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 Mirzaa; Angela E Scheuerle; Mary K Kukolich; Fernando Scaglia; Christine Eng; Helen Rankin Willsey; Michael C Braun; Dolores J Lamb; Rachel K Miller; Mir Reza Bekheirnia

doi:10.1038/s41436-019-0576-0

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

Genet Med. 2019 Dec;21(12):2755-2764. doi: 10.1038/s41436-019-0576-0. Epub 2019 Jul 2.

Authors

Alexandria T M Blackburn^{1

2}, Nasim Bekheirnia^{3

4

5}, Vanessa C Uma⁵, Mark E Corkins¹, Yuxiao Xu^{6

7}, Jill A Rosenfeld⁸, Matthew N Bainbridge^{9

10}, Yaping Yang^{8

11}, Pengfei Liu^{5

8

11}, Suneeta Madan-Khetarpal¹², Mauricio R Delgado¹³, Louanne Hudgins¹⁴, Ian Krantz¹⁵, David Rodriguez-Buritica¹⁶, Patricia G Wheeler¹⁷, Lihadh Al-Gazali¹⁸, Aisha Mohamed Saeed Mohamed Al Shamsi¹⁹, Natalia Gomez-Ospina¹⁴, Hsiao-Tuan Chao^{8

20

21

22

23}, Ghayda M Mirzaa^{24

25}, Angela E Scheuerle²⁶, Mary K Kukolich²⁷, Fernando Scaglia^{4

8

28}, Christine Eng^{5

8

11}, Helen Rankin Willsey^{6

7}, Michael C Braun^{3

4

5}, Dolores J Lamb²⁹, Rachel K Miller^{30

31

32

33}, Mir Reza Bekheirnia^{34

35

36

37}

Affiliations

¹ Department of Pediatrics, Pediatric Research Center, University of Texas Health Science Center, McGovern Medical School, Houston, TX, USA.
² Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center University of Texas Health Science Center Graduate School of Biomedical Sciences, Houston, TX, USA.
³ Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
⁴ Texas Children's Hospital, Houston, TX, USA.
⁵ Baylor College of Medicine, Houston, TX, USA.
⁶ Department of Psychiatry, Weill Institute for Neurosciences, University of California, San Francisco, CA, USA.
⁷ Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
⁸ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
⁹ Codified Genomics, LLC, Houston, TX, USA.
¹⁰ Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
¹¹ Baylor Genetics, Houston, TX, USA.
¹² Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹³ Department of neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁴ Department of Pediatrics, Division of Medical Genetics, Stanford University, Stanford, CA, USA.
¹⁵ Division of Human Genetics, The Children's Hospital of Philadelphia and the Department of Pediatrics, Perelman School of medicine at University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.
¹⁷ Arnold Palmer Hospital, Orlando, FL, USA.
¹⁸ College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates.
¹⁹ Paediatrics Department, Tawam Hospital, Al-Ain, United Arab Emirates.
²⁰ Department of Pediatrics, Section of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA.
²¹ Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
²² Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
²³ McNair Medical Institute at The Robert and Janice McNair Foundation, Houston, TX, USA.
²⁴ Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
²⁵ Department of Pediatrics, University of Washington, Seattle, WA, USA.
²⁶ Department of Pediatrics (Genetics and Metabolism), The University of Texas Southwestern Medical Center, Dallas, TX, USA.
²⁷ Clinical Genetics, Cook Children's Medical Center, Fort Worth, TX, USA.
²⁸ Joint BCM-CUHK Center of Medical Genetics, Prince of Wales Hospital, ShaTin, Hong Kong SAR.
²⁹ Department of Urology and Center for Reproductive Genomics, Weill Cornell Medicine, New York, NY, USA.
³⁰ Department of Pediatrics, Pediatric Research Center, University of Texas Health Science Center, McGovern Medical School, Houston, TX, USA. Rachel.K.Miller@uth.tmc.edu.
³¹ Program in Genetics and Epigenetics, The University of Texas MD Anderson Cancer Center University of Texas Health Science Center Graduate School of Biomedical Sciences, Houston, TX, USA. Rachel.K.Miller@uth.tmc.edu.
³² Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Rachel.K.Miller@uth.tmc.edu.
³³ Program in Biochemistry and Cell Biology, The University of Texas MD Anderson Cancer Center University of Texas Health Science Center Graduate School of Biomedical Sciences, Houston, TX, USA. Rachel.K.Miller@uth.tmc.edu.
³⁴ Renal Section, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. bekheirn@bcm.edu.
³⁵ Texas Children's Hospital, Houston, TX, USA. bekheirn@bcm.edu.
³⁶ Baylor College of Medicine, Houston, TX, USA. bekheirn@bcm.edu.
³⁷ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. bekheirn@bcm.edu.

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 DYRK1A^R205* or DYRK1A^L245R 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.

Keywords: CAKUT; DYRK1A; Xenopus; exome sequencing; kidney.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Animals
Child
Child, Preschool
Databases, Genetic
Disease Models, Animal
Dyrk Kinases
Exome / genetics
Exome Sequencing / methods
Female
Haploinsufficiency / genetics
Humans
Intellectual Disability / complications
Intellectual Disability / genetics*
Kidney / abnormalities
Kidney / embryology
Male
Nephrons / metabolism
Protein Serine-Threonine Kinases / genetics*
Protein Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / genetics*
Protein-Tyrosine Kinases / metabolism
Urinary Tract / embryology
Urinary Tract / metabolism
Urogenital Abnormalities / genetics*
Xenopus laevis / genetics
Xenopus laevis / metabolism
Young Adult

Substances

Protein-Tyrosine Kinases
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding