A NOVEL PROTEIN KINASE, DNA-ACTIVATED, CATALYTIC SUBUNIT VARIANT IDENTIFIED IN T-B-NK+ SEVERE COMBINED IMMUNODEFICIENCY

Abstract

<h3>Introduction</h3> Whole exome sequencing (WES) has led to advances in identifying genetic variants responsible for rare diseases. Here we report a novel protein kinase, DNA-activated, catalytic subunit (PRKDC) variant in a patient with T-B-NK+ severe combined immunodeficiency (SCID). <h3>Case Description</h3> A preterm male with intrauterine growth restriction (IUGR), Tetralogy of Fallot, horseshoe kidney, and numerous brain malformations presented with lymphopenia [absolute lymphocyte count (ALC) of 560 × 10³ / mcL]. Lymphocyte subpopulations demonstrated a T-B-NK+ phenotype. The infant died on day of life three from respiratory failure. Patient's NBS returned four days after he died and revealed absent T-cell receptor excision circles (TREC). The patient had a deceased older brother with similar congenital anomalies who also had absent TREC on NBS with a T-B-NK+ SCID phenotype in the setting of several variants of uncertain significance (VUS) on whole exome sequencing (WES), including a homozygosity for a variant in the PRKDC gene, p.Arg1155Gln which both parents were heterozygous for. Three months after patient's death, a post-mortem WES returned with homozygosity in the same PRKDC gene VUS identified in his older brother. <h3>Discussion</h3> The p.Arg1155Gin PRKDC gene variant found is a missense substitution. Multiple identified PRKDC variants lead to DNA repair defects which may be seen clinically as radiation-sensitive T-B-NK+ SCID. While the PRKDC gene variant in our case was identified as one of uncertain significance, the similarities between our patient and his brother strongly suggest that this is likely the pathogenic variant for this family. This PRKDC variant has yet to be reported in the literature.