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

Abstract

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.

References

  1. 1.

    Gaccioli F, ILMH Aye, Sovio U, Charnock-Jones DS, GCS Smith. Screening for fetal growth restriction using fetal biometry combined with maternal biomarkers. Am J Obstet Gynecol. 2018;218:S725–37.

    Article  Google Scholar 

  2. 2.

    Giabicani E, Pham A, Brioude F, Mitanchez D, Netchine I. Diagnosis and management of postnatal fetal growth restriction. Best Pr Res Clin Endocrinol Metab. 2018;32(Aug):523–34.

    Article  Google Scholar 

  3. 3.

    Wakeling EL, Brioude F, Lokulo-Sodipe O, O’Connell SM, Salem J, Bliek J, et al. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13:105–24.

    CAS  Article  Google Scholar 

  4. 4.

    Azzi S, Salem J, Thibaud N, Chantot-Bastaraud S, Lieber E, Netchine I, et al. A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome. J Med Genet. 2015;52(Jul):446–53.

    CAS  Article  Google Scholar 

  5. 5.

    Netchine I, Rossignol S, Dufourg M-N, Azzi S, Rousseau A, Perin L, et al. 11p15 imprinting center region 1 loss of methylation is a common and specific cause of typical Russell-Silver syndrome: clinical scoring system and epigenetic-phenotypic correlations. J Clin Endocrinol Metab. 2007;92:3148–54.

    CAS  Article  Google Scholar 

  6. 6.

    Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, et al. Epimutation of the telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet. 2005;37:1003–7.

    CAS  Article  Google Scholar 

  7. 7.

    Kotzot D, Schmitt S, Bernasconi F, Robinson WP, Lurie IW, Ilyina H, et al. Uniparental disomy 7 in Silver-Russell syndrome and primordial growth retardation. Hum Mol Genet. 1995;4:583–7.

    CAS  Article  Google Scholar 

  8. 8.

    Begemann M, Zirn B, Santen G, Wirthgen E, Soellner L, Büttel H-M, et al. Paternally inherited IGF2 mutation and growth restriction. N Engl J Med. 2015;373:349–56.

    CAS  Article  Google Scholar 

  9. 9.

    Brioude F, Oliver-Petit I, Blaise A, Praz F, Rossignol S, Le Jule M, et al. CDKN1C mutation affecting the PCNA-binding domain as a cause of familial Russell Silver syndrome. J Med Genet. 2013;50:823–30.

    CAS  Article  Google Scholar 

  10. 10.

    Abi Habib W, Brioude F, Edouard T, Bennett JT, Lienhardt-Roussie A, Tixier F, et al. Genetic disruption of the oncogenic HMGA2-PLAG1-IGF2 pathway causes fetal growth restriction. Genet Med. 2018;20:250–8.

    CAS  Article  Google Scholar 

  11. 11.

    De Crescenzo A, Citro V, Freschi A, Sparago A, Palumbo O, Cubellis MV, et al. A splicing mutation of the HMGA2 gene is associated with Silver-Russell syndrome phenotype. J Hum Genet. 2015;60:287–93.

    Article  Google Scholar 

  12. 12.

    Akawi NA, Ali BR, Hamamy H, Al-Hadidy A, Al-Gazali L. Is autosomal recessive Silver-Russel syndrome a separate entity or is it part of the 3-M syndrome spectrum? Am J Med Genet A. 2011;155A:1236–45.

    Article  Google Scholar 

  13. 13.

    Inoue T, Nakamura A, Iwahashi-Odano M, Tanase-Nakao K, Matsubara K, Nishioka J, et al. Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients. Clin Epigenetics. 2020;12:86.

    CAS  Article  Google Scholar 

  14. 14.

    Meyer R, Begemann M, Hübner CT, Dey D, Kuechler A, Elgizouli M, et al. One test for all: whole exome sequencing significantly improves the diagnostic yield in growth retarded patients referred for molecular testing for Silver-Russell syndrome. Orphanet J Rare Dis. 2021;16:42.

    Article  Google Scholar 

  15. 15.

    Meyer R, Soellner L, Begemann M, Dicks S, Fekete G, Rahner N, et al. Targeted next generation sequencing approach in patients referred for Silver-Russell syndrome testing increases the mutation detection rate and provides decisive information for clinical management. J Pediatr. 2017;187:206–212.e1.

    CAS  Article  Google Scholar 

  16. 16.

    Neuheuser L, Meyer R, Begemann M, Elbracht M, Eggermann T. Next generation sequencing and imprinting disorders: current applications and future perspectives: lessons from Silver-Russell syndrome. Mol Cell Probes. 2019;44:1–7.

    CAS  Article  Google Scholar 

  17. 17.

    Temple IK, Cockwell A, Hassold T, Pettay D, Jacobs P. Maternal uniparental disomy for chromosome 14. J Med Genet. 1991;28:511–4.

    CAS  Article  Google Scholar 

  18. 18.

    Traustadóttir GÁ, Lagoni LV, Ankerstjerne LBS, Bisgaard HC, Jensen CH, Andersen DC. The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms. Cytokine Growth Factor Rev. 2019;46:17–27.

    Article  Google Scholar 

  19. 19.

