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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.

SUBMITTER: Ichikawa S 

PROVIDER: S-EPMC7304357 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Reticular dysgenesis caused by an intronic pathogenic variant in <i>AK2</i>.

Ichikawa Shoji S   Prockop Susan S   Cunningham-Rundles Charlotte C   Sifers Travis T   Conner Blair R BR   Wu Sitao S   Karam Rachid R   Walsh Michael F MF   Fiala Elise E  

Cold Spring Harbor molecular case studies 20200612 3


Reticular dysgenesis is a form of severe combined immunodeficiency (SCID) caused by biallelic pathogenic variants in <i>AK2</i> Here we present the case of a boy diagnosed with SCID following a positive newborn screen (NBS). Genetic testing revealed a homozygous variant: <i>AK2</i> 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 t  ...[more]

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