Newborns main panel

Gene: PRDX1

The mechanism of pathogenicity is gain-of-function (GOF).

Created: 1 Jun 2023, 2:39 p.m. | Last Modified: 1 Jun 2023, 2:39 p.m.

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https://pubmed.ncbi.nlm.nih.gov/34215320/

Created: 1 Jun 2023, 12:22 p.m. | Last Modified: 1 Jun 2023, 12:22 p.m.

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Digenic inheritance. The phenotype is due to biallelic variants in MMACHC. A number of cases have been reported with one MMACHC sequence variant in trans with an epimutation. The epimutation is due to a heterozygous sequence variant in the adjacent gene PRDX1. In all instances, the PRDX1 mutations affected a canonical splice acceptor site of intron 5 and caused skipping of exon 6 and the polyA termination signal of PRDX1. Mechanism summarised on OMIM or PMID: 29302025 PMID:35190856

Created: 1 Jun 2023, 12:20 p.m. | Last Modified: 1 Jun 2023, 12:20 p.m.

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This gene initially was categorised as "digenic"; however, we are not including digenic inheritance in the study, at least initially.
David Bick comment: Hi Mafalda
Glad you pointed this out! This paper is helpful - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9020039/
Appears that the variant results in a new transcript resulting in a GOF that causes aberrant methylation of the CpG island (CpG:33) in the MMACHC promoter that silences the expression of the MMACHC gene in cis. So a homozygote for this variant causes CblC disease. Also this variant on one chromosome with a standard pathogenic variant in MMACHC also causes disease. We can easily program the pipeline for the PDX1 homozygous variant. The digenic mechanism we can forego at the start of the study. What do you think?
Regards,
David
PS….changed MOP to GOF and MOI to AR… sound ok?

Created: 10 May 2023, 8:50 a.m. | Last Modified: 10 May 2023, 8:50 a.m.

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