Mosaicism in the presence of an unbalanced translocation is extremely rare. Several possible mechanisms have been proposed including mitotic error, meiotic error followed by postzygotic rescue, and chimerism. Most de novo cases were thought to be caused by a postzygotic exchange between two nonhomologous chromatids during mitosis followed by the loss of one of the two abnormal cell lines to create mosaicism. Studies have shown that a zygote with an unbalanced rearrangement derived from a balanced parent can lose the abnormal chromosome in a subgroup of cells at an early embryonic stage. The normal homologous chromosome undergoes self-duplication (monosomy rescue) to introduce a normal cell line as well as introducing isodisomy in that chromosome[7, 10]. In other cases, the initial zygote contains three chromosomes due to 3:1 segregation which is followed by an unequal rescue event that generates two cell lines: one with the loss of the abnormal chromosome and the other with the loss of a normal chromosome. Chimerism evolved from two zygotes is another potential mechanism resulting in mosaicism, but this is thought to be extremely rare.
Previously, we demonstrated the clinical utility of using SNP microarray in detecting rare mosaic chromosomal disorders[11, 12]. Here, we discuss the utility of SNP microarray in determining the complex origin of a mosaic unbalanced translocation. We observed an 8.4 Mb mosaic gain from chromosome 3p and a 6.1 Mb mosaic loss on chromosome 12p. The estimated percentages of both abnormalities were 25% suggesting the coexistence of the two abnormalities in the same cell line. FISH and chromosome analyses confirmed the presence of the der(12)t(3;12)(p26.1;p13.31) in a minor cell line (27.2%-28.6%). Parental chromosome analyses confirmed the translocation was maternally-derived. Furthermore, the complex B-allele frequency patterns of 3p and 12p shown by array analysis suggested additional rearrangements involving the derivative chromosome 12 (figure 2) occurred. We hypothesize that during maternal meiosis I, a quadrivalent formed involving the normal chromosome 3, derivative chromosome 3, normal chromosome 12, and derivative chromosome 12 in the primary oocyte. A meiotic recombination event occurred between the normal 3p and the derivative 12 harboring the translocated 3p. The recombination site on der(12) was distal to the breakpoint of the balanced t(3;12) (figure 2a). Fertilization of the oocyte with a “normal” recombinant chromosome 3 and der(12) by a sperm containing normal chromosomes 3 and 12 resulted in a zygote with an 8.4 Mb duplication of 3p26.3->3p26.1 (figure 2b, cell line 1). The distal 5.7Mb region of the 3p duplication contains two haplotypes with two copies of the same maternal haplotype and the paternal haplotype, and the proximal 2.7 Mb region of the duplication contains three haplotypes composed of genotypes from the paternal chromosome 3, maternal recombinant 3, and maternal der(12) with 3p translocation. The zygote also contains a 6.1 Mb deletion of 12p (figure 2b).
The second cell line with a normal karyotype is thought to arise from a mitotic recombination event that occurred postzygotically between the normal paternal chromosome 12 and the maternal der(12) in an attempt to create two “normal” copies of chromosome 12 (figure 2b, cell line 2). The crossover site was 1.9 Mb proximal to the translocation breakpoint on chromosome 12. This mitotic event “corrected” cell line 1 for the partial 3p trisomy and partial deletion of 12p, resulting in mosaic ROH encompassing the entire 6.1 Mb deleted region of 12p in cell line 1 and an adjacent 1.9 Mb mosaic ROH region (figure 2b). Figure 2c shows an overall genotype composition of 3p and 12p when considering the two cell lines together explaining the complex B-allele frequency patterns on the SNP array. Compared to previously reported cases, our case proposes an unreported mechanism that a mosaic unbalanced translocation originated as an unbalanced rearrangement in a zygote followed by a mitotic recombination event in an attempt to rescue the imbalance.
The phenotype of patients with mosaic chromosomal disorders are usually variable. It is difficult to assess what cells contain the imbalances and in what percentages. To our knowledge, no patients with the exact mosaic 3p duplication or mosaic 12p deletion have been reported previously. The DECIPHER disease database lists several reported patients with 3p non-mosaic duplications of similar sizes. Clinical features include hypotonia, skeletal abnormalities, intellectual disability, speech delay, and dysmorphic features (microcephaly, broad forehead, hypertelorism, epicanthus, depressed nasal bridge, and downturned corners of the mouth). Some individuals are reported with smaller duplications including CHL1, TRNT1, CRBN, and CNTN6 from the 3p26.2->3p26.3 region. These patients presented with intellectual disability, developmental delay, epilepsy, autistic features, and behavioral abnormalities[14–16]. For 12p, there are 67 protein-coding genes including 10 genes associated with human disease (CACNA2D4, CCND2, C12orf4, NDUFA9, KCNA1, KCNA5, WNK1, FGF23, CACNA1C, VWF). A patient reported with a 6.2 Mb deletion from 12p (12p13.33->12p13.31) presented with intellectual disability, speech delay, anxiety disorder, and psychotic symptoms. A review of 20 cases of patients with deletions of 12p13.33 that included loss of CACNA1C identified most individuals with expressive language delay and motor-skill impairment. This phenotype correlates well with our patient who has global developmental delay, moderate intellectual disability, and hypotonia; however, our patient did not have dysmorphic features or psychotic symptoms.
Mosaic chromosomal disorders can have important clinical implications especially in neurodevelopmental disorders. The diagnosis might be underestimated for several reasons. First, the lack of specific clinical phenotype and variable severity pose a diagnostic challenge. Second, somatic mosaicism is easily missed due to the limitation in sampling tissue and detection method. Third, mosaicism may evolve over time with changes in the percentages of normal and abnormal cells. Genome-wide screening methods, such as chromosomal microarray, have been widely used in pediatric genetics and have increased the diagnostic yield for mosaic chromosomal disorders. Here, we provide an example of using combined cytogenetic approaches to resolve an unreported complex etiology of a rare mosaic unbalanced translocation. The presence of the unbalanced translocation in conjunction with the mitotic rescue event resulted in the clinical presentation for this patient. Importantly, we highlight the necessity to perform parental testing on patients with mosaic chromosome disorders, especially in those with unbalanced translocations. Although the mosaicism may be de novo, it could arise from a complex mitotic rescue of the unbalanced rearrangement.