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.
View Article and Find Full Text PDFFRY-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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFWe 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.
View Article and Find Full Text PDFBi-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.
View Article and Find Full Text PDFLysine-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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