46,XY/46,XY Chimerism: Prenatal Presentation and Postnatal Outcome

Abstract

Background: Human chimerism is rare, and most prevalent with discordant chromosomal sex. We report a male 46,XY/46,XY chimera, born through a spontaneously conceived pregnancy to a healthy 32-year-old G1P0 Indian, African, and Scottish female and her 34-year-old healthy Chinese partner. The prenatal presentation and postnatal outcomes are described.

Methods: A prenatal cell-free DNA screening test, amniocentesis with QF-PCR and SNP microarray, and postnatal microarray and FISH study on peripheral blood, placenta, and umbilical cord were used to evaluate chimerism.

Results: The prenatal cell-free screening test revealed high risk for triploidy/vanishing twin, but there was no confirmation from early ultrasound. Subsequent QF-PCR on amniocytes showed a profile suggestive of a tetragametic chimera. G-banding showed a 46,XY karyotype. A SNP microarray detected two copy number gains of uncertain significance on chromosome 6q, derived from the father who was a balanced carrier of ins(6;11). A postnatal microarray and FISH study confirmed the presence of two cell lines, each with a 46,XY complement but with different submicroscopic structural changes including recombinant and insertion changes. Clinical evaluations of the child at birth and 8 weeks of age were coordinated to detect the presence of chimeric symptoms.

Conclusion: With a confirmed incidental finding of 46,XY/46,XY chimerism, we present that underlying same-sex chimerism may be under-recognized.

FIGURE 1

(A) Representative short tandem repeat profiles from amniocytes for regions (right to left) of the sex chromosomes (AMEL), ratio of chromosome 3 to X (TAF9L), chromosomes X, Y, 13, 18 and 21 (DXS6803, SRY, D13S252, D18S386, D21S11, respectively) showing the presence of an equal ratio of chromosome X to Y (AMEL), a 2:1 ratio for chromosome 3 to X (TAF9L), two distinct X chromosomes (DXS6803), the SRY locus (SRY), and two distinct maternal alleles with one or two distinct paternal alleles for chromosomes 13 (D13S252), 18 (D18S386) and 21 (D21S11). (B) Representative microarray profiles from amniocytes (left to right): (left panel) Representative example of chromosome 1 microarray result showing no copy number change, with a B‐allele frequency plot showing five distinct tracks which equates to four genotypes. A similar pattern was observed across all of the autosomes; (center panel) the B‐allele plots of the X chromosomes show a pattern consistent with two unique X chromosome genotypes (3 tracks), while the pseudoautosomal regions are plotted at termini of Xp and Xq and show a pattern consistent with four genotypes (5 tracks); (right panel) the Y chromosome pattern is consistent with a single genotype (2 tracks). (C) Microarray profile of chromosome 6 obtained from postnatal peripheral blood showing interstitial gains of 6q14.1 (3.0 Mb) and 6q16.2 (1.3 Mb). Complex B‐allele frequency plots were observed across all autosomes and the X chromosome. The presence of 9 B‐allele tracks across the majority of most chromosomes was suggestive of chimeric zygote fusion with ~25% mosaicism for cell line 1 (2 copies of 6q14.1 and 6q16.2) relative to ~75% of cell line 2 (3 copies of 6q14.1 and 6q16.2) as determined with the help of fluorescence in situ hybridization (FISH). (D) Inverted DAPI images with FISH utilizing probes specific to 6q14.1 (RP11‐17086 in Spectrum green) and 6q16.2 (RP11‐464P14 in Spectrum orange); (left panel) Cell line 1 shows balanced insertional translocation of 6q14.1 and 6q16.2 into derivative chromosome 11 and loss of the 6q14.1 and 6q16.2 segments from the derivative chromosome 6 in 50 of 200 nuclei; (right panel) Cell line 2 shows an unbalanced gain of 6q14.1 and 6q16.2 on the derivative 11 together with normal hybridization patterns on the normal chromosomes 6 in 150 of 200 nuclei. (E) Photograph of proband's triple hair whorl.