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Novel 4.18 Mb deletion resulting in 2q37 microdeletion syndrome combined with PTH resistance found in one Chinese patient

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Abstract

Background

2q37 microdeletion syndrome is a rare clinical condition characterized by a series of physical abnormalities. Its Albright hereditary osteodystrophy (AHO)-like manifestations and possible complication of biochemical abnormalities indicating PTH resistance greatly increased the likelihood of misdiagnosis with classic pseudohypoparathyroidism (PHP) caused by GNAS mutation or methylation alteration, even though there have only been six reports of such clinical occasions.

Purpose

to investigate the underlying genetic defect in a male patient presenting hypocalcemia, elevated PTH and with a history of kyphosis.

Method

clinical information was collected, while the DNA was extracted from peripheral blood and subjected to methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and exome sequencing.

Result

Physical characteristics featuring short stature, obesity, round face, short neck, and shortened 4th metacarpal and laboratory examination of the patient suggested the presence of PTH resistance, which is indicative of PHP. MS-MLPA did not reveal methylation alterations or deletions of GNAS, STX16 or other monogenetic alterations responsible for iPPSDs, but WES revealed a long-range deletion of approximately 4.18 Mb of the 2q37 region that spanned AGAP1 to NDUFA10, indicating that the patient had 2q37 microdeletion syndrome with PTH resistance.

Conclusion

After undergoing MS-MLPA and exome sequencing, a novel deletion spanning 4.18 Mb on the 2q37 region was identified in one male patient, clarifying the diagnosis of 2q37 microdeletion syndrome with PTH resistance. The new genetic discovery added to our understanding of the molecular defects that cause inactivating PTH/PTH-related protein signaling disorders (iPPSDs).

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Data availability

The data that supported the findings of this study are currently unavailable according to local ethics regulations, though data is available from the corresponding author upon reasonable request.

References

  1. E.S. Doherty, F.L. Lacbawan 2q37, Microdeletion Syndrome. In: Adam M., Mirzaa G., Pagon R., Al E., editors. GeneReviews. Seattle, WA: University of Washington; 2007.

  2. A. Arefzadeh, P. Khalighinejad, B. Ataeinia, P. Parvar, Brachydactyly mental retardation syndrome with growth hormone deficiency. Endocrinol. Diabetes Metab. Case Rep. 2018, 18–0068 (2018)

    PubMed  PubMed Central  Google Scholar 

  3. F.M. Elli, L. Desanctis, M.A. Maffini, P. Bordogna, D. Tessaris, A. Pirelli et al. Association of GNAS imprinting defects and deletions of chromosome 2 in two patients: Clues explaining phenotypic heterogeneity in pseudohypoparathyroidism type 1B/iPPSD3. Clin. Epigeneti. 11, 1–8 (2019)

    Google Scholar 

  4. F.M. Elli, L. de Sanctis, B. Madeo, M.A. Maffini, P. Bordogna, A. Pirelli et al. 2q37 deletions in patients with an albright hereditary osteodystrophy phenotype and PTH resistance. Front. Endocrinol. 10, 1–7 (2019)

    Article  Google Scholar 

  5. M.M. Power, R.S. James, J.C.K. Barber, A.M. Fisher, P.J. Wood, B.A. Leatherdale et al. RDCI, the vasoactive intestinal peptide receptor: A candidate gene for the features of Albright hereditary osteodystrophy associated with deletion of 2q37. J. Med. Genet. 34, 287–290 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Y. Yang, X. Chu, M. Nie, A. Song, Y. Jiang, M. Li et al. A novel long-range deletion spanning STX16 and NPEPL1 causing imprinting defects of the GNAS locus discovered in a patient with autosomal-dominant pseudohypoparathyroidism type 1B. Endocrine 69, 212–219 (2020)

    Article  CAS  PubMed  Google Scholar 

  7. G. Mantovani, M. Bastepe, D. Monk, L. de Sanctis, S. Thiele, A. Usardi et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international Consensus Statement. Nat. Rev. Endocrinol. 14, 476–500 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. G. Mantovani, M. Bastepe, D. Monk, L. De Sanctis, S. Thiele, S.F. Ahmed et al. Recommendations for diagnosis and treatment of pseudohypoparathyroidism and related disorders: an updated practical tool for physicians and patients. Horm. Res. Paediatr. 93, 182–196 (2020)

    Article  CAS  PubMed  Google Scholar 

  9. J.L. Gorski, B.A. Cox, M. Kyine, W. Uhlmann, T.W. Glover, Terminal deletion of the long arm of chromosome 2 in a premature infant with karyotype: 46,XY,del(2)(q37). Am. J. Med. Genet. 32, 350–352 (1989)

    Article  CAS  PubMed  Google Scholar 

  10. B. Morris, C. Etoubleau, S. Bourthoumieu, S. Reynaud-Perrine, C. Laroche, A. Lebbar et al. Dose dependent expression of HDAC4 causes variable expressivity in a novel inherited case of brachydactyly mental retardation syndrome. Am. J. Med. Genet. Part A 158A, 2015–2020 (2012)

    Article  PubMed  Google Scholar 

  11. N. Chassaing, P. De Mas, M. Tauber, M.C. Vincent, S. Julia, G. Bourrouillou et al. Molecular characterization of a cryptic 2q37 deletion in a patient with Albright hereditary osteodystrophy-like phenotype. Am. J. Med. Genet. Part A 128A, 410–413 (2004)

    Article  CAS  PubMed  Google Scholar 

  12. A.E. Shrimpton, B.R. Braddock, L.L. Thomson, C.K. Stein, J.J. Hoo, Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy-like phenotype. Clin. Genet. 66, 537–544 (2004)

    Article  CAS  PubMed  Google Scholar 

  13. B. Felder, B. Radlwimmer, A. Benner, A. Mincheva, G. Tödt, K.S. Beyer et al. FARP2, HDLBP and PASK are downregulated in a patient with autism and 2q37.3 deletion syndrome. Am. J. Med. Genet. Part A 149A, 952–959 (2009)

    Article  PubMed  Google Scholar 

  14. S.R. Williams, M.A. Aldred, V.M. Der Kaloustian, F. Halal, G. Gowans, D.R. McLeod et al. Haploinsufficiency of HDAC4 causes brachydactyly mental retardation syndrome, with brachydactyly type E, developmental delays, and behavioral problems. Am. J. Hum. Genet. 87, 219–228 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Y. Yang, J. Jing, J. Wang, Y. Li, Q. Shi, A case of prenatal diagnosis of 2q37 deletion syndrome. Chin. J. Med. Genet. 39, 221 (2022)

    Google Scholar 

  16. P. Hu, L. Yang, G. Zhan, D. Ma, G. Huang, W. Zhou, Copy number variations (CNVs) analysis in one neonatal with 2q37deletion and 4q partial trisomy syndrome. Fudan University. J. Med. Sci. 41, 183–190 (2014)

    Google Scholar 

  17. Y. Zeng, P. Xu, A case of 45,XX,-22,der(2)t(2;22)(q37;q11.2). Chin. J. Med. Genet. 28, 707 (2011)

    Google Scholar 

  18. L. Qin, S.Chen, Q. Liu, A case of 46, XX, t(1;2)(1p32;2q37) with miscarriage. Chin. J. Med. Genet. 13, 49 (1996)

    Google Scholar 

  19. Q. Chen, Y. Lin, X. Li, A rare case of 46,xy,-2,+der(2),t(2;20)(q37;p11)pat full-term newborn. Guangdong Med. J. 11, 31 (1990)

    Google Scholar 

  20. A. Zeng, Q. Chen, A case of 46,XY,t(1;2)(q12;q37) with severe oligospermia. Chin. J. Med. Gene. 26, 652 (2009)

    Google Scholar 

  21. A. Liu, P. Hu, D. Ma, J. Zhou, L. Meng, Y. Sun et al. Application of array-based comparative genomic hybridization in molecular diagnosis for a boy suffered from developmental delay, mental retardation with 2q37 microdeletion. Chin. J. Clin. Lab. Sci. 30, 259–262 (2012)

    CAS  Google Scholar 

  22. Q. Geng, J. Xie, W. Wu, F. Luo, W. Chen, One case of 2q37 deletion syndrome: clinical and genetic diagnosis. Chin. J. Pediatr. 51, 934–937 (2013)

    Google Scholar 

  23. J. Qian, S. Chen, C. Li, X. Fan, J. Luo, P. Huang, Clinical and microarray analysis of two 2q37 deletion syndrome cases. Chin. J. Pract. Pediatr. 30, 475–477 (2015)

    Google Scholar 

  24. Zeng J., Huang M., Zhang X., Lian X., Lin J., Lan F., et al. Genetic diagnosis of a case of 2q37 microdeletion syndrome. Compilation of Abstracts of Papers of the 10th National Congress of Genetics of China and Symposium. 2018. 119.

  25. H. Huang, F. Lan, H. Peng, W. Huang, J. Lu, C. Yao, Detection of 2q37 deletion syndrome using chromosomal microarray technology. Chin. J. Prenat. Diagn. 11, 67–69 (2019)

    Google Scholar 

  26. H. Lin, L. Bai, Y. Yue, X. Xi, W. Chen, C. Zhou, Diagnosis of a case of 2q37 deletion syndrome by whole exome sequencing combined with whole genome low-coverage sequencing method. Chin. J. Med. Genet. 37, 883–886 (2020)

    Google Scholar 

  27. Y. Chen, Z. Feng, X. Zhang, F. Yi, M. Li, A case of 2q37 deletion combined with 4q partial trisomy and clinical gene chip analysis. Chin. J. N. Clin. Med. 14, 90–93 (2021)

    Google Scholar 

  28. Z. Zhang, S. Zhao, J. Song, R. Li, Y. Zhang, D. Li, Clinical and genetic analysis of a child with 2q37 deletion syndrome resulting from a translocation involving chromosome satellite. Chin. J. Med. Genet. 38, 373–375 (2021)

    Google Scholar 

  29. T.N. Le, S.R. Williams, J.T. Alaimo, S.H. Elsea, Genotype and phenotype correlation in 103 individuals with 2q37 deletion syndrome reveals incomplete penetrance and supports HDAC4 as the primary genetic contributor. Am. J. Med. Genet. A 179, 782–791 (2019)

    Article  CAS  PubMed  Google Scholar 

  30. R.J. Pignolo, M. Xu, E. Russell, A. Richardson, J. Kaplan, P.C. Billings et al. Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. J. Bone Miner. Res. 26, 2647–2655 (2011)

    Article  CAS  PubMed  Google Scholar 

  31. J.B. Regard, D. Malhotra, J. Gvozdenovic-Jeremic, M. Josey, M. Chen, L.S. Weinstein et al. Activation of hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat. Med. 19, 1505–1512 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. R.B. Vega, K. Matsuda, J. Oh, A.C. Barbosa, X. Yang, E. Meadows et al. Histone deacetylase 4 controls chondrocyte hypertrophy during skeletogenesis. Cell 119, 555–566 (2004)

    Article  CAS  PubMed  Google Scholar 

  33. B.T. Kile, D. Metcalf, S. Mifsud, L. DiRago, N.A. Nicola, D.J. Hilton et al. Functional analysis of Asb-1 using genetic modification in mice. Mol. Cell. Biol. 21, 6189–6197 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. T.E. Danciu, Y. Li, A. Koh, G. Xiao, L.K. McCauley, R.T. Franceschi, The basic helix loop helix transcription factor twist1 is a novel regulator of ATF4 in osteoblasts. J. Cell. Biochem. 113, 70–79 (2012)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. P. Bialek, B. Kern, X. Yang, M. Schrock, D. Sosic, N. Hong et al. A twist code determines the onset of osteoblast differentiation. Dev. Cell 6, 423–435 (2004)

    Article  CAS  PubMed  Google Scholar 

  36. D. Molina-Granada, E. González-Vioque, M.G. Dibley, R. Cabrera-Pérez, A. Vallbona-Garcia, J. Torres-Torronteras et al. Most mitochondrial dGTP is tightly bound to respiratory complex I through the NDUFA10 subunit. Commun. Biol. 5, 620 (2022)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. J.P. Bilezikian, M.L. Brandi, N.E. Cusano, M. Mannstadt, L. Rejnmark, R. Rizzoli et al. Management of Hypoparathyroidism: Present and future. J. Clin. Endocrinol. Metab. 101, 2313–2324 (2016)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. E.O. Gosmanova, O. Ayodele, K. Chen, E.E. Cook, F. Mu, J.A. Young et al. Association of calcium and phosphate levels with incident chronic kidney disease in patients with hypoparathyroidism: a retrospective case-control study. Int. J. Endocrinol. 2022, 6078881 (2022)

    Article  PubMed  PubMed Central  Google Scholar 

  39. R. Goswami, R. Sharma, V. Sreenivas, N. Gupta, A. Ganapathy, S. Das, Prevalence and progression of basal ganglia calcification and its pathogenic mechanism in patients with idiopathic hypoparathyroidism. Clin. Endocrinol. 77, 200–206 (2012)

    Article  CAS  Google Scholar 

  40. S. Ouyang, L. Gao, L. Zhang, Y. Zheng, W. Cao, G. Feng et al. A new locus in chromosome 2q37-qter is associated with posterior polar cataract. Graefe’s Arch. Clin. Exp. Ophthalmol. 250, 907–913 (2012)

    Article  CAS  Google Scholar 

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Funding

Funding

This study was funded by the National Natural Science Foundation of China (No.81873641, 82070817).

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Authors and Affiliations

  1. Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China

    Yi Yang, Siqi Jiang, Min Nie, Yan Jiang, Mei Li, Weibo Xia, Xiaoping Xing, Ou Wang & Hui Pan

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  1. Yi Yang
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Correspondence to Ou Wang or Hui Pan.

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Yang, Y., Jiang, S., Nie, M. et al. Novel 4.18 Mb deletion resulting in 2q37 microdeletion syndrome combined with PTH resistance found in one Chinese patient. Endocrine (2024). https://doi.org/10.1007/s12020-024-03740-4

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