Whole Genome Sequencing Reveals a Chromosome 9p Deletion Causing DOCK8 Deficiency in an Adult Diagnosed with Hyper IgE Syndrome Who Developed Progressive Multifocal Leukoencephalopathy

Abstract

PurposeA 30 year-old man with a history of recurrent skin infections as well as elevated serum IgE and eosinophils developed neurological symptoms and had T2-hyperintense lesions observed in cerebral MRI. The immune symptoms were attributed to Hyper IgE syndrome (HIES) and the neurological symptoms with presence of JC virus in cerebrospinal fluid were diagnosed as Progressive Multifocal Leukoencephalopathy (PML). The patient was negative for STAT3 mutations. To determine if other mutations explain HIES and/or PML in this subject, his DNA was analyzed by whole genome sequencing.MethodsWhole genome sequencing was completed to 30X coverage, and whole genome SNP typing was used to complement these data. The methods revealed single nucleotide variants, structural variants, and copy number variants across the genome. Genome-wide data were analyzed for homozygous or compound heterozygous null mutations for all protein coding genes. Mutations were confirmed by PCR and/or Sanger sequencing.ResultsWhole genome analysis revealed deletions near the telomere of both copies of chromosome 9p. Several genes, including DOCK8, were impacted by the deletions but it was unclear whether each chromosome had identical or distinct deletions. PCR across the impacted region combined with Sanger sequencing of selected fragments confirmed a homozygous deletion from position 10,211 to 586,751.ConclusionWhile several genes are impacted by the deletion, DOCK8 deficiency is the most probable cause of HIES in this patient. DOCK8 deficiency may have also predisposed the patient to develop PML.Electronic supplementary materialThe online version of this article (doi:10.1007/s10875-014-0114-4) contains supplementary material, which is available to authorized users.

Broadly neutralizing human monoclonal JC polyomavirus VP1–specific antibodies as candidate therapeutics for progressive multifocal leukoencephalopathy

“…The occurrence of PML in diseases such as systemic lupus erythematosus (SLE) during immunomodulatory treatments, which affect B cells (5, 6), and in immunodeficiencies that primarily involve antibodies [such as Franklin disease (39)] or B cells/antibodies and T cells [such as Good’s syndrome (40) and hyper IgE syndrome (41)] indicates that not only T cells but also B cells are possibly involved in the development of PML. NAT not only compromises CNS immune surveillance by reducing the migration of T cells, CD19 + B cells, and CD138 + plasma cells through the blood-brain barrier (42) but also perturbs peripheral B cell niches by increasing the number of memory- and marginal zone–like B cells (43).…”

DOCK8 deficiency: Insights into pathophysiology, clinical features and management

“…Viral infections may also be systemic or involve deeper tissues. There have been several reports of polymultifocal leukoencephalopathy (PML) secondary to JC virus [5,6,24,37]. Other noncutaneous viral infections include meningitis, encephalitis, keratitis, retinitis, blepharoconjunctivitis, periodontitis, pneumonia, hepatitis and enteritis with many implicated viruses, such as cytomegalovirus, Epstein Barr Virus, rotavirus, Herpes simplex virus, as well as hepatitis A, B and C viruses [6,13,29,40].…”

Germline Genetic Risk Variants for Progressive Multifocal Leukoencephalopathy

“…Immune dysregulation disorders, previously classified as primary immunodeficiency diseases (PID or PIDD) but now termed inborn errors of immunity, are highly heterogeneous with 344 genes now recognized by the International Union of Immunological Societies (IUIS) (29,30). To date, mutations in 11 IUIS genes (BTK, CD40LG, DOCK8, MAGT1, NFKB1, PRKDC, RAG1, RMRP, STAT1, STK4, and WAS) have been reported in PML patients, most frequently for DOCK8 (3 cases) (28,31) and STAT1 (4 cases) (26,32). In addition to IUIS-designated genes, mutations in BAG3 were reported as a potential cause of PML in an immunocompetent patient based, in part, on the gene's links to JCV (e.g., virus replication is reduced when BAG3 is over-expressed) (33).…”