    Geoffron S, Abi Habib W, Chantot-Bastaraud S, Dubern B, Steunou V, Azzi S, et al. Chromosome 14q32.2 imprinted region disruption as an alternative molecular diagnosis of Silver-Russell syndrome. J Clin Endocrinol Metab. 2018;103:2436–46.

    Article  Google Scholar 

  20. 20.

    Kagami M, Nagasaki K, Kosaki R, Horikawa R, Naiki Y, Saitoh S, et al. Temple syndrome: comprehensive molecular and clinical findings in 32 Japanese patients. Genet Med. 2017;19:1356–66.

    Article  Google Scholar 

  21. 21.

    Kagami M, Mizuno S, Matsubara K, Nakabayashi K, Sano S, Fuke T, et al. Epimutations of the IG-DMR and the MEG3-DMR at the 14q32.2 imprinted region in two patients with Silver-Russell Syndrome-compatible phenotype. Eur J Hum Genet. 2015;23:1062–7.

    CAS  Article  Google Scholar 

  22. 22.

    Poole RL, Docherty LE, Al Sayegh A, Caliebe A, Turner C, Baple E, et al. Targeted methylation testing of a patient cohort broadens the epigenetic and clinical description of imprinting disorders. Am J Med Genet A. 2013;161:2174–82.

    Article  Google Scholar 

  23. 23.

    Moon YS, Smas CM, Lee K, Villena JA, Kim K-H, Yun EJ, et al. Mice lacking paternally expressed Pref-1/Dlk1 display growth retardation and accelerated adiposity. Mol Cell Biol. 2002;22:5585–92.

    CAS  Article  Google Scholar 

  24. 24.

    Dauber A, Cunha-Silva M, Macedo DB, Brito VN, Abreu AP, Roberts SA, et al. Paternally inherited DLK1 deletion associated with familial central precocious puberty. J Clin Endocrinol Metab. 2017;102:1557–67.

    Article  Google Scholar 

  25. 25.

    Gomes LG, Cunha-Silva M, Crespo RP, Ramos CO, Montenegro LR, Canton A, et al. DLK1 is a novel link between reproduction and metabolism. J Clin Endocrinol Metab. 2019;104:2112–20.

    Article  Google Scholar 

  26. 26.

    Usher R, McLean F. Intrauterine growth of live-born Caucasian infants at sea level: standards obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr. 1969;74:901–10.

    CAS  Article  Google Scholar 

  27. 27.

    Sempé (M). — Auxologie, méthode et séquences. Bulletins et Mémoires de la Société d’Anthropologie de Paris. 1980;7:77–77.

  28. 28.

    Abi Habib W, Brioude F, Azzi S, Rossignol S, Linglart A, Sobrier M-L, et al. Transcriptional profiling at the DLK1/MEG3 domain explains clinical overlap between imprinting disorders. Sci Adv. 2019;5:eaau9425.

    Article  Google Scholar 

  29. 29.

    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.

    CAS  Article  Google Scholar 

  30. 30.

    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.

    CAS  Article  Google Scholar 

  31. 31.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  Google Scholar 

  32. 32.

    Montenegro L, Labarta JI, Piovesan M, Canton APM, Corripio R, Soriano-Guillén L, et al. Novel genetic and biochemical findings of DLK1 in children with central precocious puberty: a Brazilian-Spanish study. J Clin Endocrinol Metab. 2020;105:dgaa461.

  33. 33.

    Cheung LYM, Rizzoti K, Lovell-Badge R, Le Tissier PR. Pituitary phenotypes of mice lacking the notch signalling ligand delta-like 1 homologue. J Neuroendocrinol. 2013;25:391–401.

    CAS  Article  Google Scholar 

  34. 34.

    Charalambous M, Da Rocha ST, Radford EJ, Medina-Gomez G, Curran S, Pinnock SB, et al. DLK1/PREF1 regulates nutrient metabolism and protects from steatosis. Proc Natl Acad Sci USA. 2014;111:16088–93.

    CAS  Article  Google Scholar 

  35. 35.

    Appelbe OK, Yevtodiyenko A, Muniz-Talavera H, Schmidt JV. Conditional deletions refine the embryonic requirement for Dlk1. Mech Dev. 2013;130:143–59.

    CAS  Article  Google Scholar 

  36. 36.

    Cleaton MAM, Dent CL, Howard M, Corish JA, Gutteridge I, Sovio U, et al. Fetus-derived DLK1 is required for maternal metabolic adaptations to pregnancy and is associated with fetal growth restriction. Nat Genet. 2016;48:1473–80.

    CAS  Article  Google Scholar 

  37. 37.

    MacDonald TM, Walker SP, Hiscock R, Cannon P, Harper A, Murray E, et al. Circulating delta-like homolog 1 (DLK1) at 36 weeks is correlated with birthweight and is of placental origin. Placenta. 2020;91:24–30.

    CAS  Article  Google Scholar 

  38. 38.

    Howard M, Charalambous M. Molecular basis of imprinting disorders affecting chromosome 14: lessons from murine models. Reproduction. 2015;149:R237–249.

    CAS  Article  Google Scholar 

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Acknowledgements

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.

Funding

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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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). https://doi.org/10.1038/s41431-021-00927-5

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