Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance

Genet Med. 2011 Feb;13(2):125-30. doi: 10.1097/GIM.0b013e318202e0f6.


Purpose: Recurrence of lethal osteogenesis imperfecta in families results from either dominant (parental mosaicism) or recessive inheritance. The proportion of these two mechanisms is not known, and determination of the contribution of each is important to structure genetic counseling for these families.

Methods: We measured the recurrence rate of lethal osteogenesis imperfecta after the birth of an affected infant. We determined the rate of parental mosaicism in a subset of families in which we had identified dominant mutations. In 37 families in which two or more affected infants were born, we identified mutations and determined the proportion that resulted from recessive inheritance.

Results: The recurrence rate after the first affected pregnancy was 1.3%. The rate of parental mosaicism in families in which a dominant mutation was identified in a first affected child was 16%. In 37 families with two affected infants, 26 had dominant mutations, seven had recessive mutations, and we failed to find mutations in four. The overall recurrence rate for couples after two or more affected infants was 32%; 27% for families with parental mosaicism, 31% for recessive mutations, and 50% for families with no identified mutation.

Conclusions: In most populations, recurrence of lethal osteogenesis imperfecta usually results from parental mosaicism for dominant mutations, but the carrier frequency of recessive forms of osteogenesis imperfecta will alter that proportion. Mutation identification is an important tool to assess risk and facilitate prenatal or preimplantation diagnosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Collagen / genetics
  • Collagen Type I
  • Cyclophilins / genetics
  • Extracellular Matrix Proteins / genetics
  • Female
  • Genes, Dominant*
  • Genes, Recessive*
  • Genetic Counseling
  • Germ-Line Mutation
  • Humans
  • Infant
  • Membrane Glycoproteins / genetics
  • Molecular Chaperones
  • Mosaicism*
  • Osteogenesis Imperfecta / diagnosis*
  • Osteogenesis Imperfecta / genetics*
  • Pedigree
  • Pregnancy
  • Prenatal Diagnosis*
  • Prolyl Hydroxylases
  • Proteoglycans / genetics
  • Recurrence
  • Risk Assessment


  • CRTAP protein, human
  • Collagen Type I
  • Extracellular Matrix Proteins
  • Membrane Glycoproteins
  • Molecular Chaperones
  • Proteoglycans
  • cyclophilin B
  • Collagen
  • Prolyl Hydroxylases
  • P3H1 protein, human
  • Cyclophilins