Koolen–De Vries syndrome

Koolen–De Vries syndrome (KdVS), also known as 17q21.31 microdeletion syndrome, is a rare genetic disorder caused by a deletion of a segment of chromosome 17 which contains six genes. This deletion syndrome was discovered independently in 2006 by three different research groups.[1][2][3][4][5][6][7][8][9]

Koolen–De Vries syndrome
Other names17q21.31 microdeletion syndrome
SymptomsIntellectual disability, feeding problems, hypotonia
Usual onsetConception
DurationLifelong
CausesChromosomal microdeletion
Diagnostic methodFluorescence in situ hybridization

Presentation

The symptoms associated with this syndrome are variable, but common features include: low birthweight, low muscle tone at birth, poor feeding in infancy (often requiring feeding by tube for a period) and oromotor dyspraxia together with moderate developmental delays and learning disabilities but amiable behaviour. Other clinically important features include epilepsy, heart defects (atrial septal defect, ventricular septal defect) and kidney/urological anomalies. Silvery depigmentation of strands of hair have been noted in several patients. With age, there is an apparent coarsening of facial features.

17q21.3 was reported simultaneously in 2006 by three independent groups, with each group reporting several patients, and is now recognised to be one of the more common recurrent microdeletion syndromes.[1][2][3] In 2007, a patient with a small duplication in same segment of DNA was described.[10] An overview of the clinical features of the syndrome, by reviewing 22 individuals with a 17q21.31 microdeletion, estimated the disorder is present in 1 in every 16,000 people.[5]

Genetics

The recurrent deletion is between 500 and 650 kilobases (Kb) in size encompassing at least six genes, among them the microtubule-associated protein tau (MAPT). A review of five patients found the parental chromosome from which the deletion originated carried a common 900kb inversion polymorphism.[5] The orientation of low copy repeats flanking the deleted segment suggests the inversion in the parental chromosome influences the deletion in the child's chromosome via a non-allelic homologous recombination (NAHR) mechanism.

Affected genes

The deletion that causes this disease can remove up to six different genes. These include:

  • The uncharacterised protein C17orf69 (also known as FLJ25168).
  • The protein SPPL2c, putative intramembrane-protease, member of the presenilin-homologues, the SPP/SPPL-proteases
  • Corticotropin releasing hormone receptor 1 (CRHR1, also known as CRF-R, CRF1)
  • Microtubule-associated protein tau (MAPT)
  • The uncharacterised protein KIAA1267 (also known as DKFZP727C091, KANSL1)

Diagnosis

Diagnosis is established with a chromosome microarray analysis. The symptoms of Koolen–de Vries syndrome can be very variable, and there is no single clinical sign required to establish the diagnosis.[11]

Treatment

Treatment centres around the symptoms in each individual and can include: early physiotherapy for feeding and motor problems, physiotherapy for strengthening the muscles, speech therapy, sign language, alternative or augmentative communication devices, special education, routine antiepileptic medications, orthopaedic care for scoliosis, hip dislocation and positional deformities of the feet, treatment for cardiac, renal, urologic and other medical issues and surgery for cryptorchidism if indicated.[11]

History

The syndrome is named after Dutch geneticists David A. Koolen and Bert B. A. de Vries, who helped discover the syndrome in 2006.[3]

