Insertion of an extra copy of Xq22.2 into 1p36 results in functional
duplication of the PLP1 gene in a girl with classical
Pelizaeus-Merzbacher disease
Background: Pelizaeus-Merzbacher disease (PMD) is an X-linked
dysmyelinating disorder characterized by nystagmus, hypotonia, ataxia,
progressive spasticity, and cognitive decline. PMD classically results
from a duplication of a genomic segment encompassing the entire PLP1
gene. Since the PLP1 gene is located in Xq22, PMD affects mostly boys.
Methods and results: Here we report the case of a girl with typical PMD.
Copy number analysis of the PLP1 locus revealed a duplication of the
entire gene and FISH analysis showed that the extra copy of the PLP1
gene was actually inserted in chromosome 1p36. This insertion of an
additional copy of PLP1 in an autosome led to a functional duplication
irrespective of the X-inactivation pattern. Subsequent overexpression of
PLP1 was the cause of the PMD phenotype observed in this girl. Further
sequencing of the breakpoint junction revealed a microhomology and thus
suggested a replication based mechanism (such as FoSTeS or MMBIR).
Conclusion: This case emphasizes the susceptibility of the PLP1 locus to
complex rearrangement likely driven by the Xq22 local genomic
architecture. In addition, careful consideration should be given to
girls with classical PMD clinical features since they usually experience
complex PLP1 genomic alteration with a distinct risk of inheritance
