Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes SMC1A, SMC3, RAD21 or their regulators NIPBL and HDAC8 have been identified in CdLS as well as somatic mutations in myeloid disorders. We describe the first case of a paediatric patient with CdLS with B-cell precursor Acute Lymphoblastic Leukaemia (ALL). The patient did not show any unusual cytogenetic abnormality, and he was enrolled into the high risk arm of AIEOP-BFM ALL2009 protocol because of slow early response, but 3 years after discontinuation, he experienced an ALL relapse. We identified a heterozygous mutation in exon 46 of NIPBL, causing frameshift and a premature stop codon (RNA-Targeted Next generation Sequencing Analysis). The analysis of the family indicated a de novo origin of this previously not reported deleterious variant. As for somatic cohesin mutations in acute myeloid leukaemia, also this ALL case was not affected by aneuploidy, thus suggesting a major impact of the non-canonical role of NIPBL in gene regulation. A potential biological role of NIPBL in leukaemia has still to be dissected.
- molecular genetics
- molecular oncology
- paediatric haematology
- paediatric pathology
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GF and VM contributed equally.
Handling editor Mary Frances McMullin.
Contributors Conception and design of the article by GF, VM, AS and GC. GF, VM, AG, SR, CS and MG performed experiments. GF, VM, AG and VB analysed data. GF and VM analysed data and assembled figures. GF, VM, CR, CC, AB, AS and GC actively analysed and interpreted findings. GF, VM, AS and GC wrote the manuscript. All authors read, edited and approved the final manuscript.
Funding This work has been supported by Fondazione Cariplo (grant no. 2015-0783 to VM), by the Associazione Italiana per la Ricerca sul Cancro (AIRC IG2015 grant no. 17593 and IG2018 grant no. 21999 to GC; IG2017 grant no. 20564 to AB; fellowship 2018 no. 22620 to AG), by the fellowship program ‘PhD talent 2017’ to AG and by DIMET PhD program University of Milano-Bicocca to CS.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.