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Preimplantation Genetic Testing for Structural Rearrangements
Published in Darren K. Griffin, Gary L. Harton, Preimplantation Genetic Testing, 2020
SRs are formed via double-stranded breaks and subsequent joining of those breakpoints by DNA repair machinery [8]. This creates derivative chromosomes where the order and the linkage relationships of genes differ. They can be formed in any of the chromosomes; however, there are hot-spots or frequent breakpoints in the genome. Mechanisms such as non-allelic homologous recombination (NAHR) [9,10], DNA double strand break repair via non-homologous end-joining (NHEJ) [8,11], microhomology-mediated break-induced replication (MMBIR), fork stalling and template switching (FoSTeS) [12], “chromothripsis” [1,13], palindrome-mediated mechanisms [14], nucleolar localization of chromosomes, and exposure to chemicals and radiation [15] are thought to be responsible in the generation of rearrangements. Within the scope of PGT-SR, the types and the reproductive outcomes of rearrangement carriers are usually restricted to balanced reciprocal and Robertsonian translocations (RecT and RobT), inversions, complex chromosome rearrangements, and insertions (Figure 4.1).
Perlman Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Loss-of-function germline homozygous or compound heterozygous mutations in the DIS3L2 represent one of the mechanisms that converge on Igf2 (insulin-like growth factor 2) upregulation, leading to overgrowth and/or Wilms tumor (Figure 94.1). Indeed, homozygous deletions of DIS3L2 exon 6 or exon 9, which cause the loss of both RNA binding and degradation activity, are frequently identified in patients with Perlman syndrome. Analysis of compound heterozygous DIS3L2 mutations (c.[367-2A > G];[1328T > A]) from a Japanese patient indicates that non-allelic homologous recombination (NAHR) between two LINE-1 (L1) elements represents an important disease mechanism [10]. As missense mutation (c.1328 T > A, p.Met443Lys) retains RNA binding in both the cold-shock domains and the S1 domain, and partial exonuclease functions remain in at least one allele, long-term survival is possible [11].
Smith-Magenis Syndrome—A Developmental Disorder with Circadian Dysfunction
Published in Merlin G. Butler, F. John Meaney, Genetics of Developmental Disabilities, 2019
Ann C.M. Smith, Wallace C. Duncan
The mechanism of the 17p11.2 microdeletion was first described in SMS by Chen et al. (23) and later shown to be a common feature of genomic disorders, including other contiguous gene syndromes (34,35). The mechanism involves nonallelic homologous recombination (NAHR) of large, highly homologous flanking low-copy repeat (LCR) gene clusters. Three LCR gene clusters are present, a proximal, middle, and distal referred to as SMS-REPs (Fig. 1). The clusters (SMS-REPs) are prone to deletion, duplication, and inversion (23). The ~4-Mbgenomic segment that is commonly deleted in individuals with SMS is flanked by two large complex LCRs, the proximal and distal SMS-REPs (23). The NAHR, using the proximal and distal SMS-REP as substrates, leads to the common interstitial deletion of chromosome 17p11.2 that occurs in 75% of cases (20,21). Newly described LCR elements flanking the SMS-REP sequences are thought to mediate recombination in the atypical deletions (36) at a much higher rate than previously thought (20,21). Although reciprocal duplication of the same segment, dup(17)(p11.2p11.2), is predicted to occur at the same frequency as deletions (34), it has been identified in only a few patients. Among the seven described cases (ages 3–41 years), clinical features differ phenotypically and behaviorally from those seen in SMS (37).
Copy number variation analysis using next-generation sequencing identifies the CFHR3/CFHR1 deletion in atypical hemolytic uremic syndrome: a case report
Published in Hematology, 2022
Joonhong Park, Ho-Young Yhim, Kyung Pyo Kang, Tae Won Bae, Yong Gon Cho
Deletions within genes, occurring through both microhomology-mediated end joining and non-allelic homologous recombination, result in the formation of hybrid genes (CFH/CFHR1, CFHR1/CFH, CFH/CFHR3, CFHR3/CFHR1) related to aHUS [10]. Thus, NGS panel data can be used as a CNV screening step in a genetic diagnostics setting, and this screening step has the potential to improve the genetic diagnosis of aHUS, even though most CNV tools were designed to work with whole exome or whole genome data and struggle with the sparser data from NGS panels used in routine genetic testing [11]. This report describes a case in which copy number variation (CNV) analysis using next-generation sequencing (NGS) identified the CFHR3/CFHR1 deletion in a patient with aHUS.
Possible modifier genes in the variation of neurofibromatosis type 1 clinical phenotypes
Published in Journal of Neurogenetics, 2018
Another DNA repair mechanism that is speculated to affect NF1 is nonallelic homologous recombination (NAHR) (Messiaen et al., 2011). As mentioned above, different types of microdeletions have been identified in NF1 depending on the size of the deleted region. It has been shown that the majority of type-1 NF1 microdeletions (1.4 Mb) occur in the germline through a NAHR mechanism (Messiaen et al., 2011). Type-2 NF1 deletions (1.2 Mb) have also been reported to occur predominantly because of intrachromosomal mitotic (post-zygotic) NAHR (Roehl et al., 2012). Indeed, some hotspots of meiotic NAHR have been identified in both types of microdeletions (Raedt et al., 2006; Vogt et al., 2012).
History of radiation genetics: light and darkness
Published in International Journal of Radiation Biology, 2019
The deletions that were found could be classified into three major types. Type 1 consisted of deletions whose base sequences at the junctions comprised long similar sequence blocks (but they are not alleles). Thus, they are likely to be induced as a result of non-allelic homologous recombination at meiosis. Because they occurred in both irradiated and non-irradiated genomes, they are most likely to be spontaneous in origin. Note that the deletions in this group can be quite large, and since some of them exceed 1000 kb, they could be misclassified as radiogenic. In this respect, base sequence analysis at the deletion junctions is important in determining the mutation’s origin.