TY - JOUR
T1 - Pathogenic Variants in GPC4 Cause Keipert Syndrome
AU - Amor, David J.
AU - Stephenson, Sarah E.M.
AU - Mustapha, Mirna
AU - Mensah, Martin A.
AU - Ockeloen, Charlotte W.
AU - Lee, Wei Shern
AU - Tankard, Rick M.
AU - Phelan, Dean G.
AU - Shinawi, Marwan
AU - de Brouwer, Arjan P.M.
AU - Pfundt, Rolph
AU - Dowling, Cari
AU - Toler, Tomi L.
AU - Sutton, V. Reid
AU - Agolini, Emanuele
AU - Rinelli, Martina
AU - Capolino, Rossella
AU - Martinelli, Diego
AU - Zampino, Giuseppe
AU - Dumić, Miroslav
AU - Reardon, William
AU - Shaw-Smith, Charles
AU - Leventer, Richard J.
AU - Delatycki, Martin B.
AU - Kleefstra, Tjitske
AU - Mundlos, Stefan
AU - Mortier, Geert
AU - Bahlo, Melanie
AU - Allen, Nicola J.
AU - Lockhart, Paul J.
N1 - Funding Information:
This work was supported by the Australian Government National Health and Medical Research Council (program grant 1054618 and fellowship 1002098 ). P.J.L. was supported by the National Health and Medical Research Council (NHMRC) Career Development Fellowship GNT1032364 . M.B. was supported by an NHMRC senior research fellowship ( 1102971 ) and an NHMRC program grant ( 1054618 ). Additional funding was provided by the Independent Research Institute Infrastructure Support Scheme and the Victorian State Government Operational Infrastructure Program . M.A.M. is a participant in the BIH Charité Junior Clinician Scientist Program funded by the Charité—Universitätsmediz in Berlin and the Berlin Institute of Health . V.R.S. receives support from the National Human Genome Research Institute ( NHGRI ) UM1 HG006542-07 . C.D. and N.J.A. were supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke ( NIH-NINDS ) R01 NS089791 . M.M. was supported by the National Institute on Deafness and other Communicative Disorders (NIDCD) R01 DC09590 .
Publisher Copyright:
© 2019
PY - 2019/5/2
Y1 - 2019/5/2
N2 - 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.
AB - 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.
KW - GPC4
KW - Keipert syndrome
KW - Nasodigitoacoustic syndrome
KW - glypicans
UR - http://www.scopus.com/inward/record.url?scp=85064932182&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2019.02.026
DO - 10.1016/j.ajhg.2019.02.026
M3 - Article
C2 - 30982611
AN - SCOPUS:85064932182
SN - 0002-9297
VL - 104
SP - 914
EP - 924
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 5
ER -