Abstract 1843 Poster Session IV, Tuesday, 5/4 (poster 352)

Fatal neonatal respiratory disease may result from an inability to produce SP-B that is inherited in an autosomal recessive fashion. The most common mechanism for SP-B deficiency is a frameshift mutation (121ins2) in the SP-B gene, which is located on chromosome 2. The mechanism for lung disease in a full-term male infant with refractory respiratory failure was investigated using immunologic and genetic methods. The child was not dysmorphic and did not have problems other than his lung disease. Immunohistochemical analysis of lung tissue revealed absent staining for SP-B and strong extracellular staining for pro-surfactant protein C, findings characteristic of SP-B deficiency. Analysis of genomic DNA by PCR and restriction analysis was consistent with the child having been homozygous for the 121ins2 mutation. However, analysis of parental DNA confirmed that while the mother was a carrier for the 121ins2 mutation, the father did not have the 121ins2 mutation on either allele. Analysis of informative microsatellite markers on chromosomes 18, 19, 21 and 22 was consistent with paternity. To investigate other possible mechanisms that could account for these findings, 36 highly polymorphic microsatellite markers spanning chromosome 2 were analyzed from the child and both parents. The child was homozygous for a maternally derived allele from markers D2S285 to D2S113, an approximately 25 centimorgan region that spans the SP-B gene, and no paternal contribution was observed for informative markers within this region. Reduction to homozygosity for a maternal allele was also observed for the regions from D2S319 to D2S305, involving the end of the short arm, and D2S396 to D2S172 on the long arm. In other regions of chromosome 2, the child inherited both of the maternal alleles, but not a paternal allele. We conclude that the cause of the child's lung disease was that he inherited two copies of the maternal chromosome 2, with a region of maternal isodisomy encompassing the SP-B gene and the 121ins2 mutation, likely resulting from nondisjunction in meiosis 2. The absence of other associated findings in this child suggests that these regions of chromosome 2 do not contain imprinted genes, although the rapidly fatal course of this disease may have masked other problems. Analysis of DNA from parents of affected infants is important to properly counsel them regarding recurrence risk.