Xq27.1 palindrome mediated interchromosomal insertion likely causes familial congenital bilateral laryngeal abductor paralysis (Plott syndrome)

Bilateral laryngeal abductor paralysis is a rare entity and the second most common cause of stridor in newborns. So far, no conclusive genetic or chromosomal aberration has been reported for X-linked isolated bilateral vocal cord paralysis, also referred to as Plott syndrome. Via whole genome sequencing (WGS), we identified a complex interchromosomal insertion in a large family with seven affected males. The 404 kb inserted fragment originates from chromosome 10q21.3, contains no genes and is inserted inversionally into the intergenic chromosomal region Xq27.1, 82 kb centromeric to the nearest gene SOX3. The patterns found at the breakpoint junctions resemble typical characteristics that arise in replication-based mechanisms with long-distance template switching. Non protein-coding insertions into the same genomic region have been described to result in different phenotypes, indicating that the phenotypic outcome likely depends on the introduction of regulatory elements. In conclusion, our data adds Plott syndrome as another entity, likely caused by the insertion of non-coding DNA into the intergenic chromosomal region Xq27.1. In this regard, we demonstrate the importance of WGS as a powerful diagnostic test in unsolved genetic diseases, as this genomic rearrangement has not been detected by current first-line diagnostic tests, i.e., exome sequencing and chromosomal microarray analysis.

Automated summary

This study identified a complex interchromosomal insertion in a large family with seven affected males using WGS. The inserted fragment originated from chromosome 10q21.3 and was inserted inversionally into the intergenic chromosomal region Xq27.1. The patterns found at the breakpoint junctions resembled characteristics that arise in replication-based mechanisms with long-distance template switching. This research demonstrates the importance of WGS as a powerful diagnostic test in unsolved genetic diseases.