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

Abstract

We studied the pedigrees of 14 families segregating a reciprocal translocation with one breakpoint in chromosome 17p13 and the other in the distal region of another autosome. All 14 were ascertained on the basis of an affected 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 carriers in the line of descent to the index cases. An abnormal phentotype, unbalanced chromosome constitution, or both, were found in 33 of 127 (26%) pregnancies: 15 of 127 (12%) had MDS and an unbalanced karyotype with del (17p); 9 of 127 (7%) had a less severe phenotype with dup(17p); and 9 were unstudied, although MDS with der(17) was usually suspected based on early death and multiple congenital anomalies. When unexplained pregnancy losses, including miscarriages and stillbirths, were excluded from the total, 33 of 99 (33%) pregnancies were phenotypically or genotypically abnormal. The overall 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. Press]. The risk increases to 33% when unexplained pregnancy losses are excluded from the total. These results are consistent with Daniel's model of risk 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 pregnancies, similar to the respective population frequencies of 10-20% and 1%.

Somatic and Germline Mosaic Mutations in the doublecortin Gene Are Associated with Variable Phenotypes

“…Genetic counselors may also need to take these results into consideration when determining the recurrence risk for lissencephaly in males, since mutations in either DCX or the chromosome 17 gene LIS1 (MIM 247200) lead to nearly indistinguishable phenotypes, although the inheritance and recurrence risk are very distinct. LIS1 mutations appear to be exclusively germline, and the only documented recurrences have been in the setting of a balanced translocation in one parent that became unbalanced on transmission to the affected children (Goutieres et al 1987;Alvarado et al 1993;Pollin et al 1999). Therefore, if a LIS1 mutation is identified in the absence of a translocation, there is very little risk of recurrence.…”

Inherited Cryptic Translocation t(12;17)(q24.3;p13.3) Causing Recurrence of Miller-Dieker Syndrome

“…However, the identification of a familial chromosomal rearrangement associated to MDS modified the genetic counseling: from a very low risk of recurrence on the cases associated to de novo cytogenetic abnormality to a higher risk once associated to a familial translocation. The risk of recurrence, considering meiotic segregation of balanced translocation involving the 17p13.3 region is relatively high (12%) which alone would justify prenatal diagnosis ( Figure 3) [15]. In this case, cytogenetic analysis by GTG banding showed normal karyotype and only the FISH technique was able to detect balanced paternal translocation.…”

“…Large deletions can also be associated with other changes, such as balanced translocations. Eighty percent of patients have a "de novo" microdeletion in 17p13.3 and 20% inherited deletion from one of the progenitors carrying a balanced chromosomal rearrangement, so the risk of recurrence in cases of "de novo" mutation is negligible, but if one of the parents has a balanced translocation, this risk increase considerably [5,12].…”

“…The risk of recurrence of viable and unbalanced offspring in at least the second trimester of pregnancy was about 26% in these families and MDS appears to be the greatest risk. However, in cases of cryptic translocations in a parent the recurrent risk for future pregnancies modifies considerable [5].…”

Miller‐Dieker Syndrome with unbalanced translocation 45, X, psu dic(17;Y)(p13;p11.32) detected by fluorescence in situ hybridization and G‐banding analysis using high resolution banding technique

“…Carriers of balanced reciprocal translocation involves the critical region of MDS. Missing genetic materials from the short arm of chromosome 17 results in characteristics of MDS (Pollin et al, ). In translocation cases, chromosome deletion include distal region from p13.3 to p‐terminal of chromosome 17.…”