Expanding CEP290 mutational spectrum in ciliopathies.
Ciliopathies are an expanding group of rare conditions characterized by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.
Travaglini
Lorena
L
CSS-Mendel Institute, Casa Sollievo della Sofferenza Hospital, Rome, Italy.
Brancati
Francesco
F
Attie-Bitach
Tania
T
Audollent
Sophie
S
Bertini
Enrico
E
Kaplan
Josseline
J
Perrault
Isabelle
I
Iannicelli
Miriam
M
Mancuso
Brunella
B
Rigoli
Luciana
L
Rozet
Jean-Michel
JM
Swistun
Dominika
D
Tolentino
Jerlyn
J
Dallapiccola
Bruno
B
Gleeson
Joseph G
JG
Valente
Enza Maria
EM
Zankl
A
A
Leventer
R
R
Grattan-Smith
P
P
Janecke
A
A
D'Hooghe
M
M
Sznajer
Y
Y
Van Coster
R
R
Demerleir
L
L
Dias
K
K
Moco
C
C
Moreira
A
A
Kim
C Ae
CA
Maegawa
G
G
Petkovic
D
D
Abdel-Salam
G M H
GM
Abdel-Aleem
A
A
Zaki
M S
MS
Marti
I
I
Quijano-Roy
S
S
Sigaudy
S
S
de Lonlay
P
P
Romano
S
S
Touraine
R
R
Koenig
M
M
Lagier-Tourenne
C
C
Messer
J
J
Collignon
P
P
Wolf
N
N
Philippi
H
H
Kitsiou Tzeli
S
S
Halldorsson
S
S
Johannsdottir
J
J
Ludvigsson
P
P
Phadke
S R
SR
Udani
V
V
Stuart
B
B
Magee
A
A
Lev
D
D
Michelson
M
M
Ben-Zeev
B
B
Fischetto
R
R
Benedicenti
F
F
Stanzial
F
F
Borgatti
R
R
Accorsi
P
P
Battaglia
S
S
Fazzi
E
E
Giordano
L
L
Pinelli
L
L
Boccone
L
L
Bigoni
S
S
Ferlini
A
A
Donati
M A
MA
Caridi
G
G
Divizia
M T
MT
Faravelli
F
F
Ghiggeri
G
G
Pessagno
A
A
Briguglio
M
M
Briuglia
S
S
Salpietro
C D
CD
Tortorella
G
G
Adami
A
A
Castorina
P
P
Lalatta
F
F
Marra
G
G
Riva
D
D
Scelsa
B
B
Spaccini
L
L
Uziel
G
G
Del Giudice
E
E
Laverda
A M
AM
Ludwig
K
K
Permunian
A
A
Suppiej
A
A
Signorini
S
S
Uggetti
C
C
Battini
R
R
Di Giacomo
M
M
Cilio
M R
MR
Di Sabato
M L
ML
Leuzzi
V
V
Parisi
P
P
Pollazzon
M
M
Silengo
M
M
De Vescovi
R
R
Greco
D
D
Romano
C
C
Cazzagon
M
M
Simonati
A
A
Al-Tawari
A A
AA
Bastaki
L
L
Mégarbané
A
A
Sabolic Avramovska
V
V
de Jong
M M
MM
Stromme
P
P
Koul
R
R
Rajab
A
A
Azam
M
M
Barbot
C
C
Martorell Sampol
L
L
Rodriguez
B
B
Pascual-Castroviejo
I
I
Teber
S
S
Anlar
B
B
Comu
S
S
Karaca
E
E
Kayserili
H
H
Yüksel
A
A
Akcakus
M
M
Al Gazali
L
L
Sztriha
L
L
Nicholl
D
D
Woods
C G
CG
Bennett
C
C
Hurst
J
J
Sheridan
E
E
Barnicoat
A
A
Hennekam
R
R
Lees
M
M
Blair
E
E
Bernes
S
S
Sanchez
H
H
Clark
A E
AE
DeMarco
E
E
Donahue
C
C
Sherr
E
E
Hahn
J
J
Sanger
T D
TD
Gallager
T E
TE
Dobyns
W B
WB
Daugherty
C
C
Krishnamoorthy
K S
KS
Sarco
D
D
Walsh
C A
CA
McKanna
T
T
Milisa
J
J
Chung
W K
WK
De Vivo
D C
DC
Raynes
H
H
Schubert
R
R
Seward
A
A
Brooks
D G
DG
Goldstein
A
A
Caldwell
J
J
Finsecke
E
E
Maria
B L
BL
Holden
K
K
Cruse
R P
RP
Swoboda
K J
KJ
Viskochil
D
D
D000015:Abnormalities, Multiple / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D018797:Cell Cycle Proteins; D002923:Cilia / Q000235:genetics / Q000473:pathology; D003598:Cytoskeletal Proteins; D004252:DNA Mutational Analysis; D005260:Female; D005333:Fetus / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D005820:Genetic Testing; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D013577:Syndrome
D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C493903:Cep290 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger