Causes of Chromosome 2 Microdeletions
Primary Mechanism: Nonallelic Homologous Recombination and Microhomology-Mediated Processes
Chromosome 2 microdeletions primarily result from microhomology-mediated repair mechanisms, including microhomology-mediated end-joining (MMEJ), fork stalling and template switching (FoSTeS), and microhomology-mediated break-induced replication (MMBIR), with genomic architectural features driving DNA breakage susceptibility. 1
Molecular Mechanisms
Microhomology-Mediated Mechanisms (Most Common)
Microhomology-mediated end-joining (MMEJ) represents the predominant mechanism, with microhomology sequences ranging from 1 bp to 66 bp found in 91.7% of characterized breakpoint junctions 1
Fork stalling and template switching (FoSTeS) occurs when DNA replication forks stall and switch templates, creating deletions during the repair process 1
Microhomology-mediated break-induced replication (MMBIR) involves DNA breaks that trigger replication-based repair using microhomologous sequences 1
Serial replication slippage (SRS) and break-induced SRS (BISRS) contribute to deletion formation through repetitive slippage events during DNA replication 1
Genomic Architectural Predisposition
Sequence motifs and non-B DNA conformations are present in all breakpoint regions, increasing susceptibility for DNA breakage 1
Repetitive elements flank deletion regions and promote replication fork stalling, facilitating microhomology-mediated mechanisms 1
Low copy repeats (LCRs) create genomic instability through their repetitive nature, though this mechanism is more characteristic of chromosome 22q11.2 deletions than chromosome 2 deletions 2
Origin and Inheritance Pattern
De Novo Events (Predominant)
Most chromosome 2 microdeletions occur as de novo events during gametogenesis or early embryonic development 3, 4
Sporadic formation accounts for the majority of cases, with no family history of similar deletions 3, 4
Rare Inherited Cases
Parental mosaicism can occasionally result in transmission, though this is uncommon for chromosome 2 deletions 2
Balanced translocations in parents may predispose to unbalanced deletions in offspring, though this is rare 2
Detection Methodology Context
Array-Based Detection
Chromosomal microarray analysis (array CGH) identifies these submicroscopic deletions that are missed by standard karyotyping 3, 4, 5
SNP arrays provide both copy number detection and breakpoint mapping with ultra-high resolution 5
Breakpoint Characterization
Long-range PCR and Sanger sequencing of junction products definitively characterize the exact breakpoint sequences and confirm microhomology 1
Quantitative PCR (qPCR) validates deletion boundaries identified by array-based methods 1
Clinical Implications of Mechanism
Recurrence Risk
De novo deletions carry low recurrence risk (<1%) for future pregnancies in the same family 2
Parental testing is essential to exclude rare parental mosaicism that would increase recurrence risk 2
Phenotypic Variability
Deletion size variation results from different breakpoint locations, explaining phenotypic heterogeneity among patients with 2p11.2-p12 deletions 3, 4
Gene dosage effects from haploinsufficiency of genes within the deleted region (CTNNA2, LRRTM1, REEP1) drive the clinical manifestations 4, 5
Common Pitfalls in Understanding Etiology
Do not assume recurrent deletions mediated by LCRs like those in 22q11.2DS; chromosome 2 deletions are typically non-recurrent with unique breakpoints 1
Do not overlook the role of genomic architecture in predisposing specific regions to deletion formation through DNA structural instability 1
Do not confuse mechanism with inheritance pattern; microhomology-mediated mechanisms explain how deletions form, while de novo occurrence explains why they typically lack family history 3, 1