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Screening of patients born small for gestational age with the Silver-Russell syndrome phenotype for DLK1 variants


Silver–Russell syndrome (SRS) is a rare imprinting disorder associated with prenatal and postnatal growth retardation. Loss of methylation (LOM) on chromosome 11p15 is observed in 40 to 60% of patients and maternal uniparental disomy (mUPD) for chromosome 7 (upd(7)mat) in ~5 to 10%. Patients with LOM or mUPD 14q32 can present clinically as SRS. Delta like non-canonical Notch ligand 1 (DLK1) is one of the imprinted genes expressed from chromosome 14q32. Dlk1-null mice display fetal growth restriction (FGR) but no genetic defects of DLK1 have been described in human patients born small for gestational age (SGA). We screened a cohort of SGA patients with a SRS phenotype for DLK1 variants using a next-generation sequencing (NGS) approach to search for new molecular defects responsible for SRS. Patients born SGA with a clinical suspicion of SRS and normal methylation by molecular testing at the 11p15 or 14q32 loci and upd(7)mat were screened for DLK1 variants using targeted NGS. Among 132 patients, only two rare variants of DLK1 were identified (NM_003836.6:c.103 G > C (p.(Gly35Arg) and NM_003836.6: c.194 A > G p.(His65Arg)). Both variants were inherited from the mother of the patients, which does not favor a role in pathogenicity, as the mono-allelic expression of DLK1 is from the paternal-inherited allele. We did not identify any pathogenic variants in DLK1 in a large cohort of SGA patients with a SRS phenotype. DLK1 variants are not a common cause of SGA.

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Fig. 1: Schematic representation of the imprinted domain of the 14q32 region.
Fig. 2: Intrafamilial segregation of variants.


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We thank the patients, their families and physicians, and the « Association Française des Familles ayant un enfant atteint du Syndrome Silver-Russell ou ne´ Petit pour l’âge Gestationnel (AFIF/PAG) ». We thank Cristina DAS NEVES and Nathalie THIBAUD for their contribution of this work.

Author contributions

A.P.: conception of the work, analysis and interpretation of the data, drafting of the manuscript, and final approval of the published version. M.-L.S., D.M., E.G., F.B., and I.N.: conception of the work, analysis and interpretation of the data, critical revision of the work for important intellectual content, and final approval of the published version. M.L.J.F.: Acquisition of the data and final approval of the published version.


This study received collaborative grant funding from the Agence Nationale de la Recherche (project “IMP-REGULOME”, ANR-18-CE12-0022-02).

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Correspondence to Irène Netchine.

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The authors declare no competing interests.

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Written informed consent for participation was received from all patients or parents, in accordance with national ethics rules (Assistance Publique–Hôpitaux de Paris authorization no. 681).

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Pham, A., Sobrier, ML., Giabicani, E. et al. Screening of patients born small for gestational age with the Silver-Russell syndrome phenotype for DLK1 variants. Eur J Hum Genet 29, 1756–1761 (2021).

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