Publications by authors named "Kimberly Ezell"
Background: The number of known inherited metabolic diseases (IMDs) has been expanding, and the rate of diagnosis is improving with the development of innovative approaches including next generation sequencing (NGS). However, a substantial proportion of IMDs remain undetected by traditional diagnostic approaches. We aim to highlight the spectrum of IMDs diagnosed by the Undiagnosed Diseases Network (UDN) and to learn from the UDN diagnostic processes that were able to detect IMDs.
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- Autosomal dominant congenital disorder of glycosylation (CDG) type Iw is caused by a mutation in a specific gene and differs from most CDGs, which are typically autosomal recessive.
- A 17-year-old male presented with a range of symptoms including macrocephaly, epilepsy, and developmental delays, but initial genetic tests and biochemical analyses did not indicate a clear diagnosis.
- Genome sequencing revealed a novel mutation that disrupts a glycosylation site, and the patient was ultimately diagnosed with CDG type Iw based on abnormal transferrin profiling, illustrating the variability in genetic disorders and the need for comprehensive testing.
Article Synopsis
- * The study identifies RNU4-2, a non-coding RNA gene, as a significant contributor to syndromic NDD, revealing a specific 18-base pair region with low variation that includes variants found in 115 individuals with NDD.
- * RNU4-2 is highly expressed in the developing brain, and its variants disrupt splicing processes, indicating that non-coding genes play a crucial role in rare disorders, potentially aiding in the diagnosis of thousands with NDD worldwide.
Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes. Increasingly, large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA as a novel syndromic NDD gene.
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- The Undiagnosed Disease Network (UDN) is a collaborative effort funded by the NIH, focused on diagnosing rare diseases through 12 clinical sites, including Vanderbilt University Medical Center (VUMC).
- At VUMC, experts in fields like bioinformatics, structural biology, and genetics worked together to identify a rare genetic variant in a 5-year-old girl with various neurological issues.
- The team diagnosed her with Primary Aldosteronism, Seizures, and Neurologic abnormalities (PASNA), showcasing the value of a multidisciplinary approach in addressing complex, rare diseases.
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- The study analyzed electronic health records (EHR) to examine X-linked (XL) disorders in both males and females at Vanderbilt University over a 20-year period, involving 477 males and 203 females diagnosed with 108 different XL disorders.
- It revealed significant variations in the female-to-male (F/M) ratios for XL disorders, with some XL recessive disorders observed in women that were previously documented only in men.
- The findings suggested that traditional Mendelian predictions about gender ratios in XL disorders may not accurately reflect real-world data, indicating a need for further research to confirm these insights in larger EHR cohorts.
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- Recent research identified a new mutation linked to a rare axonal Charcot-Marie-Tooth disease in both Caucasian and black African families, expanding the understanding of its genetic basis.
- The study involved eight patients and their relatives, with a diagnosis average age of 33.9 years; common symptoms included walking difficulties, muscle weakness, and deformities in hands and feet.
- Whole exome sequencing uncovered a novel variant in the gene responsible, revealing notable decreases in protein levels and structural changes, emphasizing the importance of including diverse populations in genetic research.
Article Synopsis
- - The study explores the role of mosaicism in genetic diseases and how it relates to disease-causing variants that arise spontaneously (de novo variants) in families, involving data from nearly 15,000 individuals.
- - Researchers found that about 4.51% of individuals with confirmed genetic diseases showed mosaic genetic disease (MGD), and approximately 2.86% of parents had parental mosaicism, especially in cases involving de novo variants.
- - The findings highlight the complexity and variability of MGD, suggesting it contributes significantly to genetic disorders, although further investigation is needed to better understand its implications for diagnoses and familial risks.