Pathogenic Variants in GPC4 Cause Keipert Syndrome.

TitlePathogenic Variants in GPC4 Cause Keipert Syndrome.
Publication TypeJournal Article
Year of Publication2019
AuthorsAmor, DJ, Stephenson, SEM, Mustapha, M, Mensah, MA, Ockeloen, CW, Lee, WShern, Tankard, RM, Phelan, DG, Shinawi, M, de Brouwer, APM, Pfundt, R, Dowling, C, Toler, TL, V Sutton, R, Agolini, E, Rinelli, M, Capolino, R, Martinelli, D, Zampino, G, Dumić, M, Reardon, W, Shaw-Smith, C, Leventer, RJ, Delatycki, MB, Kleefstra, T, Mundlos, S, Mortier, G, Bahlo, M, Allen, NJ, Lockhart, PJ
JournalAm J Hum Genet
Date Published2019 May 02

Glypicans are a family of cell-surface heparan sulfate proteoglycans that regulate growth-factor signaling during development and are thought to play a role in the regulation of morphogenesis. Whole-exome sequencing of the Australian family that defined Keipert syndrome (nasodigitoacoustic syndrome) identified a hemizygous truncating variant in the gene encoding glypican 4 (GPC4). This variant, located in the final exon of GPC4, results in premature termination of the protein 51 amino acid residues prior to the stop codon, and in concomitant loss of functionally important N-linked glycosylation (Asn514) and glycosylphosphatidylinositol (GPI) anchor (Ser529) sites. We subsequently identified seven affected males from five additional kindreds with novel and predicted pathogenic variants in GPC4. Segregation analysis and X-inactivation studies in carrier females provided supportive evidence that the GPC4 variants caused the condition. Furthermore, functional studies of recombinant protein suggested that the truncated proteins p.Gln506 and p.Glu496 were less stable than the wild type. Clinical features of Keipert syndrome included a prominent forehead, a flat midface, hypertelorism, a broad nose, downturned corners of mouth, and digital abnormalities, whereas cognitive impairment and deafness were variable features. Studies of Gpc4 knockout mice showed evidence of the two primary features of Keipert syndrome: craniofacial abnormalities and digital abnormalities. Phylogenetic analysis demonstrated that GPC4 is most closely related to GPC6, which is associated with a bone dysplasia that has a phenotypic overlap with Keipert syndrome. Overall, we have shown that pathogenic variants in GPC4 cause a loss of function that results in Keipert syndrome, making GPC4 the third human glypican to be linked to a genetic syndrome.

Alternate JournalAm. J. Hum. Genet.
PubMed ID30982611
PubMed Central IDPMC6507040
Grant ListR01 DC009590 / DC / NIDCD NIH HHS / United States
R01 NS089791 / NS / NINDS NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States