TY - JOUR
T1 - DYRK1A-related intellectual disability
T2 - a syndrome associated with congenital anomalies of the kidney and urinary tract
AU - Blackburn, Alexandria T.M.
AU - Bekheirnia, Nasim
AU - Uma, Vanessa C.
AU - Corkins, Mark E.
AU - Xu, Yuxiao
AU - Rosenfeld, Jill A.
AU - Bainbridge, Matthew N.
AU - Yang, Yaping
AU - Liu, Pengfei
AU - Madan-Khetarpal, Suneeta
AU - Delgado, Mauricio R.
AU - Hudgins, Louanne
AU - Krantz, Ian
AU - Rodriguez-Buritica, David
AU - Wheeler, Patricia G.
AU - Gazali, Lihadh Al
AU - Mohamed Saeed Mohamed Al Shamsi, Aisha
AU - Gomez-Ospina, Natalia
AU - Chao, Hsiao Tuan
AU - Mirzaa, Ghayda M.
AU - Scheuerle, Angela E.
AU - Kukolich, Mary K.
AU - Scaglia, Fernando
AU - Eng, Christine
AU - Willsey, Helen Rankin
AU - Braun, Michael C.
AU - Lamb, Dolores J.
AU - Miller, Rachel K.
AU - Bekheirnia, Mir Reza
N1 - Publisher Copyright:
© 2019, American College of Medical Genetics and Genomics.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Purpose: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. Methods: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a’s role in renal development. Results: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA. Conclusion: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.
AB - Purpose: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. Methods: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a’s role in renal development. Results: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA. Conclusion: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.
KW - CAKUT
KW - DYRK1A
KW - Xenopus
KW - exome sequencing
KW - kidney
UR - http://www.scopus.com/inward/record.url?scp=85068414026&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068414026&partnerID=8YFLogxK
U2 - 10.1038/s41436-019-0576-0
DO - 10.1038/s41436-019-0576-0
M3 - Article
C2 - 31263215
AN - SCOPUS:85068414026
SN - 1098-3600
VL - 21
SP - 2755
EP - 2764
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 12
ER -