Human Autosomal Recessive DNA Polymerase Delta 3 Deficiency Presenting as Omenn Syndrome.

The DNA polymerase δ complex (PolD), comprising catalytic subunit POLD1 and accessory subunits POLD2, POLD3, and POLD4, is essential for DNA synthesis and is central to genome integrity. We identified, by whole exome sequencing, a homozygous missense mutation (c.1118A > C; p.K373T) in POLD3 in a patient with Omenn syndrome. The patient exhibited severely decreased numbers of naïve T cells associated with a restricted T-cell receptor repertoire and a defect in the early stages of TCR recombination. The patient received hematopoietic stem cell transplantation at age 6 months. He manifested progressive neurological regression and ultimately died at age 4 years. We performed molecular and functional analysis of the mutant POLD3 and assessed cell cycle progression as well as replication-associated DNA damage. Patient fibroblasts showed a marked defect in S-phase entry and an enhanced number of double-stranded DNA break-associated foci despite normal expression levels of PolD components. The cell cycle defect was rescued by transduction with WT POLD3. This study validates autosomal recessive POLD3 deficiency as a novel cause of profound T-cell deficiency and Omenn syndrome.

Human bocavirus infection in Belgian children with respiratory tract disease.

Human bocavirus (HBoV) has been detected primarily in children with acute lower respiratory tract disease (LRTD), but its occurrence, clinical profile, and role as a causative agent of RTD are not clear. The aim of this study was to investigate the prevalence and the potential clinical relevance of HBoV. Using molecular tests, we tested 1352 nasopharyngeal samples obtained between October 1, 2017 and April 30, 2018 from children up to the age of 16 with RTD for the presence of HBoV DNA and 20 other respiratory pathogens at three different hospitals in Belgium. HBoV was detected in 77 children with a median age of 10.6 months. Consecutive samples were available for 15 HBoV-positive children and showed persistent HBoV positivity in four of them. Monoinfection was observed in six infants. Four of them were born prematurely and were infected during hospitalization at the neonatal intensive care unit (NICU). Only one of these six monoinfected children was diagnosed with recurrent wheezing due to HBoV. This child was carried to term and had a high viral load. Coinfections, most frequently with rhinovirus (52.1%) and adenovirus (49.3%), were observed in 72 patients. In seventeen of them in which HBoV was present at high viral load or higher viral load than its copathogens, bronchi(oli)tis (n = 8), recurrent wheezing (n = 8) or episodic wheezing (n = 1) were diagnosed. Our results suggest that HBoV infection at high viral load in infants is associated with wheezing (P = 0.013, Cramer's V = 0.613).