Introduction:
Introduction: CTCF-Related Disorder (CRD) is a rare autosomal dominant neurodevelopmental disorder caused by pathogenic variants in the CTCF gene. Since 2013, 130 individuals and their phenotypes have been reported in the literature. Individuals with CRD have a wide range of presentations, including interfamilial and intrafamilial variation. Because of this, CRD does not yet have a clear genotype phenotype relationship and additional analysis of the clinical spectrum of CRD is needed. In this study, we aimed to expand the genotype and phenotype of CRD through deep phenotyping with the use of Human Phenotype Ontology (HPO) terminology.

 

Methods:
Methods: We recruited a new cohort of 31 previously unreported individuals with variants in CTCF. We also included 1 previously reported individual with new clinical updates. Data was collected through a detailed medical history questionnaire sent to participants through REDCAP with any unclear information clarified through direct follow-up communication. Facial photos of new patients at different ages were collected and analyzed using Face2Gene DeepGeastalt tool. In addition, we reviewed 130 previously reported patients in the literature for phenotype information.  Phenotypes were coded into HPO terminology as well.

 

Results:
Results: Through this approach, we describe the phenotype spectrum of 161 individuals with 104 different CTCF variants.  Here, we report 31 new participants and 16 novel variants. Using HPO terminology, we confirm core features, including intellectual disability/developmental delay (94%), speech delays (72%), atypical behavior (74%), ocular concerns (72%), and feeding difficulty/failure to thrive (71%). We are able to continue refining the facial gestalt for CRD through Face2Gene for early clinical recognition. In our cohort we report new features including: recurrent ketotic hypoglycemia (2 individuals), asymptomatic persistently elevated gamma-glutamyltransferase (GGT) levels (2 adult patients), abnormal pain sensation (32%), and postural instability (40%). Previous literature reported Wilms tumor as a possible concern for these patients, but this new cohort did not report cases of Wilms Tumor. This study further expands the spectrum of the severity of intellectual disability and developmental delays, types of sleep disturbance and recurrent infections reported in individuals with CRD. Notably, our cohort of individuals with pathogenic variants reports a higher frequency of sleep disturbances (84%) compared to previous reports in the literature (32%). The difficulty falling asleep (76%) and frequent nighttime waking (52%) are predominant sleep challenges impacting quality of life significantly. Intrafamilial variation is illustrated through three families with inherited CTCF variants. With over 25% of the cohort being adults, the study broadens the understanding of CRD into adulthood.

 

Conclusion:
Conclusions: This study provides a detailed report of all currently known features associated with 161 individuals with CTCF variants. This expanding genotype and phenotype information adds to the complex clinical picture of individuals with CRD, as well as aids in their recognition and management.