Unique Evidence for Autosomal Dominant Inheritance of Severe Congenital Neutropenia.

Severe congenital neutropenia was originally described as an autosomal recessive disorder characterized by severe neutropenia and recurrent bacterial infections from birth, but other reports indicate that autosomal dominant inheritance occurs. Several report now indicate that most, but not all, patients with severe congential neutropenia have heterozygous mutation in the gene for neutrophil elastase (NE or ELA2). We recently investigated an unusual series of cases of severe congenital neutropenia occurring when the same sperm donor was utilitized by four different families to impregnate mothers by either artificial insemination or in vitro fertilization. Three sets of twins were conceived and a single child in the four families. Collectively one set of twins and one child each from the other two families conceiving twins and the single child were all found to have severe congenital neutropenia. The mean for their median blood neutrophils (ANC) at diagnosis was 84 +/−32 x10⁹/L (range 0–166 x 10⁹ /L); and their other blood counts were remarkably similar. On treatment with G-CSF (mean dose 6.7+/− 1.3 SEM mcg/kg/day) the mean for the median ANC increased to 3290 +/−1410 x10⁹/L( range 420–8600 x 10⁹ /L )

To determine whether the sperm donor was responsible for transmitting severe congenital neutropenia, geonomic DNA from peripheral blood leukocytes was used to sequence the gene for neutrophil elastase in the affected children and their mothers using standard techniques. None of the mothers had a mutation in their NE gene but all five affected children had the same mutation effecting the fourth exon at site S97L. Since it was not possible to perform genetic analysis on biological samples from the donor, more detailed genetic linkage analysis was performed on the affected children and their mothers. Linkage mapping analysis of 22 microsatellite markers on chromosome 14 and 19 confirmed that all affected children possessed one of the two paternal alleles. For an 11 centiMorgan region immediately adjacent to the NE gene on chromosome 19, all affected children shared a single paternal allele, and 4 of 5 affected children shared a single paternal allele for a 20 centiMorgan region adjacent to the NE gene. The studies indicate that the father of the affected children provided consistent haplotypes that led to the expression of severe congenital neutropenia in all of the affected children. This investigation strongly implicates that autosomal dominant inheritance for severe congenital neutropenia. It also raises important questions for the evaluation of subjects in sperm donor programs.