Risk of abnormal pregnancy outcome in carriers of balanced reciprocal translocations involving the Miller-Dieker syndrome (MDS) critical region in chromosome 17p13.3

We studied the pedigrees of 14 families segregating a reciprocal translocat ion with one breakpoint in chromosome 17p13 and the other in the distal reg ion of another autosome. All 14 were ascertained on the basis of an affecte d index case: 13 had Miller-Dieker syndrome (MDS) and one had dup(17p). In these 14 families, 38 balanced translocation carriers had 127 pregnancies, corrected for ascertainment bias by the exclusion of all index cases and ca rriers in the line of descent to the index cases. An abnormal phentotype, u nbalanced chromosome constitution, or both, were found in 33 of 127 (26%) p regnancies: 15 of 127 (12%) had MDS and an unbalanced karyotype with del (1 7p); 9 of 127 (7%) had a less severe phenotype with dup(17p); and 9 were un studied, although MDS with der(17) was usually suspected based on early dea th and multiple congenital anomalies. When unexplained pregnancy losses, in cluding miscarriages and stillbirths; were excluded from the total, 33 of 9 9 (33%) pregnancies were phenotypically or genotypically abnormal. The over all risk of abnormal pregnancy outcome of 26% is in the upper range of the reported risk for unbalanced offspring of carrier parents assessed through liveborn aneuploid offspring [Gardner and Sutherland (1996), Oxford Univ, P ress], The risk increases to 33% when unexplained pregnancy losses are excl uded from the total. These results are consistent with Daniel's model of ri sk based on the size of the unbalanced fragments [Daniel (1985) Clin Genet 28:216-224, Daniel et al, (1989) Am J Med Genet 31:14-53], Pregnancy losses included 26 miscarriages (20%) and two stillbirths (2%) among the 127 preg nancies, similar to the respective population frequencies of 10-20% and 1%. (C) 1999 Wiley-Liss, Inc.