Frugoni et al. (2016) studied a 5-year-old boy born to related parents of Saudi origin, who was referred with a history of omphalitis and erythroderma in the neonatal period, systemic Bacillus Calmette-Guerin infection after immunization, and multiple respiratory infections subsequently.  He had dysmorphic features (low anterior hairline, flat supraorbital ridges, downturned corners of the mouth, and a short philtrum).  Agammaglobulinemia, absence of circulating B cells, T-cell lymphopenia, and neutropenia were discovered by laboratory investigations.  At 3-years, he developed generalized lymphadenopathy and a lymph node biopsy showed effaced architecture with lack of follicles, an increased number of CD1631-activated macrophages, and activated (CD45R01) T lymphocytes.  Laboratory evaluation confirmed lymphopenia with absence of B lymphocytes, markedly increased proportion of effector memory T-cells, and undetectable T-cell receptor excision circles (TRECs).  The clinical course of the patient was complicated by a severe episode of hemophagocytic lymphohistiocytosis that led to death at the age of 7-years.  By performing whole exome sequencing, a homozygous splice-site mutation (G>T) at position -1 of intron 13 of the POLE2 gene was identified.  This novel splice-site mutation was confirmed by Sanger sequencing.  Both parents were heterozygous for the mutation, and none of the four healthy siblings were homozygous for the mutation.   RT-PCR showed a normal-sized transcript with a deletion of three nucleotides resulting from the usage of a cryptic acceptor splice site at position 13 in exon 14 and a shorter transcript due to skipping of exon 14.  The product with the 3-nt deletion was predicted to result in loss of a single highly conserved amino acid residue, Ser359.  Similar expression in patient and control samples was discovered by Immunoblot analysis for POLE2 protein.  The study pointed towards an important role for the POLE holoenzyme in cell proliferation, and particularly in the lymphoid lineage.