17q21.31 microdeletion / KANSL1 mutations: Koolen-de Vries syndrome

Summary

Koolen syndrome or Koolen-de Vries syndrome is characterized by moderate to severe intellectual disability, hypotonia, amiable behavior, and highly distinctive facial features. Koolen syndrome is most frequently a chromosomal disorder (when caused by microdeletion 17q21.31, also called monosomy 17q21.31), but can also arise as a monogenic disorder (when caused by a point mutation in the KANSL1 gene).

Detailed clinical description

Mild to severe global psychomotor developmental delay in Koolen syndrome begins early. Hypotonia is evident as difficult suction and nutrition. Specific facial dysmorphisms include tall, broad forehead, long face, upslanting palpebral fissures, epicanthal folds, tubular nose with bulbous nasal tip, and large ears. Face elongation increases with age. Abnormal hair pigmentation can be seen.

Inconstant features include cardiac or genitourinary anomalies (cryptorchidism), joint hypermobility and/or hip dislocation/dysplasia, ectodermal anomalies of the hair, skin, and teeth, elbow dislocation, conductive hearing loss, hypertension due to renal scarring and seizures.

Prevalence

The prevalence of Koolen-de Vries syndrome is unknown. Males and females are equally affected. It has been suggested that the syndrome is currently underestimated (see also differential diagnosis). Penetrance of the disorder is 100%, while extent and severity of clinical features are variable.

Molecular genetics

Most cases of Koolen-de Vries syndrome are caused by the loss of a small chromosomal region (microdeletion) which leads to monosomy 17q21.31. The microdeletion, which spans from 500-650 kb, arises as a de novo consequence of a 900 kb polymorphic inversion (H2), of which one of the parents is invariably found to be carrier. All the following genes are usually lost because of the microdeletion:  C17orf69, CRHR1, IMP5, MAPT, STH and KANSL1 (previously known as KIAA1267). The recurrence risk of microdeletion 17q21.31 is low, but cases of recurrence in siblings have already been reported in independent families. The 900 kb polymorphic inversion in one of the parents may predispose to Non-Allelic Homologous Recombination (NHAR), which then leads to the microdeletion. It has been proposed that a parent with the inversion may have low level gonadal mosaicism for the microdeletion. Empirical recurrence risk of 5% is usually given whenever gonadal mosaicism is possible. Hence prenatal diagnosis by FISH/array-CGH should be offered in the next pregnancies.

However, Koolen-de Vries syndrome can be caused also by a heterozygous point mutation in the KANSL1 gene. Loss-of-function mutations have been so far identified, including nonsense, frameshift and splice mutations. All mutations identified are de novo. Empirical recurrence risk of 5% should be given in such families because of the possibility of parental gonadal mosaicism for the disease-causing mutation.

Prenatal diagnosis

Because an empirical recurrence risk of at least 5% should be given in any couple with a son affected by Koolen-de Vries syndrome (either caused by 17q21.31 microdeletion or by KANSL1 mutation), early prenatal diagnosis by targeted molecular testing must be offered. The analysis can be done by FISH (to detect the microdeletion) or by sequencing (to detect the KANSL1 mutation).

Differential diagnosis

The differential diagnosis of Koolen-de Vries syndrome is mainly with Prader-Willi syndrome in the early stages and with velo-cardio-facial syndrome at a later age. The similarity with velo-cardial-facial syndrome is because of the large number of naevi and other pigmentary skin abnormalities. Coarse facial appearance, relative macrocephaly and significant learning disabilities may also be misleading and generate an earlier suspicion of cardio-facio-cutaneous syndrome instead of Koolen syndrome.

Genetic testing strategy

In case of clinical suspicion of Koolen-de Vries syndrome, array-CGH or targeted FISH analysis can be done. As an alternative, CNV detection by specific algorithms applied to exome sequencing data can be used to infer the presence of the 17q21.31 microdeletion. Exome sequencing offers the advantage of scanning the KANSL1 gene sequence in parallel and opens the possibility to screen for any kind of differential diagnosis in case of negative results.

References:

A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. 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. Nat Genet. 2006 Sep;38(9):999-1001. PMID: 16906164

A further contribution to the delineation of the 17q21.31 microdeletion syndrome: central nervous involvement in two Italian patients. Terrone G, D’Amico A, Imperati F, Carella M, Palumbo O, Gentile M, Canani RB, Melis D, Romano A, Parente I, Riccitelli M, Del Giudice E. Eur J Med Genet. 2012 Aug-Sep;55(8-9):466-71. PMID 22659270

Cutaneous features in 17q21.31 deletion syndrome: a differential diagnosis for cardio-facio-cutaneous syndrome. Wright EB, Donnai D, Johnson D, Clayton-Smith J. Clin Dysmorphol. 2011 Jan;20(1):15-20. PMID 21084979

Two families with sibling recurrence of the 17q21.31 microdeletion syndrome due to low-grade mosaicism. Koolen DA, Dupont J, de Leeuw N, Vissers LE, van den Heuvel SP, Bradbury A, Steer J, de Brouwer AP, Ten Kate LP, Nillesen WM, de Vries BB, Parker MJ. Eur J Hum Genet. 2012 Jul;20(7):729-33. PMID 22293690

Additional resources: a website dedicated to the research on the microdeletion of 17q21.31 is available at http://www.17q21.com/en/.