PMID- 38544803
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240329
IS  - 1664-8021 (Print)
IS  - 1664-8021 (Electronic)
IS  - 1664-8021 (Linking)
VI  - 15
DP  - 2024
TI  - Long-read sequencing reveals chromothripsis in a molecularly unsolved case of 
      Cornelia de Lange syndrome.
PG  - 1358334
LID - 10.3389/fgene.2024.1358334 [doi]
LID - 1358334
AB  - Thanks to a long-read sequencing (LRS) approach, in this study, we have reported 
      a molecularly solved case of a proband with a clinical diagnosis of Cornelia de 
      Lange syndrome (CDLS), which is a multisystemic disorder whose causative 
      molecular defects involve cohesin complex genes, with NIPBL located at 5p13.2 
      accounting for approximately 50%-60% of CDLS cases. The first-tier tests revealed 
      an abnormal karyotype 46,XY,t(5;15)(p13;q25)dn and a preserved NIPBL sequencing. 
      Copy number variants (CNVs) at the translocation breakpoints, in disease genes, 
      or in probably pathogenic loci were excluded by a-CGH analysis. Through 
      fluorescence in situ hybridization (FISH) analysis on derivative chromosome 5, 
      the breakpoint was relocated 3 Mb far from NIPBL 5'UTR, which seemed fully 
      maintained as FISH-probe mapping to the gene showed no split signals. Moreover, 
      tri-color FISH revealed an apparently balanced paracentric inversion including 
      NIPBL on derivative 5. Based on the strong clinical suspicion, we evaluated the 
      NIPBL transcript by RT-qPCR that revealed a normal amount of transcript till exon 
      22 and a halved amount of the transcript from exon 23 to 3'UTR, indicating the 
      expression of a truncated transcript probably leading to a defective protein. 
      Despite RT-qPCR confirmed the patient's CDLS clinical diagnosis, the molecular 
      mechanism underlying this event remained to be an unsolved challenge for years. 
      The LRS approach with nanopore technologies was able to fill the gap in this 
      complex scenario and highlighted a chromothripsis event marked out at 5p13.2 by 
      36 breaks clustered in a 7.3-Mb region. The NIPBL gene was disrupted by 16 breaks 
      and the resulting fragments were relocated in different positions and 
      orientations. LRS confirmed the previous findings, and it has been proven to be 
      crucial to define the complex chromosomal rearrangement in this patient which 
      escaped current diagnostic investigations. Its application in the clinical 
      practice will contribute to solve the unsolved.
CI  - Copyright (c) 2024 Bestetti, Crippa, Sironi, Bellini, Tumiatti, Ballabio, Ceriotti, 
      Memo, Iascone, Larizza and Finelli.
FAU - Bestetti, Ilaria
AU  - Bestetti I
AD  - SC Patologia Clinica, SS Laboratorio Genetica Medica, Fondazione IRCCS Ca' Granda 
      Ospedale Maggiore Policlinico, Milano, Italy.
FAU - Crippa, Milena
AU  - Crippa M
AD  - Laboratorio Sperimentale di Ricerche di Citogenetica Medica e Genetica 
      Molecolare, IRCCS Istituto Auxologico Italiano, Milano, Italy.
FAU - Sironi, Alessandra
AU  - Sironi A
AD  - Laboratorio Sperimentale di Ricerche di Citogenetica Medica e Genetica 
      Molecolare, IRCCS Istituto Auxologico Italiano, Milano, Italy.
FAU - Bellini, Matteo
AU  - Bellini M
AD  - Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy.
FAU - Tumiatti, Francesca
AU  - Tumiatti F
AD  - SC Patologia Clinica, SS Laboratorio Genetica Medica, Fondazione IRCCS Ca' Granda 
      Ospedale Maggiore Policlinico, Milano, Italy.
FAU - Ballabio, Sara
AU  - Ballabio S
AD  - SC Patologia Clinica, SS Laboratorio Genetica Medica, Fondazione IRCCS Ca' Granda 
      Ospedale Maggiore Policlinico, Milano, Italy.
FAU - Ceriotti, Ferruccio
AU  - Ceriotti F
AD  - SC Patologia Clinica, SS Laboratorio Genetica Medica, Fondazione IRCCS Ca' Granda 
      Ospedale Maggiore Policlinico, Milano, Italy.
FAU - Memo, Luigi
AU  - Memo L
AD  - SC Genetica Medica, IRCCS Burlo Garofolo, Trieste, Italy.
FAU - Iascone, Maria
AU  - Iascone M
AD  - Laboratorio di Genetica Medica, ASST Papa Giovanni XXIII, Bergamo, Italy.
FAU - Larizza, Lidia
AU  - Larizza L
AD  - Laboratorio Sperimentale di Ricerche di Citogenetica Medica e Genetica 
      Molecolare, IRCCS Istituto Auxologico Italiano, Milano, Italy.
FAU - Finelli, Palma
AU  - Finelli P
AD  - SC Patologia Clinica, SS Laboratorio Genetica Medica, Fondazione IRCCS Ca' Granda 
      Ospedale Maggiore Policlinico, Milano, Italy.
AD  - Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Universita degli 
      Studi di Milano, Milano, Italy.
LA  - eng
PT  - Journal Article
DEP - 20240313
PL  - Switzerland
TA  - Front Genet
JT  - Frontiers in genetics
JID - 101560621
PMC - PMC10965544
OTO - NOTNLM
OT  - Cornelia de Lange syndrome
OT  - NIPBL
OT  - RT-qPCR
OT  - bkps mapping
OT  - chromothripsis
OT  - complex chromosomal rearrangement
OT  - long-read sequencing
OT  - translocation
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest. The author(s) declared that they were an editorial board 
      member of Frontiers, at the time of submission. This had no impact on the peer 
      review process and the final decision.
EDAT- 2024/03/28 06:45
MHDA- 2024/03/28 06:46
PMCR- 2024/03/13
CRDT- 2024/03/28 03:55
PHST- 2023/12/19 00:00 [received]
PHST- 2024/02/15 00:00 [accepted]
PHST- 2024/03/28 06:46 [medline]
PHST- 2024/03/28 06:45 [pubmed]
PHST- 2024/03/28 03:55 [entrez]
PHST- 2024/03/13 00:00 [pmc-release]
AID - 1358334 [pii]
AID - 10.3389/fgene.2024.1358334 [doi]
PST - epublish
SO  - Front Genet. 2024 Mar 13;15:1358334. doi: 10.3389/fgene.2024.1358334. eCollection 
      2024.