Strong evidence for autosomal dominant inheritance of severe congenital neutropenia associated with ELA2 Mutations
Received 30 August 2005; received in revised form 15 November 2005; accepted 8 December 2005.
Objective
To investigate cases of severe congenital neutropenia (SCN) to ascertain SCN inheritance after determining that the same sperm donor was used by 4 different families to impregnate mothers.
Study design
Because the donor sperm was not available, alternative methods were used to determine whether the sperm donor transmitted SCN. DNA isolated from leukocytes was used to sequence the ELA2 gene in the affected children and their mothers. ELA2 was amplified by polymerase chain reaction (PCR), and the product was sequenced. PCR was also performed with genomic DNA from the mothers and affected children using a set of 22 microsatellite PCR primers on chromosomes 14 and 19 to establish linkage to the paternal allele.
Results
None of the mothers had a mutation in ELA2, but all 5 affected children had the same mutation affecting the fourth exon at site S97L. Linkage mapping analysis confirmed that all affected children had the same paternal allele on chromosome 19, which contains ELA2.
Conclusions
Our findings indicate that the father provided consistent haplotypes leading to the expression of SCN in all affected children, supporting an autosomal dominant inheritance in which ELA2 mutations occur.
aDivison of Pediatric Hematology/Oncology, Department of Pediatrics, C.S. Mott Children’s Hospital, University of Michigan, Ann Arbor, Michigan
bDivision of Hematology, Department of Medicine and Department of Genetics, University of Washington, Seattle, Washington
Reprint requests: Laurence A. Boxer, MD, L2112 Women’s Hospital, Box 0238, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0238
Supported by a National Institutes of Health (NIH) grant (R24AI049393) to David Dale for the Severe Chronic Neutropenia International Registry, a gift from the Amgen Foundation to the Severe Chronic Neutropenia International Registry, and an NIH grant (5PSOHG007351) for the University of Washington Center for Excellence to Maynard Olson.
ABSTRACT