A recurrent de novo CTBP1 mutation is associated with developmental delay, hypotonia, ataxia, and tooth enamel defects.
Exome sequencing is an effective way to identify genetic causes of etiologically heterogeneous conditions such as developmental delay and intellectual disabilities. Using exome sequencing, we have identified four patients with similar phenotypes of developmental delay, intellectual disability, failure to thrive, hypotonia, ataxia, and tooth enamel defects who all have the same de novo R331W missense variant in C-terminal binding protein 1 (CTBP1). CTBP1 is a transcriptional regulator critical for development by coordinating different regulatory pathways. The R331W variant found in these patients is within the C-terminal portion of the PLDLS (Pro-Leu-Asp-Leu-Ser) binding cleft, which is the domain through which CTBP1, interacts with chromatin-modifying enzymes and mediates chromatin-dependent gene repression pathways. This is the first report of mutations within CTBP1 in association with any human disease.
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA.
David B
DB
Beck
GeneDx, Gaithersburg, MD, USA.
Megan T
MT
Cho
GeneDx, Gaithersburg, MD, USA.
Francisca
F
Millan
GeneDx, Gaithersburg, MD, USA.
Carin
C
Yates
Department of Pediatrics and Communicable Diseases, Division of Pediatric Genetics, Metabolism & Genomic Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Mark
M
Hannibal
Department of Pediatrics and Communicable Diseases, Division of Pediatric Genetics, Metabolism & Genomic Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Bridget
B
O'Connor
Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Marwan
M
Shinawi
Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA.
Anne M
AM
Connolly
Department of Pediatrics, University of Chicago, Chicago, IL, USA.
Darrel
D
Waggoner
Department of Pediatrics, University of Chicago, Chicago, IL, USA.
Sara
S
Halbach
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Brad
B
Angle
Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Victoria
V
Sanders
Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY, USA.
Yufeng
Y
Shen
GeneDx, Gaithersburg, MD, USA.
Kyle
K
Retterer
GeneDx, Gaithersburg, MD, USA.
Amber
A
Begtrup
GeneDx, Gaithersburg, MD, USA.
Renkui
R
Bai
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA. wkc15@columbia.edu.
Wendy K
WK
Chung
D000328:Adult; D000429:Alcohol Oxidoreductases / Q000235:genetics*; D001259:Ataxia / Q000150:complications / Q000235:genetics*; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D003743:Dental Enamel / Q000473:pathology*; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics*; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics; D008297:Male; D009123:Muscle Hypotonia / Q000150:complications / Q000235:genetics*; D020125:Mutation, Missense; D000073359:Exome Sequencing; D055815:Young Adult
D004268:DNA-Binding Proteins; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein
Ataxia; CTBP1; Chromatin; Developmental delay; Enamel defects; Hypotonia; Whole exome sequencing