel H.; Niederhuth, Chad (April 2024, BMC Plant Biology)

   Abstract BackgroundBud sports occur spontaneously in plants when new growth exhibits a distinct phenotype from the rest of the parent plant. The Witch’s Broom bud sport occurs occasionally in various grapevine (Vitis vinifera) varieties and displays a suite of developmental defects, including dwarf features and reduced fertility. While it is highly detrimental for grapevine growers, it also serves as a useful tool for studying grapevine development. We used the Witch’s Broom bud sport in grapevine to understand the developmental trajectories of the bud sports, as well as the potential genetic basis. We analyzed the phenotypes of two independent cases of the Witch’s Broom bud sport, in the Dakapo and Merlot varieties of grapevine, alongside wild type counterparts. To do so, we quantified various shoot traits, performed 3D X-ray Computed Tomography on dormant buds, and landmarked leaves from the samples. We also performed Illumina and Oxford Nanopore sequencing on the samples and called genetic variants using these sequencing datasets. ResultsThe Dakapo and Merlot cases of Witch’s Broom displayed severe developmental defects, with no fruit/clusters formed and dwarf vegetative features. However, the Dakapo and Merlot cases of Witch’s Broom studied were also phenotypically different from one another, with distinct differences in bud and leaf development. We identified 968–974 unique genetic mutations in our two Witch’s Broom cases that are potential causal variants of the bud sports. Examining gene function and validating these genetic candidates through PCR and Sanger-sequencing revealed one strong candidate mutation in Merlot Witch’s Broom impacting the gene GSVIVG01008260001. ConclusionsThe Witch’s Broom bud sports in both varieties studied had dwarf phenotypes, but the two instances studied were also vastly different from one another and likely have distinct genetic bases. Future work on Witch’s Broom bud sports in grapevine could provide more insight into development and the genetic pathways involved in grapevine. 

   more » « less
3. Innovative Family-Based Genetically Informed Series of Analyses of Whole-Exome Data Supports Likely Inheritance for Grammar in Children with Specific Language Impairment

   https://doi.org/10.3390/children10071119  

   Andres, Erin M.; Earnest, Kathleen Kelsey; Xuan, Hao; Zhong, Cuncong; Rice, Mabel L.; Raza, Muhammad Hashim (July 2023, Children)

   Individuals with specific language impairment (SLI) struggle with language acquisition despite average non-verbal intelligence and otherwise typical development. One SLI account focuses on grammar acquisition delay. The current study aimed to detect novel rare genetic variants associated with performance on a grammar assessment, the Test of Early Grammatical Impairment (TEGI), in English-speaking children. The TEGI was selected due to its sensitivity and specificity, consistently high heritability estimates, and its absence from all but one molecular genetic study. We performed whole exome sequencing (WES) in eight families with SLI (n = 74 total) and follow-up Sanger sequencing in additional unrelated probands (n = 146). We prioritized rare exonic variants shared by individuals with low TEGI performance (n = 34) from at least two families under two filtering workflows: (1) novel and (2) previously reported candidate genes. Candidate variants were observed on six new genes (PDHA2, PCDHB3, FURIN, NOL6, IQGAP3, and BAHCC1), and two genes previously reported for overall language ability (GLI3 and FLNB). We specifically suggest PCDHB3, a protocadherin gene, and NOL6 are critical for ribosome synthesis, as they are important targets of SLI investigation. The proposed SLI candidate genes associated with TEGI performance emphasize the utility of precise phenotyping and family-based genetic study. 

   more » « less
4. Assessing variants of uncertain significance implicated in hearing loss using a comprehensive deafness proteome

   https://doi.org/10.1007/s00439-023-02559-9  

   Tollefson, Mallory R.; Gogal, Rose A.; Weaver, A. Monique; Schaefer, Amanda M.; Marini, Robert J.; Azaiez, Hela; Kolbe, Diana L.; Wang, Donghong; Weaver, Amy E.; Casavant, Thomas L.; et al (April 2023, Human Genetics)

   Abstract Hearing loss is the leading sensory deficit, affecting ~ 5% of the population. It exhibits remarkable heterogeneity across 223 genes with 6328 pathogenic missense variants, making deafness-specific expertise a prerequisite for ascribing phenotypic consequences to genetic variants. Deafness-implicated variants are curated in the Deafness Variation Database (DVD) after classification by a genetic hearing loss expert panel and thorough informatics pipeline. However, seventy percent of the 128,167 missense variants in the DVD are “variants of uncertain significance” (VUS) due to insufficient evidence for classification. Here, we use the deep learning protein prediction algorithm, AlphaFold2, to curate structures for all DVD genes. We refine these structures with global optimization and the AMOEBA force field and use DDGun3D to predict folding free energy differences (∆∆G_Fold) for all DVD missense variants. We find that 5772 VUSs have a large, destabilizing ∆∆G_Foldthat is consistent with pathogenic variants. When also filtered for CADD scores (> 25.7), we determine 3456 VUSs are likely pathogenic at a probability of 99.0%. Of the 224 genes in the DVD, 166 genes (74%) exhibit one or more missense variants predicted to cause a pathogenic change in protein folding stability. The VUSs prioritized here affect 119 patients (~ 3% of cases) sequenced by the OtoSCOPE targeted panel. Approximately half of these patients previously received an inconclusive report, and reclassification of these VUSs as pathogenic provides a new genetic diagnosis for six patients. 

   more » « less
5. The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel

   https://doi.org/10.3390/diagnostics13182993  

   Alsolme, Ebtehal; Alqahtani, Saleh; Fageeh, Musa; Barakeh, Duna; Sharma, Nitesh K.; Mangul, Serghei; Robinson, Heather A.; Fathaddin, Amany; Hauser, Charlotte A.; Abedalthagafi, Malak (September 2023, Diagnostics)

   Next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients. Patients and Methods: We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS in 107 Saudi Arabian patients without a family history of CRC. Results: Approximately 98% of patients had genetic alterations. Frequent mutations were observed in BRCA2 (79%), CHEK1 (78%), ATM (76%), PMS2 (76%), ATR (74%), and MYCL (73%). The APC gene was not included in the panel. Statistical analysis using the Cox proportional hazards model revealed an unusual positive association between poorly differentiated tumors and survival rates (p = 0.025). Although no significant univariate associations between specific mutations or overall mutation rate and overall survival were found, our preliminary analysis of the molecular markers for CRC in a predominantly Arab population can provide insights into the molecular pathways that play a significant role in the underlying disease progression. Conclusions: These results may help optimize personalized therapy when drugs specific to a patient’s mutation profile have already been developed. 

   more » « less