The 17q21.31 microdeletion syndrome is a clinically recognizable multisystem disorder that is characterized by intellectual disability, hypotonia, epilepsy, distinctive facial features, heart defects and urogenital anomalies. The recurrent deletion encompasses five known protein coding genes (CRHR1, SPPL2C, MAPT, STH, and KANSL1), but the role of these genes in the pathogenesis of the syndrome was unclear.
Researchers from the Human Genetics Department at the Radboud University Nijmegen Medical Centre, including 3 groups at the NCMLS, and collaborators in France, UK and the US now report that haploinsufficiency of the chromatin modifier gene KANSL1 is sufficient to cause the 17q21.31 microdeletion syndrome. This work was published online in Nature Genetics, on April 29th.
In their interdisciplinary study, the team of clinicians and researchers led by David Koolen and Bert de Vries identified two small deletions and two heterozygous mutations in KANSL1 that caused the typical phenotype. They further supported the important role of the gene in neuronal development and cognitive (dys)function by showing that genes differentially expressed in patient-derived EBV-transformed cell lines are enriched in genes with known neuronal/synaptic function, and by demonstrating learning defects in a Drosophila knockdown mutant of the KANSL1 orthologue wah.
D.A. Koolen*, J.M. Kramer*, K. Neveling*, W.M. Nillesen, H.L. Moore-Barton, F.V. Elmslie, A. Toutain, J. Amiel, V. Malan, A.C. Tsai, S.W. Cheung, C. Gilissen, E.T.P. Verwiel, S. Martens, T. Feuth, E.M.H.F. Bongers, P. de Vries, H. Scheffer, L.E.L.M. Vissers, A.P.M. de Brouwer, H.G. Brunner, J.A. Veltman, A. Schenck, H.G. Yntema, B.B.A. de Vries. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nature Genetics, April 29th, 2012 (Advance online publication).
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