[CIS PIDD] [cis-pidd] 13yo boy with exome variants

[CIS-PIDD]

Colleagues:

We recently started to follow a 13yo boy with the following:

·         Chronic, severe, restrictive lung disease (bronchiectasis with only dilated alveolar spaces and peribronchiolar inflammation on biopsy)

·         Marked growth failure, possibly related to growth hormone insensitivity

·         Eczematoid rash on face and neck, non-pruritic; biopsy showed "mild chronic spongiotic dermatitis."  Dermatologists concerned for Bloom syndrome.

·         Combined immune deficiency

IgG 494;  IgA 52;  IgM 18  Low antibodies to measles, tetanus and Hib; poor response to pneumovax (+2/23); positive antibody to VZV

CD3+ 45% (285);  CD4+ 20% (127);  CD8+ 23% (144);  NK 21% (135);  poor responses to mitogens

CD19+ 33% (207);  Naïve 97%;  Switched <1%;  Switched memory <1%

·         Chromosomal Microarray:  no clinically relevant genomic deletions or duplications were identified

·         Exome sequencing: both de novo/not observed in either parent, and neither reported previously.

-       Variant of uncertain significance in DOCK8 (pR1380H, c4139 G>A).  This results in a conservative amino acid substitution in a non-conserved position, and is predicted unlikely to alter protein structure/function.

-       Variant of uncertain significance in NFE2L2 (nuclear factor, erythroid 2-like 2)(pG31R, c91G>A).  This results in a non-conservative amino acid substitution in a position that is conserved across species.  It is likely to impact secondary protein structure as the residues differ in polarity, charge and size.  It is predicted to be damaging.  This gene encodes a transcription factor that regulates antioxidant responses.

Has anyone seen variants in NFE2L2 associated with immune deficiency etc?

Is anyone interested in in vitro study of this variant?

Joe Church
Children's Hospital Los Angeles





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