References
  1. Sharp AJ, Hansen S, Selzer RR, et al. (September 2006). "Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome". Nat. Genet. 38 (9): 1038–42. doi:10.1038/ng1862. PMID 16906162. S2CID 34024895.
  2. Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, Curley R, Cumming S, Dunn C, Kalaitzopoulos D, Porter K, Prigmore E, Krepischi-Santos AC, Varela MC, Koiffmann CP, Lees AJ, Rosenberg C, Firth HV, de Silva R, Carter NP (2006). "Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability". Nat Genet. 38 (9): 1032–7. doi:10.1038/ng1858. PMID 16906163. S2CID 38047848.
  3. Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, Regan R, Kooy RF, Reyniers E, Romano C, Fichera M, Schinzel A, Baumer A, Anderlid BM, Schoumans J, Knoers NV, van Kessel AG, Sistermans EA, Veltman JA, Brunner HG, De Vries BB (2006). "A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism". Nat Genet. 38 (9): 999–1001. doi:10.1038/ng1853. PMID 16906164. S2CID 25422992.
  4. Lupski JR (2006). "Genome structural variation and sporadic disease traits". Nat Genet. 38 (9): 974–6. doi:10.1038/ng0906-974. PMID 16941003. S2CID 34491336.
  5. Koolen DA, Sharp AJ, Hurst JA, Firth HV, Knight SJ, Goldenberg A, Saugier-Veber P, Pfundt R, Vissers LE, Destrée A, Grisart B, Rooms L, Van der Aa N, Field M, Hackett A, Bell K, Nowaczyk MJ, Mancini GM, Poddighe PJ, Schwartz CE, Rossi E, De Gregori M, Antonacci-Fulton LL, McLellan MD, Garrett JM, Wiechert MA, Miner TL, Crosby S, Ciccone R, Willatt L, Rauch A, Zenker M, Aradhya S, Manning MA, Strom TM, Wagenstaller J, Krepischi-Santos AC, Vianna-Morgante AM, Rosenberg C, Price SM, Stewart H, Shaw-Smith C, Brunner HG, Wilkie AO, Veltman JA, Zuffardi O, Eichler EE, De Vries BB (2008). "Clinical and molecular delineation of the 17q21.31 microdeletion syndrome". J Med Genet. 45 (11): 710–20. doi:10.1136/jmg.2008.058701. PMC 3071570. PMID 18628315.
  6. Tan TY, Aftimos S, Worgan L, Susman R, Wilson M, Ghedia S, Kirk EP, Love D, Ronan A, Darmanian A, Slavotinek A, Hogue J, Moeschler JB, Ozmore J, Widmer R, Bruno D, Savarirayan R, Peters G (2009). "Phenotypic expansion and further characterisation of the 17q21.31 microdeletion syndrome". J Med Genet. 46 (7): 480–9. doi:10.1136/jmg.2008.065391. PMID 19447831. S2CID 42220574.
  7. Varela MC, Krepischi-Santos AC, Paz JA, Knijnenburg J, Szuhai K, Rosenberg C, Koiffmann CP (2006). "A 17q21.31 microdeletion encompassing the MAPT gene in a mentally impaired patient". Cytogenet Genome Res. 114 (1): 89–92. doi:10.1159/000091934. PMID 16717456. S2CID 1124145.
  8. Zody MC, Jiang Z, Fung HC, Antonacci F, Hillier LW, Cardone MF, Graves TA, Kidd JM, Cheng Z, Abouelleil A, Chen L, Wallis J, Glasscock J, Wilson RK, Reily AD, Duckworth J, Ventura M, Hardy J, Warren WC, Eichler EE (2008). "Evolutionary toggling of the MAPT 17q21.31 inversion region". Nat Genet. 40 (9): 1076–83. doi:10.1038/ng.193. PMC 2684794. PMID 19165922.
  9. Sharkey FH, Morrison N, Murray R, Iremonger J, Stephen J, Maher E, Tolmie J, Jackson AP (2009). "17q21.31 microdeletion syndrome: further expanding the clinical phenotype". Cytogenet Genome Res. 127 (1): 61–6. doi:10.1159/000279260. PMID 20110647. S2CID 42477257.
  10. Kirchhoff M, Bisgaard AM, Duno M, Hansen FJ, Schwartz M (2007). "A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features". Eur J Med Genet. 50 (4): 256–63. doi:10.1016/j.ejmg.2007.05.001. PMID 17576104.
  11. "Koolen de Vries syndrome | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-03-11.

Further reading
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