The copy-number neutral AOH segment can encompass > 50 Mb extending to the telomere and reflects segmental uniparental isodisomy (UPD) whereas the triplications are formed by biparental contributions, and both variant types are potentially generated concomitantly in a post-zygotic event. TRP segments are inverted and can be as large as 21.7 Mb in size in addition to being flanked by small duplications of a few Kb, a structure named inverted triplication flanked by duplications (DUP-TRP/INV-DUP). We and others have reported a rare type of de novo complex genomic rearrangement (CGR) constituted by TRP followed by absence of heterozygosity (AOH) in patients clinically referred for multiple congenital abnormalities. quadruplication and further amplification) copy-number gains this molecular diagnostic challenge may result in triplications being miscalled as duplications. The contribution and impact of triplication on disease etiology is still under-recognized due, in part, to the technical limitations in distinguishing duplications from triplications or higher order (e.g. Moreover, locus duplication increases the risk of triplication formation as a result of unequal crossover (i.e., nonallelic homologous recombination NAHR) by about 100X such type of rearrangement within a given locus can result in altered inter-generational disease penetrance with the appearance of genetic anticipation. Triplication of dosage-sensitive genes can increase phenotypic severity in triplication versus duplication carriers, lower the disease age-of-onset, or result in distinct clinical phenotypes compared to duplications affecting the same locus. TRP can potentially contribute to disease etiology via gene dosage effects, gene disruption at breakpoint junctions, position effects, or fusion gene formation. For a TRP locus, the total number of alleles will be equivalent to four copies for autosomes and equal to three copies for the X-chromosome of 46, XY males. Intrachromosomal triplications (TRP) are defined as a heterozygous segmental 3X copy-number amplification of a given locus in which all three copies are inserted in cis. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology. UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases. The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation.
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