A recurrent 14q32.2 microdeletion mediated by expanded TGG repeats

Area of Science:

• Genetics
• Genomic Instability
• Human Disease

Background:

• Recurrent microdeletion syndromes typically involve flanking low copy repeats facilitating non-allelic homologous recombination (NAHR).
• Gene dosage alterations due to NAHR can lead to various genetic disorders.

Observation:

• Two unrelated patients presented with an identical 1.11 Mb heterozygous deletion at 14q32.2, encompassing the DLK1/GTL2 imprinted gene cluster.
• The deletion occurred on the paternal chromosome 14, and patients exhibited clinical features consistent with maternal uniparental disomy (UPD (14)mat).
• High-resolution array mapping revealed breakpoints within large, highly homologous (TGG)(n) tandem repeats flanking the deleted region.

Findings:

• The recurrent 14q32.2 deletion is mediated by flanking (TGG)(n) repeats, representing a novel mechanism for genomic rearrangement.
• These expanded (TGG)(n) repeats share characteristics with fragile sites and can form stable guanine quadruplex structures.
• The deletion may result from NAHR between the (TGG)(n) repeats or from their inherent instability and secondary structure.

Implications:

• This discovery expands the known mechanisms of recurrent genomic rearrangements beyond typical NAHR substrates.
• Expanded triplet repeats, particularly those forming G-quadruplexes, may contribute to genomic instability and disease.
• The findings suggest that similar repeat structures could be implicated in other pathogenic rearrangements throughout the genome.