Deletion and Duplication Syndromes
المؤلف:
Cohn, R. D., Scherer, S. W., & Hamosh, A.
المصدر:
Thompson & Thompson Genetics and Genomics in Medicine
الجزء والصفحة:
9th E, P86-88
2025-12-04
170
Genomic disorders result from gain or loss of hundreds of kilobases of DNA. There are at least two mechanisms whereby SVs can be formed that lead to genomic disorders. NAHR leads to recurrent SVs, whereas nonhomologous end joining (NHEJ) and other non homologous recombination repair mechanisms (see Fig. 1B and C) lead to nonrecurrent SVs.
Fig1. Model of rearrangements underlying genomic disorders. (A) Nonallelic homologous recombination (NAHR), unequal crossing over between misaligned sister chromatids or homologous chromosomes containing highly homologous copies of segmental duplications can lead to deletion or duplication. (B) Nonhomologous end joining (NHEJ), double-strand breaks (DSBs) occur and NHEJ polymerase, nuclease, and ligase complexes initiate SV formation. Red dashed boxes represent microhomology between the two DNA ends, which is used to guide end joining. The process could result in structural variant formation. (C) Fork stalling or template switching (FoSTeS) and microhomology-mediated break-induced replication (MMBIR) model is represented. When a replication fork encounters a nick (striking arrowhead) in a template strand, one arm of the fork breaks off and results in a collapsed fork. At the single double-strand end, the 5′ end of the lagging strand (dashed black lines) is resected, giving a 30 overhang. The 3′ single-strand end of lagging-strand template (solid red lines) invades the sister leading-strand DNA (gray lines) guided by regions of microhomology (MH), forming a new replication fork. The 3′ end invasion of the lagging-strand template can reform replication forks on different genomic templates before returning to the original sister chromatid and forming a processive replication fork that completes replication. Each line represents a DNA nucleotide strand. New DNA synthesis is shown by dashed lines. For examples of genomic disorders, segmental duplications, and the size of the deleted or duplicated region. (Modified from Carvalho CM, Lupski JR: Mechanisms underlying structural variant formation in genomic disorders, Nat Rev Genet 17:224–238, 2016; Chang HH, Pannunzio NR, Adachi N, et al: Non-homologous DNA end joining and alternative pathways to double-strand break repair, Nat Rev Mol Cell Biol 18:495–506, 2017; Malhotra D, Sebat J: CNVs: harbingers of a rare variant revolution in psychiatric genetics, Cell 148:1223–1241, 2012.)
Recurrent Structural variants
NAHR is the key mechanism causing recurrent SVs. These rearrangements usually have the same size in unrelated individuals because the breakpoints are localized to interspersed, highly similar paralogous copies of SDs. Extensive analysis of over 30,000 patients worldwide has now implicated this general sequence-dependent mechanism in 50 to 100 syndromes involving contiguous gene rearrangements, which collectively are sometimes referred to as genomic disorders. Here we focus on syndromes involving chromosome 22 to illustrate underlying genomic features of this class of disorders.
Deletions and Duplications Involving Chromosome 22q11.2. A particularly common deletion, 1 in 3400 live births, involves deletions at chromosome region 22q11.2 and is referred to as 22q11.2 deletion syndrome (DS), or DiGeorge syndrome, or velocardiofacial syndrome. This clinical syndrome is caused by a deletion of ~3 Mb within 22q11.2 on one copy of chromosome 22. The deletion and other rearrangements of this region shown in Fig. 2 are each mediated by NAHR between SDs in the region.
Fig2. Chromosomal deletions, duplications, and rearrangements in 22q11.2 mediated by homologous recombination between segmental duplications. (A) Normal karyotypes show two copies of 22q11.2, each containing multiple copies of a family of related segmental duplications within the region (dark blue). In DiGeorge syndrome (DGS) or velocardiofacial syndrome (VCFS), a 3-Mb region is deleted from one homologue, removing ~30 genes; in ~10% of patients, a smaller 1.5-Mb deletion (nested within the larger segment) is deleted. The reciprocal duplication is seen in patients with dup(22)(q11.2q11.2). Tetrasomy for 22q11.2 is seen in patients with cat-eye syndrome. Note that the duplicated region in the cat-eye syndrome chromosome is in an inverted orientation relative to the duplication seen in dup(22) patients, indicating a more complex genomic rearrangement involving these segmental duplications. (B) Expanded view of the 22q11.2 genomic region, indicating the common DGS/VCFS deletions (red) and more distal deletions (also mediated by recombination involving segmental duplications) that are seen in patients with other phenotypes (orange). Genes in the region (from www.genome.ucsc.edu browser) are indicated above the region. (C) Two-color fluorescence in situ hybridization analysis of proband with DGS, demonstrating deletion of 22q11.2 on one homologue. Green signal is hybridization to a control region in distal 22q. Red signal shows hybridization to a region in proximal 22q that is present on one copy of the chromosome but deleted from the other (arrow). (C, fluorescence in situ hybridization image courtesy Kato T, Kosaka K, Kimura M, et al: Thrombocytopenia in patients with 22q11. 2 deletion syndrome and its association with glycoprotein Ib-β, Genet Med 5:113–119, 2003.)
Patients show characteristic craniofacial anomalies, intellectual disability, immunodeficiency, and heart defects, likely reflecting haploinsufficiency for one or more of the several dozen genes that are normally found in this region. Because the phenotype is often attributed to deficient copies of multiple, contiguous genes, the term contiguous gene syndrome can be applied to this condition. Among the genes deleted, one of the most well studied is the TBX1 gene, which has been mutated or deleted in as many as 5% of all patients with congenital heart defects, particularly for left-sided outflow tract abnormalities.
The reciprocal duplication of 22q11.2 is much rarer and leads to a series of distinct dysmorphic malformations and birth defects called the 22q11.2 duplication syndrome (see Fig. 2).
The general concepts illustrated for disorders associated with 22q11.2 also apply to many other chromosomal and genomic disorders, some of the most common or more significant of which are summarized in Table 1 and Box 1.
Table1. Examples of Genomic Disorders Involving Recombination Between Segmental Duplications
Box1. LESSONS FROM GENOMIC DISORDERS
Nonrecurrent Structural Variants
Nonrecurrent SVs usually do not have the same size in unrelated individuals. The breakpoints of these rearrangements can be localized to anywhere in the genome and are often characterized by microhomologies, small insertions, or blunt ends. At least 70 genomic disorders have now been shown to be caused by nonrecurrent SVs. Although NHEJ is the presumed mechanism for many of these rearrangements, other mechanisms for nonrecurrent SV formation include DNA replication during the aberrant repair and include fork stalling or template switching (FoSTeS) and microhomology mediated break-induced replication (MMBIR) (see Fig. 1B and C). In each of these mechanisms, a stalled replication fork is repaired using microhomology to prime for DNA synthesis.
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