9q34.3 deletion syndrome

From WikiProjectMed
Jump to navigation Jump to search
9q34.3 deletion syndrome
Other names: Kleefstra syndrome

9q34 deletion syndrome is a rare genetic disorder. Terminal deletions of chromosome 9q34 have been associated with childhood hypotonia, a distinctive facial appearance and developmental disability. The facial features typically described include arched eyebrows, small head circumference, midface hypoplasia, prominent jaw and a pouting lower lip. Individuals with this disease may often have speech impediments, such as speech delays. Other characteristics of this disease include: epilepsy, congenital and urogenital defects, microcephaly, corpulence, and psychiatric disorders.[1] From analysis of chromosomal breakpoints, as well as gene sequencing in suggestive cases, Kleefstra and colleagues identified EHMT1 as the causative gene.[2] This gene is responsible for producing the protein histone methyltransferase which functions to alter histones. Ultimately, histone methyltransferases are important in deactivating certain genes, needed for proper growth and development. Moreover, a frameshift, missense, or nonsense error in the coding sequence of EHMT1 can result in this condition in an individual.[citation needed]

Signs and symptoms

Individual has microcephaly, eyes widely spaced with epicanthal folds, and synophrys

Physical symptoms

  • Heart defects
  • Characteristics of autism
  • Genital defects (in males)
  • Childhood hypotonia
  • Respiratory infections
  • Motor delay
  • Renal defects
  • Severe delay or total lack of speech
  • Happy disposition
  • Dysmorphic facial features

Behavioural symptoms

  • Passiveness
  • Sociability
  • Aggression
    • Biting or hitting
  • Moodiness
  • Disliking routine changes[3][4]


Despite the associated effects of Kleefstra, there is insubstantial information regarding to the lethality of Kleefstra's. Most of the documented cases are de novo with the exception of one case due to hereditary factors; however, some cases may be a result of chromosomal translocations. In the exception case, the mother transferred the EHMT1 point mutation on to her child as she was a carrier of this gene defect. According to Mitter, et al. (2012), the mother's phenotype of the NM_024757.4:c.2712+1G>A mutation displayed mosaicism at certain tissues. This mutation resulted in the disregard of exon 18 on the EHMT1 gene, as opposed to removing it through the spliceosomes. In another transcript, however, an intron was placed between exon 18 and 19 of the EHMT1 gene. The combination of the intron insertion and the mosaicism in the mother was transferred to the child, resulting in the pathogenesis of the disease.[5]

In the past, research showed that the austerity of the disease was directly proportional to the number of EHMT1 deletions prevalent in an individual. The greater the deletions, the greater the severity of the condition. However, in recent studies, 9q34 deletion syndrome occurs when the EHMT1 gene is non-functioning, as opposed to strictly deletion.[6]


Tests are either conducted at birth, or later in early childhood via: fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (aCGH), and EHMT1 sequencing.[6]

FISH is a screening test that uses multicolour probes or comparative genomic hybridization to find any chromosome irregularities in a genome. It can be used for gene mapping, detecting aneuploidy, locating tumours etc. The multicolour probes attach to a certain DNA fragment.[7] MLPA is a test that finds and records DNA copy change numbers through the use of PCR. MLPA can be used to detect tumours in the glial cells of the brain, as well as chromosomal abnormalities.[8] Array-based comparative genomic hybridization (aCGH) tracks chromosome deletions and or amplifications using fluorescent dyes on genomic sequences of DNA samples. The DNA samples (which are 25-80 base pairs in length) are then placed on slides to be observed under microscope.[9] Lastly, EHMT1 sequencing is a process in which a single-strand of DNA from the EHMT1 gene is removed, and DNA polymerase is added in order to synthesize complementary strands. In turn, this allows scientists to map out a person's DNA sequence allowing for a diagnosis to be made.[10]


Individual manifestations are treated by a multidisciplinary team.[3]


Kleefstra syndrome affects males and females equally and approximately 75% of all documented cases are caused by Eu-HMTase1 disruptions while only 25% are caused by 9q34.3 deletions.[3] There are no statistics on the effect the disease has on life expectancy due to the lack of information available.[3]


Kleefstra syndrome is a new condition that has only been known about for a few years and there have been fewer than 200 cases, reported. Due to the lack of cases worldwide, the history behind the origination is unclear.[11]


A study published by the American Journal of Human Genetics performed an EHMT1 mutation analysis on 23 patients that showed symptoms of 9q34 deletion syndrome. The patients all varied in age. With respect to all the analyses, however, the clinical data focused on five patients, the majority being children. The first patient developed epilepsy early on in childhood, and had speech problems past age 8. He had hypoplasia and had prominent facial features, such as lips and mouth. The second patient had no trace of mitral regurgitation (MR) in her family history, but had slight hypotonia. Patient three was the oldest at 36 who began to walk at age 3. She later gained weight at eleven and developed epilepsy in her late twenties. The fourth patient had problems associated with eating as a young child and was diagnosed with slowed development. Patient five had behavioural issues and struggled with MR in addition to being overweight. The geneticists discovered three new mutations within the EHMT1 gene. The first was an interstitial deletion, while the second and third were a nonsense and frameshift. Their findings supported the notion that a disruption in the EHMT1 gene contributes to the pathogenesis of Kleefstra syndrome.[12]

