Application of molecular cytogenetic techniques to characterize the aberrant Y chromosome arising de novo in a male fetus with mosaic 45,X and solve the discrepancy between karyotyping, chromosome microarray, and multiplex ligation dependent probe amplification

Abstract

We present a rare male fetus with karyotype of mosaic 45,X that comprises two types of aberrant Y chromosomes arising de novo (Yq12 deletion and isodicentric Yq11.22). Both types of the aberrant Y chromosomes lack the AZFc region which are expected to result in oligospermia but unaffected male external genitalia. Genetic analyses by karyotyping, chromosome microarray (CMA), and multiplex ligation-dependent probe amplification (MLPA) for the fetus revealed conflicting results. Additional molecular cytogenetics tools including fluorescence in situ hybridization (FISH) and multicolor banding (mBAND) were performed, which help resolving the discrepancy and delineated the composition of the aberrant Y chromosomes. This report highlighted the importance of incorporating multiple genetic technologies for accurate characterization of complex chromosomal rearrangements, which aid in the prenatal diagnosis and genetic counseling.

Clinical, cytogenetic, and molecular findings of isodicentric Y chromosomes

“…These findings are consistent with most isodicentric Y chromosome cases reported [4, 11, 14, 25–29]. There are also many other aberrant chromosomes that could arise with isodicentric Y chromosomes, leading to a very complicated karyotype [3, 4, 17, 30–32]. This mosaicism might be related to the time (i.e., during meiosis or postzygote) during which the isodicentric Y chromosome originated, instability during mitosis, and whether other chromosomes were involved [23].…”

“…A combination of cytogenetic and molecular analysis would provide detailed information on the gain and loss of isodicentric Y chromosomes, assisting in the interpretations of the test results [19]. However, inconsistent results might arise in cases of very complicated mosaicism, which require apanoramic view of the results in a retrospective manner [17]. Additionally, cryptic mosaics make it even more difficult to identify small supernumerary marker chromosomes [20].…”

Prenatal genetic analysis and differential pregnancy outcomes of two de novo cases showing mosaic isodicentric Y chromosome

“…In contrast, when a patient presents as they might also have symptoms of azoospermia or oligospermia, asthenospermia, hypospadias and cryptorchidism. Some patients also have gender ambiguity and gonadal dysgenesis [12] and others might also be at higher risk for mental retardation and disorders [11,13]. Therefore, gender should be determined by ultrasound when prenatal test results show sex chromosome abnormalities in a fetus.…”

Multicolor-FISH Characterization of a Prenatal Mosaicism for a Chromosomal Rearrangement Undetected by Molecular Cytogenetics

“…Among cytogenetic techniques, multicolor-FISH (M-FISH), using up to 24 chromosome painting probes in a single FISH experiment, is superseded by molecular techniques such as chromosomal microarray analysis (CMA) or high-throughput sequencing. However, M-FISH is still of interest to supplement these techniques in some cases, such as characterizing sSMCs [Jang et al, 2016] or mosaic complex chromosomal rearrangements [Lin et al, 2018].…”