DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract

Alexandria T.M. Blackburn, Nasim Bekheirnia, Vanessa C. Uma, Mark E. Corkins, Yuxiao Xu, Jill A. Rosenfeld, Matthew N. Bainbridge, Yaping Yang, Pengfei Liu, Suneeta Madan-Khetarpal, Mauricio R. Delgado, Louanne Hudgins, Ian Krantz, David Rodriguez-Buritica, Patricia G. Wheeler, Lihadh Al Gazali, Aisha Mohamed Saeed Mohamed Al Shamsi, Natalia Gomez-Ospina, Hsiao Tuan Chao, Ghayda M. MirzaaAngela E. Scheuerle, Mary K. Kukolich, Fernando Scaglia, Christine Eng, Helen Rankin Willsey, Michael C. Braun, Dolores J. Lamb, Rachel K. Miller, Mir Reza Bekheirnia

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalGenetics in Medicine
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Intellectual Disability
Nephrons
Xenopus
RNA
Exome
Haploinsufficiency
Xenopus laevis
Anura
Embryonic Development
Embryonic Structures
Observation
Databases
Phenotype
Kidney
Cakut

Keywords

  • CAKUT
  • DYRK1A
  • exome sequencing
  • kidney
  • Xenopus

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Blackburn, A. T. M., Bekheirnia, N., Uma, V. C., Corkins, M. E., Xu, Y., Rosenfeld, J. A., ... Bekheirnia, M. R. (Accepted/In press). DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract. Genetics in Medicine. https://doi.org/10.1038/s41436-019-0576-0

DYRK1A-related intellectual disability : a syndrome associated with congenital anomalies of the kidney and urinary tract. / Blackburn, Alexandria T.M.; Bekheirnia, Nasim; Uma, Vanessa C.; Corkins, Mark E.; Xu, Yuxiao; Rosenfeld, Jill A.; Bainbridge, Matthew N.; Yang, Yaping; Liu, Pengfei; Madan-Khetarpal, Suneeta; Delgado, Mauricio R.; Hudgins, Louanne; Krantz, Ian; Rodriguez-Buritica, David; Wheeler, Patricia G.; Gazali, Lihadh Al; Mohamed Saeed Mohamed Al Shamsi, Aisha; Gomez-Ospina, Natalia; Chao, Hsiao Tuan; Mirzaa, Ghayda M.; Scheuerle, Angela E.; Kukolich, Mary K.; Scaglia, Fernando; Eng, Christine; Willsey, Helen Rankin; Braun, Michael C.; Lamb, Dolores J.; Miller, Rachel K.; Bekheirnia, Mir Reza.

In: Genetics in Medicine, 01.01.2019.

Research output: Contribution to journalArticle

Blackburn, ATM, Bekheirnia, N, Uma, VC, Corkins, ME, Xu, Y, Rosenfeld, JA, Bainbridge, MN, Yang, Y, Liu, P, Madan-Khetarpal, S, Delgado, MR, Hudgins, L, Krantz, I, Rodriguez-Buritica, D, Wheeler, PG, Gazali, LA, Mohamed Saeed Mohamed Al Shamsi, A, Gomez-Ospina, N, Chao, HT, Mirzaa, GM, Scheuerle, AE, Kukolich, MK, Scaglia, F, Eng, C, Willsey, HR, Braun, MC, Lamb, DJ, Miller, RK & Bekheirnia, MR 2019, 'DYRK1A-related intellectual disability: a syndrome associated with congenital anomalies of the kidney and urinary tract', Genetics in Medicine. https://doi.org/10.1038/s41436-019-0576-0
Blackburn, Alexandria T.M. ; Bekheirnia, Nasim ; Uma, Vanessa C. ; Corkins, Mark E. ; Xu, Yuxiao ; Rosenfeld, Jill A. ; Bainbridge, Matthew N. ; Yang, Yaping ; Liu, Pengfei ; Madan-Khetarpal, Suneeta ; Delgado, Mauricio R. ; Hudgins, Louanne ; Krantz, Ian ; Rodriguez-Buritica, David ; Wheeler, Patricia G. ; Gazali, Lihadh Al ; Mohamed Saeed Mohamed Al Shamsi, Aisha ; Gomez-Ospina, Natalia ; Chao, Hsiao Tuan ; Mirzaa, Ghayda M. ; Scheuerle, Angela E. ; Kukolich, Mary K. ; Scaglia, Fernando ; Eng, Christine ; Willsey, Helen Rankin ; Braun, Michael C. ; Lamb, Dolores J. ; Miller, Rachel K. ; Bekheirnia, Mir Reza. / DYRK1A-related intellectual disability : a syndrome associated with congenital anomalies of the kidney and urinary tract. In: Genetics in Medicine. 2019.
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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

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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.

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