Acta Medica Iranica 2017. 55(10):650-654.

Kleefstra Syndrome: The First Case Report From Iran
Mehrdad Noruzinia, Mohammad Ahmadvand, Oranous Bashti, Ahmad Reza Salehi Chaleshtori


Kleefstra Syndrome is characterized by severe mental retardation, brachycephaly, microcephaly, epileptic seizures, distinct facial features, and infantile weak muscle tone and heart defects. Deletion of EHMT1 is the main player in 75% of cases. Because of blurriness in genotype-phenotype correlation through clinical and molecular features of both 9q34.3 microdeletion patients and those with an intragenic EHMT1 mutation in Kleefstra Syndrome, genetic characterization of patients with clinical symptoms of such spectrum is desirable. We report the first Kleefstra Syndrome patient in Iran characterized through genetic approaches. Our report could improve KS diagnosis in Iran and prepare PND and PGs options for involved families.


Kleefstra syndrome; Iran; EHMT1; Deletion

Full Text:



Harada N, Visser R, Dawson A, Fukamachi M, Iwakoshi M, Okamoto N, et al. A 1-Mb critical region in six patients with 9q34.3 terminal deletion syndrome. J Hum Genet 2004;49;440-4.

Iwakoshi M, Okamoto N, Harada N, Nakamura T, Yamamori S, Fujita H, et al. 9q34.3 deletion syndrome in three unrelated children. Am J Med Genet A 2004;126A:278-83.

Stewart DR, Huang A, Faravelli F, Anderlid BM, Medne L, Ciprero K, et al. Subtelomeric deletions of chromosome 9q: a novel microdeletion syndrome. Am J Med Genet A 2004;128A:340-51.

Neas KR, Smith JM, Chia N, Huseyin S, St Heaps L, Peters G, et al. Three patients with terminal deletions within the subtelomeric region of chromosome 9q. Am J Med Genet A 2005;132A:425-30.

Verhoeven WM, Egger JI, Vermeulen K, van de Warrenburg BP, Kleefstra T. Kleefstra syndrome in three adult patients: further delineation of the behavioral and neurological phenotype shows aspects of a neurodegenerative course. Am J Med Genet A 2011;155A:2409-15.

Rosello M, Monfort S, Orellana C, Oltra S, Martinez Garay I, Martinez F. Subtelomeric deletion 9qter: definition of the syndrome and parental origin in 2 patients. Med Clin 2007;128:419-21.

Kleefstra T, van Zelst-Stams WA, Nillesen WM, Cormier-Daire V, Houge G, Foulds N, et al. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 2009;46:598-606.

Willemsen MH, Vulto-van Silfhout AT, Nillesen WM, Wissink-Lindhout WM, van Bokhoven H, Philip N, et al.Update on Kleefstra SyndromeMolSyndromol2012;2:202-12.

Kleefstra T, Nillesen WM, Yntema HG. KleefstraSyndrome. InPagon RA, Adam MP, Ardinger HH,Wallace SE, Amemiya A, Bean LJH, et al, eds.GeneReviews(R). Seattle (WA): University of Washington,Seattle University of Washington, Seattle, 1993.

Kleefstra T, Smidt M, Banning MJ, Oudakker AR, VanEsch H, de Brouwer AP, et al. Disruption of the geneEuchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34subtelomericdeletion syndrome. J Med Genet 2005;42:299-306.

Kleefstra T, Brunner HG, Amiel J, Oudakker AR,Nillesen WM, Magee A, et al. Loss-of-function mutationsin euchromatin histone methyl transferase 1 (EHMT1)cause the 9q34 subtelomeric deletion syndrome. Am JHum Genet 2006;79:370-7.

Ravnan JB, Tepperberg JH, Papenhausen P, Lamb AN,Hedrick J, Eash D, et al. Subtelomere FISH analysis of 11688 cases: an evaluation of the frequency and pattern ofsubtelomere rearrangements in individuals withdevelopmental disabilities. J Med Genet 2006;43:478-89.

Barber P. Extraction protocol. chelex. (AccessedDecember 2016, 30, at

Campbell CL, Collins RT, Zarate YA. Severe neonatal presentation of Kleefstra syndrome in a patient withhypoplastic left heart syndrome and 9q34.3microdeletion. Birth defects research Part A. Clin Mol Teratol 2014;100:985-90.

Li Y, Li X, Wang K, Ho M. Kleefstra syndrome: one casereport. Zhonghua Er Ke Za Zhi 2014;52:710-1.

Matsumoto H, Zaha K, Nakamura Y, Hayashi S, InazawaJ, Nonoyama S. Chromosome 9q33q34 microdeletionwith early infantile epileptic encephalopathy, severedystonia, abnormal eye movements, and nephroureteralmalformations. Pediatr Neurol 2014;51:170-5.

Tug E, Cavdarli B, Karaoguz MY, Percin FE. A patientwith 9q subtelomeric deletion syndrome with additionalfindings. Genet Couns 2012;23:465-71.

Willemsen MH, Beunders G, Callaghan M, de Leeuw N,Nillesen WM, Yntema HG, et al. Familial Kleefstrasyndrome due to maternal somatic mosaicism forinterstitial 9q34.3 microdeletions. Clin Genet 2011;80:31-8.

Rump A, Hildebrand L, Tzschach A, Ullmann R, SchrockE, Mitter D. A mosaic maternal splice donor mutation inthe EHMT1 gene leads to aberrant transcripts and toKleefstra syndrome in the offspring. Eur J Hum Genet2013;21:887-90.

la Cour Sibbesen E, Jespersgaard C, Alosi D, BisgaardAM, Tumer Z. Ring chromosome 9 in a girl withdevelopmental delay and dysmorphic features: case reportand review of the literature. Am J Med Genet A2013;161A:1447-52.

Penacho V, Galan F, Martin-Bayon TA, Mayo S,Manchon I, Carrasco A, et al. Prenatal diagnosis of afemale fetus with ring chromosome 9,46,XX,r(9)(p24q34), and a de novo interstitial 9pdeletion. Cytogenet Genome Res 2014;144:275-9.

Balemans MC, Ansar M, Oudakker AR, van Caam AP,Bakker B, Vitters EL, et al. Reduced Euchromatin histonemethyltransferase 1 causes developmental delay,hypotonia, and cranial abnormalities associated withincreased bone gene expression in Kleefstra syndromemice. Dev Biol 2014;386:395-407.

Schwaibold EM, Smogavec M, Hobbiebrunken E, WinterL, Zoll B, Burfeind P, et al. Intragenic duplication ofEHMT1 gene results in Kleefstra syndrome. MolCytogenet 2014;7:74.

Northcott PA, Nakahara Y, Wu X, Feuk L, Ellison DW,Croul S, et al. Multiple recurrent genetic events convergeon control of histone lysine methylation inmedulloblastoma. Nat Genet 2009;41:465-72.

Kleefstra T, Schenck A, Kramer JM, van Bokhoven H.The genetics of cognitive epigenetics.Neuropharmacology 2014;8083-94.

Khakpour G, Pooladi A, Izadi P, Noruzinia M, TavakkolyBazzaz J. DNA methylation as a promising landscape: Asimple blood test for breast cancer prediction. TumourBiol 2015;36:4905-12.

Deininger PL, Batzer MA. Alu repeats and humandisease. Mol Genet Metab 1999;67:183-9


  • There are currently no refbacks.

Creative Commons Attribution-NonCommercial 3.0

This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.