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


METHODS
Whole 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.


RESULTS
Whole 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.


CONCLUSIONS
While 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.
Translational Sciences, Biogen Idec, Cambridge, MA, USA.
Aaron G
AG
Day-Williams
Translational Sciences, Biogen Idec, Cambridge, MA, USA.
Chao
C
Sun
Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
Ilijas
I
Jelcic
Translational Sciences, Biogen Idec, Cambridge, MA, USA.
Helen
H
McLaughlin
Translational Sciences, Biogen Idec, Cambridge, MA, USA.
Tim
T
Harris
Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
Roland
R
Martin
Translational Sciences, Biogen Idec, Cambridge, MA, USA. john.carulli@biogenidec.com.
John P
JP
Carulli
D000328:Adult; D002872:Chromosome Deletion; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics / Q000276:immunology; D004252:DNA Mutational Analysis; D017353:Gene Deletion; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007589:Job Syndrome / Q000235:genetics* / Q000276:immunology*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000235:genetics* / Q000276:immunology*; D008297:Male; D016615:Telomere / Q000235:genetics
C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors
DOCK8 deficiency; Hyper IgE Syndrome; JC virus; Progressive Multifocal Leukoencephalopathy (PML); primary immune deficiency