Phenotypic and genotypic insights into concurrent tertiary trisomy for 9p and 18p

Abstract

Background: Carriers of balanced reciprocal translocation are usually phenotypically normal; however, they have an increased risk of producing gametes with chromosomal imbalance through different types of meiotic segregation of the translocation quadrivalent. The genetically imbalanced gametes when they survive can result in embryos with chromosomal abnormalities. Here we report a family with two siblings inheriting partial trisomy for 9p and 18p concurrently resulting from a 3:1 meiotic segregation of a maternal balanced translocation involving chromosome 9q and 18p, and the associated phenotype.

The family - case presentation: The family was ascertained because of severe congenital anomalies in a newborn male (sibling 1). The karyotype of this patient was 47,XY,+del(9)(q13q34). Cytogenetic analysis revealed that the phenotypically normal mother harbored a balanced translocation 46,XX,t(9;18)(q13;p11.21). Chromosomal microarray analysis (CMA) of the abnormal child detected segmental trisomy for 9p and 18p. In conjunction with conventional cytogenetic results of the mother and CMA results of the affected child, the final karyotype of sibling one was 47,XY,+der(9)t(9;18) (q13;p11.22)dmat. arr[GRCh36] 9p24.3q13(199254_70163189)× 3, 18p11.32p11.22(131491_9640590)× 3; this resulted in segmental duplication of 69.96 Mb on 9pter->q13 and 9.51 Mb on 18p. There was a subsequent birth of a female sibling (sibling two) with multiple anomalies, including dysmorphic facial features, kidney aberration, cardiac defects, and abnormal brain MRI. The G-banded karyotype of this sibling was 47,XX,+del(9)(q13q34). The final karyotype of this sibling after CMA results was 47,XX,+der(9)t(9;18)(q13;p11.22)dmat. arr[GRCh37] 9p24.3p13.1(209020_38763958)× 3; 18p11.32p11.22(146484_9640912)× 3. The apparent discrepancy between the array results of the two siblings is attributed to difference in the design of array chips and genome builds used for these patients (NimbleGen/Roche v2.0 3-plex and GRCh36 for sibling one, and GGXChip + SNP array and GRCh37 of Agilent Technologies for sibling two). There are 182 OMIM genes in the duplicated region of 9p and 33 OMIM genes in the duplicated region of 18p which may have contributed to the clinical features of the affected siblings.

Conclusions: To our knowledge, we report the first two cases of concurrent partial trisomy 9p and 18p in the same family. This report adds more information about phenotypic effects of these chromosomal copy number gains and supports chromosomal microarray analysis as the standard for precise identification or demarking regions of duplications, particularly when the translocation involves at least one subterminal segment. In view of the recurring infants with congenital anomalies the couple may benefit from prenatal chromosome analysis of future pregnancies or opting to assisted reproductive methods and transferring normal embryos for implantation.

Keywords: CMA anlysis; Concurrent trisomy 9p and 18p; Familial t(9;18)(q13;p11.2).

Fig 1

G-banded karyotypes (475–500 band level) showing maternal balanced translocation 46,XX,t(9;18)(q13;p11.21) (arrows point to interchanged chromosomes) (A), and sibling two karyotype: 47,XX,+der(9)t(9;18)(q13;p11.22)dmat (arrow point to the der(9) chromosome inherited from the mother) (B)

Fig 2

Microarray results of peripheral blood from sibling one (A, B), and from sibling two (C, D). A. Duplication of 9p24.3q13.arr [GRCh36] (199254_70163189) × 3. Note that the genomic region of duplication extended to 9q13, but the probe coverage ended at 9p13.1 (red arrow). B. Duplication of 18p11.32p11.22.arr [GRCh36] (131491_9640590) × 3 C. Duplication of 9p24.3p13.1.arr [GRCh37](209020_38763958)× 3 D. Duplication of 18p11.32p11.22 [GRCh37] (146484_9640912)× 3