In another study published by the Journal of Medical Genetics, DNA from forty patients were extracted and subjected to MLPA, FISH or EHMT1 sequencing. The forty patients were divided into two groups: 1 group of 16 patients with the 9q34 deletion, and 1 group of 24 with typical FISH/MPLA results. The geneticists examined how a missense mutation would affect the function of the DNA by looking at DNA models. After, they screened each person's DNA using one of three tests, the results for the first group showed six patients had the same deletion of the same size (700 kb). In the second group, after EHMT1 sequencing was performed, six intragenic mutations were discovered. The scientists investigating this experiment conclude these mutations may be infective agents for the disease. Lastly, the patients' behavioural, physical, and psychiatric symptoms are included on the data chart.[13]


  1. Willemsen MH, Vulto-van Silfhout AT, Nillesen WM, Wissink-Lindhout WM, van Bokhoven H, Philip N, Berry-Kravis EM, Kini U, van Ravenswaaij-Arts CM, Delle Chiaie B, Innes AM, Houge G, Kosonen T, Cremer K, Fannemel M, Stray-Pedersen A, Reardon W, Ignatius J, Lachlan K, Mircher C, Helderman van den Enden PT, Mastebroek M, Cohn-Hokke PE, Yntema HG, Drunat S, Kleefstra T (2012). "Update on Kleefstra Syndrome". Mol Syndromol. 2 (3–5): 202–212. doi:10.1159/000335648. PMC 3366700. PMID 22670141.
  2. Kleefstra, T (2005). "Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome". Journal of Medical Genetics. 42 (4): 299–306. doi:10.1136/jmg.2004.028464. ISSN 1468-6244. PMC 1736026. PMID 15805155.
  3. 3.0 3.1 3.2 3.3 Kleefstra T, Nillesen WM, Yntema HG (7 May 2015). "Kleefstra Syndrome". Seattle:GeneReviews. GeneReviews. PMID 20945554. Archived from the original on 27 February 2021. Retrieved 3 February 2017.
  4. Andrea Belanger, "Kleefstra Syndrome", Mommies of Miracles, 2011
  5. Rump, A; Hildebrand, L; Tzschach, A; Ullmann, R; Schrock, E; Mitter, D (August 2013). "A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring". European Journal of Human Genetics. 21 (8): 887–90. doi:10.1038/ejhg.2012.267. PMC 3722677. PMID 23232695.
  6. 6.0 6.1 Rare Chromosome Disorder Support Group, "Kleefstra Syndrome" Archived 2013-07-04 at the Wayback Machine, Kleefstra Syndrome, 2009
  7. Bishop, R. (27 February 2010). "Applications of fluorescence in situ hybridization (FISH) in detecting genetic aberrations of medical significance". Bioscience Horizons. 3 (1): 85–95. doi:10.1093/biohorizons/hzq009.
  8. Jeuken, Judith; Cornelissen, Sandra; Boots-Sprenger, Sandra; Gijsen, Sabine; Wesseling, Pieter (September 2006). "Multiplex Ligation-Dependent Probe Amplification". The Journal of Molecular Diagnostics. 8 (4): 433–443. doi:10.2353/jmoldx.2006.060012. PMC 1867615. PMID 16931583.
  9. Peng, H.H., & Van den Veyyer, I.B. "HOW DOES ARRAY-BASED COMPARATIVE GENOMIC HYBRIDIZATION WORK?" Archived 2014-11-01 at the Wayback Machine, 2008
  10. N/A, "Principles of DNA Sequencing" Archived 2013-04-04 at the Wayback Machine, 2013
  11. "What is Kleefstra syndrome?". Kleefstrasyndrome.org. Archived from the original on 27 November 2020. Retrieved 3 February 2017.
  12. Kleefstra, Tjitske; Brunner, Han G.; Amiel, Jeanne; Oudakker, Astrid R.; Nillesen, Willy M.; Magee, Alex; Geneviève, David; Cormier-Daire, Valérie; van Esch, Hilde; Fryns, Jean-Pierre; Hamel, Ben C.J.; Sistermans, Erik A.; de Vries, Bert B.A.; van Bokhoven, Hans (August 2006). "Loss-of-Function Mutations in Euchromatin Histone Methyl Transferase 1 (EHMT1) Cause the 9q34 Subtelomeric Deletion Syndrome". The American Journal of Human Genetics. 79 (2): 370–377. doi:10.1086/505693. PMC 1559478. PMID 16826528.
  13. Kleefstra, T; van Zelst-Stams, W A; Nillesen, W M; Cormier-Daire, V; Houge, G; Foulds, N; van Dooren, M; Willemsen, M H; Pfundt, R; Turner, A; Wilson, M; McGaughran, J; Rauch, A; Zenker, M; Adam, M P; Innes, M; Davies, C; Lopez, A G.-M.; Casalone, R; Weber, A; Brueton, L A; Navarro, A D.; Bralo, M P.; Venselaar, H; Stegmann, S P A; Yntema, H G; van Bokhoven, H; Brunner, H G (4 March 2009). "Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype". Journal of Medical Genetics. 46 (9): 598–606. doi:10.1136/jmg.2008.062950. PMC 3395372. PMID 19372089.

External links

External resources