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

Abstract

BackgroundPelizaeus-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 resultsHere 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).ConclusionThis 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.

Severe Hypotonia, Nystagmus and Hypomyelination in A 9-Month Female Infant: Diagnosing Pelizaeus–Merzbacher Disease Outside the Usual Inheritance Patterns

“…PLP1 triplications have already been described [7] and are often associated with a more severe phenotype. Nevertheless, in our patient the triplicated segment did not include the entire PLP1 gene, but neighboring regions embedded in the PLP1 duplication [9]. This result suggests a milder phenotype that is consistent with our case.…”

“…Even though X chromosome inactivation studies failed to prove the mechanism above, high clinical suspicion due to classic manifestations of PMD disease did lead to further genetic investigation. Indeed, aCGH and FISH analysis verified the insertion of a PLP1 extra copy in the autosomal loci 1p36 [9]. Eventually, a total gain of 3 copies of the referred gene was proved irrespective of the X-inactivation pattern.…”

Mechanisms for Complex Chromosomal Insertions

“…Most of the previous studies on insertions were based on relatively low resolution genome analysis by clinical arrays in combination with molecular cytogenetics, FISH, and chromosome analysis; only a few breakpoint junctions have been mapped to nucleotide resolution. [5, 18, 19]…”

X Chromosome Deletion in an Iranian Woman with Premature Ovarian Failure and a Mini Review

“…X-linked gene is required for ovarian development [40] therefore; each of the discussed deleted genes from X chromosome could cause defective cell division directly or indirectly resulting in POF. Besides, centromeric heterochromatin area may influence the translocated genetic material to its neighbourhood through positional effect [41][42][43][44][45][46][47][48]. Moreover, donor piece may positively/ negatively influence the acceptor piece in the breakpoint when rejoining happens.…”