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Heterozygous variants in POLR1A cause diverse human phenotypes

ABSTRACT: Heterozygous variants in POLR1A cause diverse human phenotypes

PROVIDER: PRJNA849583 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19663588_1.fastq.gz	Fastqsanger.gz
	SRR19663588_2.fastq.gz	Fastqsanger.gz
	SRR19663589_1.fastq.gz	Fastqsanger.gz
	SRR19663589_2.fastq.gz	Fastqsanger.gz
	SRR19663590_1.fastq.gz	Fastqsanger.gz

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Heterozygous variants in POLR1A cause diverse human phenotypes

Project description:Heterozygous pathogenic variants in POLR1A were identified as the cause of Acrofacial Dysostosis, Cincinnati-type in 2015. Craniofacial anomalies reminiscent of Treacher Collins syndrome were the predominant phenotype observed in the first 3 affected individuals. We have subsequently identified 17 additional individuals with 12 unique (11 novel) heterozygous variants in POLR1A and observed numerous additional phenotypes including developmental delay, infantile spasms, and structural cardiac defects. To understand the pathogenesis of this pleiotropy, we created an allelic series of POLR1A using a combination of in vivo (mouse) and in vitro models. We describe distinct spatiotemporal requirements for Polr1a during mouse embryogenesis and identify a requirement for Polr1a for survival of pre migratory and migratory neural crest cells, forebrain precursors, and the second heart field. We used CRISPR/Cas9 to recapitulate two human alleles in mouse, demonstrating pathogenicity of one and likely benign nature of the other. Our work greatly expands the phenotype of human POLR1A-related disorders, provides new evidence of reduced penetrance and variable expression of POLR1A heterozygous variants, and demonstrates a multi-faceted approach to characterize and define pathogenicity of variants.

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De novo heterozygous variants in POLR2A cause a neurodevelopmental syndrome with infantile-onset hypotonia

Project description: ABSTRACT POLR2A encodes RPB1, the largest subunit of the RNA polymerase II (pol II) complex, which is responsible for transcription of all ~21,000 protein-encoding genes. Here we describe the first fifteen patients harboring de novo heterozygous variants in POLR2A. The majority presents with profound infantile onset hypotonia and developmental delay. Missense variants that were expected to exert only mild structural effects, lead to malfunctioning RPB1, thereby inducing a dominant negative effect on pol II function. Intriguingly, these patients presented with a severe clinical phenotype. Conversely, variants expected to result in loss-of-function, leading to reduced availability of RPB1 were better tolerated: these patients exhibited the mildest phenotypes.

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