Reticular dysgenesis caused by an intronic pathogenic variant in AK2 Journal Article
| Authors: | Ichikawa, S.; Prockop, S.; Cunningham-Rundles, C.; Sifers, T.; Conner, B. R.; Wu, S.; Karam, R.; Walsh, M. F.; Fiala, E. |
| Article Title: | Reticular dysgenesis caused by an intronic pathogenic variant in AK2 |
| Abstract: | Reticular dysgenesis is a form of severe combined immunodeficiency (SCID) caused by biallelic pathogenic variants in AK2 Here we present the case of a boy diagnosed with SCID following a positive newborn screen (NBS). Genetic testing revealed a homozygous variant: AK2 c.330 + 5G > A. In silico analyses predicted weakened native donor splice site. However, this variant was initially classified as a variant of uncertain significance (VUS) given lack of direct evidence. To determine the impact on splicing, we analyzed RNA from the proband and his parents, using massively parallel RNA-seq of cloned RT-PCR products. Analysis showed that c.330 + 5G > A results in exon 3 skipping, which encodes a critical region of the AK2 protein. With these results, the variant was upgraded to pathogenic, and the patient was given a diagnosis of reticular dysgenesis. Interpretation of VUS at noncanonical splice site nucleotides presents a challenge. RNA sequencing provides an ideal platform to perform qualitative and quantitative assessment of intronic VUS, which can lead to reclassification if a significant impact on mRNA is observed. Genetic disorders of hematopoiesis and immunity represent fruitful areas to apply RNA-based analysis for variant interpretation given the high expression of RNA in blood. © 2020 Ichikawa et al.; Published by Cold Spring Harbor Laboratory Press. |
| Keywords: | severe combined immunodeficiency |
| Journal Title: | Cold Spring Harbor Molecular Case Studies |
| Volume: | 6 |
| Issue: | 3 |
| ISSN: | 2373-2873 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2020-06-01 |
| Start Page: | a005017 |
| Language: | English |
| DOI: | 10.1101/mcs.a005017 |
| PUBMED: | 32532877 |
| PROVIDER: | scopus |
| PMCID: | PMC7304357 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2020 -- Source: Scopus |
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