Publications by authors named "Anna Hurst"

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for 'actionable' genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.

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Objective: To investigate the current genetic counseling practices involving a cfDNA result indicating mosaic monosomy X of likely maternal origin, and to better understand the perspectives of patients who have received this result.

Method: A total of 60 prenatal genetic counselors completed surveys about their experiences with this result, cfDNA consenting practices, and management practices. In addition, qualitative interviews were conducted with 5 patients to gain insight into their experiences with result disclosure and follow-up care.

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Loeys-Dietz syndrome (LDS) is a connective tissue disorder representing a wide spectrum of phenotypes, ranging from isolated thoracic aortic aneurysm or dissection to a more severe syndromic presentation with multisystemic involvement. Significant clinical variability has been noted for both related and unrelated individuals with the same pathogenic variant. We report a family of five affected individuals with notable phenotypic variability who appear to have two distinct molecular causes of LDS, one attributable to a missense variant in and the other an intronic variant 6 bp upstream from a splice junction in .

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Aplastic anemia, characterized by pancytopenia and hypoplastic bone marrow, is associated with various acquired cytogenetic abnormalities, including trisomy 8, in 4%-15% of patients. Constitutional mosaic trisomy 8 notably increases the risks for cytopenia and myeloid malignancies. Duplications near chromosome 8 centromere are associated with developmental delays, autism, and trisomy 8p11.

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Article Synopsis
  • Long-read genome sequencing (lrGS) offers more accurate and comprehensive variant detection for rare diseases compared to short-read genome sequencing (srGS), though its exact impact on diagnostic yield remains unclear.
  • In a study involving 96 individuals suspected of having genetic rare diseases, lrGS identified new or potentially relevant genetic variants in 16.7% of participants, with 9.4% possessing pathogenic or likely pathogenic variants.
  • While lrGS provided additional insights beyond what was captured by srGS, particularly with structural variations, the study suggests that growing lrGS datasets will further enhance diagnostic capabilities in the future.
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  • Long-read genome sequencing (lrGS) outperforms short-read genome sequencing (srGS) in detecting genetic variants associated with rare diseases.
  • In a study of 96 probands who tested negative with srGS, lrGS identified new disease-relevant variants in 16.7% of cases, with 8.33% containing pathogenic or likely pathogenic variants.
  • lrGS revealed unique variants not detectable by srGS, highlighting that while reanalyzing previous data can improve diagnostic yield, lrGS provides significant additional insights into rare genetic conditions.
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  • CREB-binding protein (CBP) and E1A-associated protein (p300) are crucial for histone acetylation and gene regulation; mutations in these proteins lead to conditions like Rubinstein-Taybi syndrome (RSTS) and Menke-Hennekam syndrome (MKHK).
  • A study on 82 individuals with CBP/p300 variants revealed distinct phenotypes and identified three subtypes of MKHK based on specific protein domains (ZZ, TAZ2, and ID4), rather than the genes themselves.
  • DNA methylation profiles showed characteristic patterns associated with the different protein domains, allowing for better classification and understanding of the molecular mechanisms behind these syndromes.
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Neurons form the basic anatomical and functional structure of the nervous system, and defects in neuronal differentiation or formation of neurites are associated with various psychiatric and neurodevelopmental disorders. Dynamic changes in the cytoskeleton are essential for this process, which is, inter alia, controlled by the dedicator of cytokinesis 4 (DOCK4) through the activation of RAC1. Here, we clinically describe 7 individuals (6 males and one female) with variants in DOCK4 and overlapping phenotype of mild to severe global developmental delay.

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  • The DIP2 gene, first found in fruit flies, is crucial for neuron branching and regeneration, with vertebrate versions (DIP2A, DIP2B, and DIP2C) being highly conserved in the central nervous system.
  • Research showed that mutations in DIP2C are linked to developmental delays in expressive language and speech articulation in 23 affected individuals.
  • Alongside developmental issues, some individuals with DIP2C variants also presented with various cardiac defects and minor facial anomalies, highlighting a connection between the gene's loss-of-function and neurocognitive and physical phenotypes.
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Background: Screening for germline pathogenic or variants (gBRCA) in high-risk breast cancer patients is known to be cost-effective in high-income countries. Nationwide adoption of genetics testing in high-risk breast cancer population remains poor. Our study aimed to assess gBRCA health economics data in the middle-income country setting of Thailand.

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Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail.

