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.


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).


CONCLUSIONS
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.
UF de Génétique moléculaire, Hôpital Robert Debré, AP-HP, Paris, France. julien.masliah@gmail.com.|Inserm U1141, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France. julien.masliah@gmail.com.|New adresse: Unité de Génétique Somatique, Institut Curie, Paris, France. julien.masliah@gmail.com.
Julien
J
Masliah-Planchon
UF de Cytogénétique, Hôpital Robert Debré, AP-HP, Paris, France. celine.dupont@jvr.aphp.fr.
Céline
C
Dupont
Paediatric Neurology, P&A Kyriakou Paed. Hospital, Athens Medical School, Athens, Greece. vartzelis@gmail.com.
George
G
Vartzelis
UF de Génétique moléculaire, Hôpital Robert Debré, AP-HP, Paris, France. yayatrimouille@hotmail.com.|Inserm U1141, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France. yayatrimouille@hotmail.com.
Aurélien
A
Trimouille
Cytogénétique Médicale, Univ Clermont1, UFR Médecine, CHU Estaing, Clermont-Ferrand, France. e_pierre@chu-clermontferrand.fr.|ERTICa, EA 4677, Univ Clermont1, UFR Médecine, Clermont-Ferrand, France. e_pierre@chu-clermontferrand.fr.
Eléonore
E
Eymard-Pierre
Cytogénétique Médicale, Univ Clermont1, UFR Médecine, CHU Estaing, Clermont-Ferrand, France. mgay-bellile@chu-clermontferrand.fr.|ERTICa, EA 4677, Univ Clermont1, UFR Médecine, Clermont-Ferrand, France. mgay-bellile@chu-clermontferrand.fr.
Mathilde
M
Gay-Bellile
Inserm U1141, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France. florence.renaldo@rdb.aphp.fr.|Neurologie et maladie métabolique, Hôpital Robert Debré, AP-HP, Paris, France. florence.renaldo@rdb.aphp.fr.
Florence
F
Renaldo
Inserm U1141, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France. imen.dorboz@inserm.fr.
Imen
I
Dorboz
UF de Génétique moléculaire, Hôpital Robert Debré, AP-HP, Paris, France. Cecile.pagan@chu-lyon.fr.
Cécile
C
Pagan
IUH, Hôpital Saint-Louis, Paris, France. samuel.quentin@sls.aphp.fr.
Samuel
S
Quentin
Imagerie pédiatrique, Hôpital Robert Debré, AP-HP, Paris, France. monique.elmaleh@rdb.aphp.fr.
Monique
M
Elmaleh
Paediatric Neurology, P&A Kyriakou Paed. Hospital, Athens Medical School, Athens, Greece. christal_doc@yahoo.gr.
Christina
C
Kotsogianni
Paediatric Neurology, P&A Kyriakou Paed. Hospital, Athens Medical School, Athens, Greece. eliskonst@yahoo.gr.
Elissavet
E
Konstantelou
UF de Génétique moléculaire, Hôpital Robert Debré, AP-HP, Paris, France. severine.drunat@rdb.aphp.fr.|Inserm U1141, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France. severine.drunat@rdb.aphp.fr.
Séverine
S
Drunat
UF de Cytogénétique, Hôpital Robert Debré, AP-HP, Paris, France. anne-claude.tabet@rdb.aphp.fr.
Anne-Claude
AC
Tabet
Inserm U1141, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France. odile.boespflug-tanguy@rdb.aphp.fr.|Neurologie et maladie métabolique, Hôpital Robert Debré, AP-HP, Paris, France. odile.boespflug-tanguy@rdb.aphp.fr.
Odile
O
Boespflug-Tanguy
D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005260:Female; D020440:Gene Duplication / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008279:Magnetic Resonance Imaging; D046228:Microarray Analysis; D016254:Mutagenesis, Insertional / Q000235:genetics*; D018991:Myelin Proteolipid Protein / Q000235:genetics*; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics* / Q000473:pathology; D049951:X Chromosome Inactivation / Q000235:genetics
D018991:Myelin Proteolipid Protein; C472930:PLP1 protein, human