Publications by authors named "Lauren O Grady"

Mucopolysaccharidosis type I (MPS I), a lysosomal disorder caused by variants in IDUA, was added to the Recommended Uniform Screening Panel for newborn screening in 2016. Positive screening results for MPS I are commonly due to variants known as "pseudodeficiency alleles," which decrease in vitro alpha-L-iduronidase enzyme activity but are thought to provide sufficient in vivo activity. Despite the historic assumption that these variants are biologically benign, the possibility that they could give rise to complex, multigenic, or attenuated phenotypes has not been systemically evaluated in adults.

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FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems.

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Article Synopsis
  • The study investigates protein-truncating variants (PTVs) that may bypass nonsense-mediated decay (NMD) in 29,031 neurodevelopmental disorder (NDD) parent-offspring trios, identifying significant de novo mutations (DNMs).
  • Researchers found 1,376 PTVs in 133 genes significantly associated with Mendelian diseases, including known disease genes like SEMA6B and PPM1D, and uncovered 22 additional genes with potential disease links.
  • The analysis highlights phenotypic similarities among individuals with PTVs in the same genes, suggesting novel disease associations in genes not previously linked to Mendelian conditions.
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Article Synopsis
  • MEGD(H)EL syndrome is a rare genetic disorder caused by mutations in the SERAC1 gene, leading to a variety of symptoms such as aciduria, hearing loss, and neurological issues.
  • A specific case of a child with this syndrome shows signs of liver disease, developmental delays, and two novel SERAC1 mutations, showing varying degrees of severity.
  • Despite initial serious symptoms, the child's development has improved significantly by age 4, now displaying only mild delays, and a liver biopsy revealed mitochondrial abnormalities, which are important for understanding the disorder.
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The pre-mRNA-processing factor 8, encoded by PRPF8, is a scaffolding component of a spliceosome complex involved in the removal of introns from mRNA precursors. Previously, heterozygous pathogenic variants in PRPF8 have been associated with autosomal dominant retinitis pigmentosa. More recently, PRPF8 was suggested as a candidate gene for autism spectrum disorder due to the enrichment of sequence variants in this gene in individuals with neurodevelopmental disorders.

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We report an in-depth genetic analysis in an 11-year-old boy with drug-resistant, generalized seizures and developmental disability. Three distinct variants of unknown clinical significance (VUS) were detected by whole exome sequencing (WES) but not by initial genetic analyses (microarray and epilepsy gene panel). These variants involve the , and genes, which were subsequently evaluated by computational analyses using the InterVar tool and MutationTaster.

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Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants.

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Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders.

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