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Article Synopsis
  • - The study explores pre-mRNA splicing, its critical role in neurodevelopment, and how mutations in spliceosome-related genes U2AF2 and PRPF19 contribute to neurodevelopmental disorders (NDDs).
  • - Researchers found multiple pathogenic variants in U2AF2 and PRPF19 across unrelated individuals, with functional analysis showing that specific U2AF2 variants disrupted normal splicing and neuritogenesis in human neurons.
  • - Additionally, investigations in Drosophila models revealed that the loss of function in U2AF2 and PRPF19 caused severe developmental defects and social issues, pointing to a genetic network wherein splicing factors like Rbfox1 play a significant role in brain development and function. *
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Purpose: Multiple studies suggest an association between DLG2 and neurodevelopmental disorders and indicate the haploinsufficiency of this gene; however, few cases have been thoroughly described. We performed additional studies to confirm this clinical association and DLG2 haploinsufficiency.

Methods: Chromosomal microarray analysis was performed on 11,107 patients at the Cytogenetics Laboratory at the University of Alabama at Birmingham.

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  • This study investigates patient and parent experiences after participating in an Undiagnosed Diseases Program (UDP) at UAB, using in-depth interviews to gain insights.
  • Participants appreciated the opportunity to be seen by the UDP, but their perspectives on the experience varied depending on whether they received a diagnosis.
  • The findings highlight positive aspects of the program while revealing unmet needs in communication and follow-up, suggesting areas for improvement that could benefit similar clinics.
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  • - Parents of newborns in the NICU found genome sequencing (GS) valuable for decision-making about future care and resolving diagnostic uncertainties.
  • - Most parents accepted the timing of receiving GS results, though they noted the NICU environment could be overwhelming during the process.
  • - Parents indicated that GS did not negatively affect their bonding with their infants and had mixed feelings about guilt related to the results.
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  • Genetic variants in the EZH1 chromatin modifier are linked to both dominant and recessive neurodevelopmental disorders in 19 individuals, highlighting its role in disease etiology.
  • EZH1 impacts histone modification and is essential for the differentiation of neural progenitor cells, with recessive variants causing loss of function and dominant variants resulting in gain of function due to mutations.
  • The findings underscore EZH1's crucial role in neurogenesis and offer a molecular basis for diagnosing certain neurodevelopmental disorders that were previously unclassified.
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  • De novo variants contribute significantly to neurodevelopmental disorders (NDDs), but due to their rarity, understanding the full range of symptoms and genetic variations linked to specific genes like KDM6B poses a challenge.
  • The study of 85 individuals with KDM6B variants reveals that cognitive deficits are common, while features like coarse facies and skeletal issues are rare, indicating that existing descriptions may be misleading.
  • Through innovative testing methods and studies on Drosophila, the researchers highlight the critical role of KDM6B in cognitive function and the importance of international collaboration for accurate diagnosis of rare disorders.
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  • Neurodevelopmental disorders (NDDs) are often linked to rare genetic variations, yet standard genomic testing misses many clinically relevant variants, prompting the need for alternative analyses like examining "poison exons" (PEs).
  • The study involved curating RNA sequencing data to identify 1937 conserved PE regions relevant to NDDs and analyzing genetic variants across 2999 patients.
  • The researchers discovered six novel relevant variants, mostly in genes associated with epilepsy, demonstrating that including PE analysis can enhance diagnostic yields for NDDs with minimal additional effort.
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GM3 synthase deficiency (GM3SD) is caused by biallelic variants in . The ganglioside GM3, enriched in neuronal tissues, is a component of lipid rafts and regulates numerous signaling pathways. Affected individuals with GM3SD exhibit global developmental delay, progressive microcephaly, and dyskinetic movements.

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Article Synopsis
  • Neurodevelopmental disorders (NDDs) can be linked to rare genetic variations, but standard genomic testing often misses key variants, particularly those in "poison exons" (PEs), which lead to premature termination of protein production.
  • Researchers analyzed RNA sequencing data and identified 1,937 conserved PE regions to assess the impact of specific genetic variants in NDD cohorts.
  • From nearly 3,000 individuals studied, six previously overlooked variants were found in PE regions that could explain certain NDDs, suggesting that including PE analysis could enhance diagnostic accuracy without significantly increasing the testing burden.
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Introduction: There are two major categories of peroxisomal disorders (PDs): peroxisomal biogenesis disorders (PBDs) due to defects in peroxisomal (PEX) genes and deficiency of other peroxisomal enzymes (such as D-bifunctional enzyme deficiency due to HSD17B4). PDs are characterized by abnormal elevations of very-long-chain fatty acids (VLCFA). We aimed to evaluate the clinical phenotype of adrenal insufficiency in patients with PD and to assess any genotype-phenotype correlations with adrenal insufficiency.

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Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants.

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