Abstract
Objective, the application of genomic sequencing in clinical practice has allowed us to appreciate the contribution of co-occurring pathogenic variants to complex and unclassified clinical phenotypes. Besides the clinical relevance, these findings have provided evidence of previously unrecognized functional links between genes in the context of developmental processes and physiology. Patients and Methods, a 5-year-old patient showing an unclassified phenotype characterized by developmental delay, speech delay, peculiar behavioral features, facial dysmorphism and severe cardiopathy was analyzed by trio-based whole exome sequencing (WES) analysis to identify the genomic events underlying the condition. Results, two co-occurring heterozygous truncating variants in CNOT3 and SMAD6 were identified. Heterozygous loss-of-function variants in CNOT3, encoding a subunit of the CCR4-NOT protein complex, have recently been reported to cause a syndromic condition known as intellectual developmental disorder with speech delay, autism and dysmorphic facies (IDDSADF). Enrichment of rare/private variants in the SMAD6 gene, encoding a protein negatively controlling transforming growth factor β/bone morphogenetic protein (TGFB/BMP) signaling, has been described in association with a wide spectrum of congenital heart defects. We dissected the contribution of individual variants to the complex clinical manifestations and profiled a previously unappreciated set of facial features and signs characterizing IDDSADF. Conclusions, two concomitant truncating variants in CNOT3 and SMAD6 are the cause of the combination of features documented in the patient resulting in the unique multisystem neurodevelopmental condition. These findings provide evidence for a functional link between the CCR4-NOT complex and TGFB/BMP signaling in processes controlling cardiac development. Finally, the present revision provides evidence that IDDSADF is characterized by a distinctive facial gestalt.
Highlights
Proband-parents whole exome sequencing analysis has substantially improved the chance of obtaining a genetic diagnosis in rare and ultra-rare diseases
As a paradigmatic example of complex dual diagnosis requiring accurate dissection of clinical features after whole exome sequencing (WES) to explain the whole presentation, here we describe a 5-year-old boy affected with a syndromic intellectual disability (ID) disorder with speech delay, peculiar behavioral phenotype, facial dysmorphism and a severe cardiopathy, who carried two co-occurring pathogenic variants in CCR4-NOT protein complex subunit 3 (CNOT3) and small mother against decapentaplegic family member 6 (SMAD6)
We provide evidence for a functional link between the CCR4-NOT complex and TGFB/bone morphogenetic protein (BMP) signaling in processes controlling cardiac development
Summary
Proband-parents whole exome sequencing (trio-WES) analysis has substantially improved the chance of obtaining a genetic diagnosis in rare and ultra-rare diseases. Patients with dual diagnoses can be characterized by either qualitatively distinct phenotypes or attenuated/strengthened clinical presentation with respect to the individual diseases depending on the functional link and the role of the genes involved in terms of developmental processes and physiology, eventually resulting in a modulated expression of one or several features [3]. In both cases, a priori discrimination of the contribution of individual pathogenic variants to the complexity of the clinical phenotype is generally a hard task [1]. To add complexity to this landscape, the presence of multiple genetic diseases within a family, each affecting different members with variable modes of inheritance and age-of-onset, might represent an additional confounding element
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