Novel interstitial 2q12.3q13 microdeletion predisposes to developmental delay and behavioral problems


Microarray-based comparative genomic hybridization (aCGH) is being increasingly applied to delineate novel genomic disorders and related syndromes in patients with developmental delay. In this study, detailed clinical and cytogenetic data of three unrelated patients with interstitial 2q12.3q13 microdeletion were described and compared with thirteen 2q12.3q13 microdeletion patients, gathered from the medical literature and public databases. 60 K aCGH analysis revealed three overlapping 2q12.3q13 microdeletions measuring 1.88 Mb in patient 1, 1.25 Mb in patient 2, and 0.41 Mb in patient 3, respectively. Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative real-time PCR. Variable clinical features of 2q12.3q13 microdeletion including microcephaly, prenatal growth retardation, developmental delay, short stature, behavioral problems, learning difficulties, skeletal anomalies, congenital heart defects, and features of ectodermal dysplasia were observed. The boundaries and sizes of the 2q12.3q13 deletions in the sixteen patients were different, but an overlapping region of 249 kb in 2q12.3 was defined. The SRO (smallest region of overlap) encompasses four genes, including LIMS1, RANBP2, CCDC138, and EDAR. Among these genes, RANBP2 is a strong candidate gene for neurological phenotype and genetic susceptibility to viral infections. To our knowledge, this is the first published report of 2q12.3q13 microdeletion syndrome and our observations strongly suggest that these recurrent CNVs may be a novel risk factor for developmental delay with variable expressivity and incomplete penetrance.

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  1. 1.

    Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA et al (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86(5):749–764

    CAS  Article  Google Scholar 

  2. 2.

    Dittwald P, Gambin T, Szafranski P, Li J, Amato S, Divon MY, Rodriguez Rojas LX, Elton LE, Scott DA, Schaaf CP, Torres-Martinez W et al (2013) NARH-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits. Genome Res 23(9):1395–1409

    CAS  Article  Google Scholar 

  3. 3.

    Huynh MT, Tosca L, Petit F, Martinovic J, Proust A, Bouligand J, Amiel J, Azria E, Parisot F, Benoit V, Receveur A, Drévillon L, Tachdjian G, Brisset S (2018) First prenatal case of proximal 19p13.12 microdeletion syndrome: new insights and new delineation of the syndrome. Eur J Med Genet 61(6):322–328

    Article  Google Scholar 

  4. 4.

    Coe BP, Witherspoon K, Rosenfeld JA, van Bon BW, Vulto-van Silfhout AT, Bosco P et al (2014) Refining analyses of copy-number variation identifies specific genes associated with developmental delay. Nat Genet 46(10):1063–1071

    CAS  Article  Google Scholar 

  5. 5.

    Kaminsky BE, Kaul V, Paschall J, Church MD, Bunke B, Kunig D, Moreno-De-Luca D, Moreno-De-Luca A, Mulle GJ, Warren TS, Richard G, Compton GJ, Fuller EA, Gliem JT, Huang S, Collison NM, Beal JS, Ackley T, Pickering LD, Golden MD, Aston E, Whitby H, Shetty S, Rossi RM, Rudd KM, South TS, Brothman RA, Sanger GW, Lyer KR, Crolla AJ, Thorland CE, Aradhya S, Ledbetter HD, Martin LC (2011) An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med 13(9):777–784

    Article  Google Scholar 

  6. 6.

    Bock-Marquette I, Saxena A, White MD, DiMaio M, Srivastava D (2004) Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432(7016):466–472

    CAS  Article  Google Scholar 

  7. 7.

    Liang X, Sun Y, Schneider J, Ding JH, Cheng H, Ye M, Bhattacharya S, Rearden A, Evans S, Chen J (2007) Pinch1 is required for normal development of cranial and cardiac neural crest-derived structures. Circ Res 100(4):527–535

    CAS  Article  Google Scholar 

  8. 8.

    Prasad MS, Charney RM, Garcia-Castro M (2019) Specification and formation of the neural crest cells: perspectives on lineage segregation. Genesis 57(1):e23276

    Article  Google Scholar 

  9. 9.

    Meinl W, Donath C, Schneider H, Sommer Y, Glatt H (2008) SULT1C3, an orphan sequence of the human genome, encodes an enzyme activating various promutagens. Food Chem Toxicol 46(4):1249–1256

    CAS  Article  Google Scholar 

  10. 10.

    Liu Y, Chang X, Glessner J, Qu H, Tian L, Li D, Nguyen K, Sleiman MAP, Hakonarson H (2019) Association of rare recurrent copy number variants with congenital heart defects based on next-generation sequencing data from family trios. Front Genet 10:819.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Maarifi G, Fernandez J, Portilho MD, Boulay A, Dutrieux J, Oddos S, Butler-Browne G, Nisole S, Arhel JN (2018) RanBP2 regulates the anti-retroviral activity of TRIM5α by SUMOylation at a predicted phosphorylated SUMOylation motif. Commun Biol 1:193.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Wu X, Wu W, Pan W, Wu L, Liu K, Zhang HL (2015) Acute necrotizing encephalopathy: an underrecognized clinicoradiologic disorder. Mediators Inflamm.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Neilson ED, Adams DM, Orr MDC, Schelling KD, Eiben MR, Kerr SD, Anderson J, Bassuk GA, Bye MA et al (2009) Infection-triggered familial or recurrent cases of acute necrotizing of encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am J Hum Genet 84(1):44–51

    CAS  Article  Google Scholar 

  14. 14.

    Cho IK, Searle K, Webb M, Yi H, Ferreira AP (2012) Ranbp2 haploinsufficiency mediates distinct cellular and biochemical phenotypes in brain and retinal dopaminergic and glia cells elicited by the Parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Cell Mol Life Sci 69(20):3511–3527

    CAS  Article  Google Scholar 

  15. 15.

    Cho IK, Yoon D, Qiu S, Danziger Z, Grill MW, Wetsel CW, Ferreira AP (2017) Loss of Ranbp2 in motoneurons causes disruption of nucleocytoplasmic and chemokine signaling, proteostasis of hnRNPH3 and Mmp28, and development of amyotrophic lateral sclerosis-like syndromes. Dis Model Mech 10(5):559–579

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Griggs LB, Ladd S, Decker A, DuPont RB, Asamoah A, Srivastava KA (2009) Identification of ectodysplasin-A receptor gene deletion at 2q12.2 and a potential autosomal MR locus. Eur J Hum Genet 17(1):30–36

    CAS  Article  Google Scholar 

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We thank to the patients and their families for their kind cooperation.

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Correspondence to Minh-Tuan Huynh.

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Clinical information was obtained for patients 1, 2, and 3 following informed consent under a protocol approved by Nantes University Hospital.

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Informed consent for medical photographs was obtained for patients 1 and 3.

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Huynh, MT., Gérard, M., Ranguin, K. et al. Novel interstitial 2q12.3q13 microdeletion predisposes to developmental delay and behavioral problems. Neurogenetics 22, 195–206 (2021).

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  • Novel 2q12.3q13 microdeletion syndrome
  • Smallest region of overlap
  • Developmental delay
  • Behavioral problems
  • Susceptibility to viral infections
  • RANBP2