ABSTRACT
Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter-individual phenotypic variability was observed, even in individuals with the same recurrent variant (n = 13). SON haploinsufficiency was previously shown to lead to downregulation of downstream genes, contributing to specific phenotypic features. Similar functional analysis for one missense variant, however, suggests a different mechanism than for heterozygous loss-of-function. Although small in numbers and while pathogenicity of these variants is not certain, these data allow for speculation whether de novo missense variants cause ZTTK syndrome via another mechanism, or a separate overlapping syndrome. In conclusion, heterozygous loss-of-function variants in SON define a recognizable syndrome, ZTTK, associated with a broad, severe phenotypic spectrum, characterized by a large inter-individual variability. These observations provide essential information for affected individuals, parents, and healthcare professionals to ensure appropriate clinical management.
Subject(s)
DNA-Binding Proteins , Intellectual Disability , Minor Histocompatibility Antigens , DNA-Binding Proteins/genetics , Humans , Intellectual Disability/genetics , Minor Histocompatibility Antigens/genetics , Mutation, Missense , Phenotype , SyndromeABSTRACT
BACKGROUND AND AIMS: Chronic obstructive pulmonary disease (COPD) has many comorbidities such as coronary artery disease (CAD) and stroke. Chronic low-grade systemic inflammation and oxidative stress play a significant role in CAD and COPD. We analysed that impact of COPD on intensity and severity of coronary artery lesions on the angiogram in the groups of patients with COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) grades updated in 2015. METHODS: The study included 102 COPD patients and 80 randomly selected subjects without any pulmonary disease who underwent coronary angiography. According to the GOLD grade for COPD, patients were divided into four groups: A, B, C and D. The severity and extent of CAD were determined using the Gensini score. RESULTS: There were no significant between-group differences in age, body mass index, smoking history, plasma lipids levels, frequency of hypertension, diabetes and CAD. The mean Gensini score in patients with COPD was significantly higher than those without (respectively, 25.7 ± 32.9 vs 17.5 ± 24.8, P = 0.01). While Gensini score was the highest level in the patient group D (64.9 ± 34.9), it was the lowest level in the patient group A (10.2 ± 19.4, P = 0.0001). The Gensini scores increased in accordance with increases in the GOLD grades. We observed that COPD was independently predictive for Gensini score after a multi-variate logistic regression analysis (odds ratio 1.374; 95% confidence interval 1.672-9.232; P = 0.001). CONCLUSION: Severity and intensity of coronary atherosclerosis increases in accordance with increases in the GOLD grades for COPD.