Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes.
BACKGROUND
Cyclic neutropenia (CN) and severe congenital neutropenia (SCN) are disorders of neutrophil production that differ markedly in disease severity. Mutations of the ELANE gene (the symbol recently replacing ELA2) are considered largely responsible for most cases of CN and SCN, but specific mutations are typically associated with one or the other.


METHODS
We performed ELANE genotyping on all individuals and paternal sperm in an SCN kindred with eight SCN progeny of a sperm donor and six different mothers.


RESULTS
One patient with CN had the same S97L ELANE mutation as seven patients with the SCN phenotype. The mutant allele was detected in the donor's spermatozoa, representing 18% of the ELANE gene pool, but not in DNA from his lymphocytes, neutrophils, or buccal mucosa, indicating gonadal mosaicism.


CONCLUSIONS
The coexistence of CN and SCN phenotypes in this kindred with a shared paternal haplotype strongly suggests both a role for modifying genes in determination of congenital neutropenia disease phenotypes, and the classification of CN and SCN within a spectrum of phenotypes expressing varying degrees of the same disease process.
Newburger
Peter E
PE
Department of Pediatrics, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA. peter.newburger@umassmed.edu
Pindyck
Talia N
TN
Zhu
Zhiqing
Z
Bolyard
Audrey Anna
AA
Aprikyan
Andrew A G
AA
Dale
David C
DC
Smith
Gary D
GD
Boxer
Laurence A
LA
D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005220:Fathers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007223:Infant; D040582:Inheritance Patterns / Q000235:genetics*; D019272:Leukocyte Elastase / Q000235:genetics*; D008297:Male; D009154:Mutation; D009503:Neutropenia / Q000151:congenital / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D013094:Spermatozoa / Q000201:enzymology
D019272:Leukocyte Elastase