A cryptic balanced translocation (5;17), a puzzle revealed through a critical evaluation of the pedigree and a FISH focused on candidate loci suggested by the phenotype

Abstract

We report a case of a woman with a cryptic balanced translocation between chromosomes 5 and 17, suspected during genetic counseling. The woman had a history of previous fetal losses attributed to lissencephaly and intra uterine growth retardation (IUGR) and a daughter with dysmorphic features and mental retardation, previously attributed to a small deletion 5pter, detected years ago by a first generation CGH-array. This peculiar combination of personal and family history suggested the opportunity to carry out a FISH approach, focusing on chromosomes 5 and 17, based on the idea that a malsegregation secondary to a balanced translocation, might have escaped the first CGH array. This approach allowed the identification of a balanced translocation in the mother, FISH in the affected child confirmed the partial 5p deletion predicted by the previous CGH array and identified a new 17p duplication that had not been detected before. The described translocation opens the possibility of alternative imbalances that were probably responsible for previous fetal losses. The imbalances were confirmed by a new high resolution SNP array. We conclude that despite the availability of highly effective and sensitive genomic approaches a careful evaluation of medical history is highly recommended since it can suggest clinical hypothesis that can be confirmed by more classical and molecular cytogenetic based approaches.

Fig. 1

a The child had long triangular shaped face, narrow forehead with a lower front hairline, mild synophrys, broad nasal bridge, a small mouth and a horizontal labial fissure. b Low set prominent ears posteriorly rotated with abnormally folded anthelices, (c) Abnormal dermatoglyphics, with long three finger crease (TFC), incomplete five finger crease (FFC) (starts under the fouth finger and end on radial side), short thumb crease (TC). short palm. d Short toes with clinodactily of the fourth and second left toes

Fig. 2

GTG banded Karyotype (Mother)

Fig. 3

a: FISH for Miller Diecker Region on chromosome 17p: red probe LIS1 gene on 17p13.3, green probe RARA on 17q21.1(Mother). b: FISH with specific probes for chromosomes 5 p and q subtelomeric region: probe 5p15.33 (green), probe 5q35.3(red) (Mother)

Fig. 4

a: FISH for Miller Diecker Region on chromosome 17p: red probe LIS1 gene on 17p13.3, green probe RARA on 17q21.1 (Daughter). b: FISH with specific probes for chromosomes 5 p and q: green probe 5p15.33, red probe 5q35.3 (Daughter)

Fig. 5

The results of SNP- array analysis analyzed and imaged using ChAS 2.0 software showing the deletion of the subterminal region of the short of a chromosome 5, of about 4.5 Mb, and the duplication of the subterminal region of the short arm of a chromosome 17, of about 3.1 Mb. Both log2 ratios and Allele Peaks calls indicated the locations and sizes of the chromosome anomalies