Expansion of the genotypic and phenotypic spectrum of CTCF‐related disorder guides clinical management: 43 new subjects and a comprehensive literature review

Monoallelic variants of CTCF cause an autosomal dominant neurodevelopmental disorder with a wide range of features, including impacts on the brain, growth, and craniofacial development. A growing number of subjects with CTCF‐related disorder (CRD) have been identified due to the increased applicatio...

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Published inAmerican journal of medical genetics. Part A Vol. 191; no. 3; pp. 718 - 729
Main Authors Valverde de Morales, Hannah Gabriela, Wang, Hsiao‐Lin V., Garber, Kathryn, Cheng, Xiaodong, Corces, Victor G., Li, Hong
Format Journal Article
LanguageEnglish
Published Hoboken, USA John Wiley & Sons, Inc 01.03.2023
Wiley Subscription Services, Inc
Subjects
Congenital defects
Craniofacial growth
CTCF
facial gestalt
gene
Genetic counseling
Genotype
Hereditary diseases
Humans
Intellectual disabilities
Intellectual Disability - diagnosis
Intellectual Disability - genetics
Language Development Disorders - genetics
Literature reviews
Mutation
Neurodevelopmental disorders
Phenotype
variant
phenotype
variant
CTCF
facial gestalt
gene
genotype
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Summary:Monoallelic variants of CTCF cause an autosomal dominant neurodevelopmental disorder with a wide range of features, including impacts on the brain, growth, and craniofacial development. A growing number of subjects with CTCF‐related disorder (CRD) have been identified due to the increased application of exome sequencing, and further delineation of the clinical spectrum of CRD is needed. Here, we examined the clinical features, including facial profiles, and genotypic spectrum of 107 subjects with identified CTCF variants, including 43 new and 64 previously described subjects. Among the 43 new subjects, 23 novel variants were reported. The cardinal clinical features in subjects with CRD included intellectual disability/developmental delay (91%) with speech delay (65%), motor delay (53%), feeding difficulties/failure to thrive (66%), ocular abnormalities (56%), musculoskeletal anomalies (53%), and behavioral problems (52%). Other congenital anomalies were also reported, but none of them were common. Our findings expanded the genotypic and phenotypic spectrum of CRD that will guide genetic counseling, management, and surveillance care for patients with CRD. Additionally, a newly built facial gestalt on the Face2Gene tool will facilitate prompt recognition of CRD by physicians and shorten a patient's diagnostic odyssey.
Bibliography:Funding information
F32 ES031827; R35 GM134744 (XC); R35 GM139408
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This manuscript has been read and approved by all listed authors, and there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.
Author Contribution Hannah Gabriela Valverde de Morales: intensively involved with the patient/family consent, questionnaire design, data collection and analysis, literature review, drafted initial manuscript, and continuing review and editing.Hsiao-Lin V. Wang: involved in extensive literature review on CTCF function, variant database and reference management, writing the related content in the manuscript. Critically reviewed and revised the manuscript.Kathryn Garber: intensively involved in variant curation and reclassification based on the updated clinical data and biochemical properties of CTCF protein. Critically reviewed and revised the manuscript.Xiaodong Cheng: conducted the graphic modeling of CTCF variants and provided expertise in interpreting their potential structural or functional effects to assist in variant curation. Reviewed and revised the manuscript.Victor G. Corces: Conceptualized this study as a part of Emory CRD project, provided his expertise on current knowledge of the CTCF gene and protein. Critically reviewed and revised the manuscript.Hong Li: Conceptualized this study on expanding the genotype and phenotype spectrum of CRD, and supervised the consent, data collection, analysis and review. Critically reviewed and revised the manuscript.
ISSN:1552-4825
1552-4833
1552-4833
DOI:10.1002/ajmg.a.63065