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Article

Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype

1
Unità di Genetica Medica, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, 89124 Reggio Calabria, Italy
2
Area di Ricerca Genetica e Malattie Rare, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy
3
Dipartimento di Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, 00161 Rome, Italy
4
UOC di Neuroradiologia, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, 89124 Reggio Calabria, Italy
*
Authors to whom correspondence should be addressed.
Academic Editor: Giuseppe Limongelli
Genes 2021, 12(7), 1009; https://doi.org/10.3390/genes12071009
Received: 24 May 2021 / Revised: 23 June 2021 / Accepted: 26 June 2021 / Published: 30 June 2021
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. View Full-Text
Keywords: IDDSADF; CNOT3; facial features profiling; SMAD6; aortic coarctation; bicuspid aortic valve; dual molecular diagnosis; exome sequencing IDDSADF; CNOT3; facial features profiling; SMAD6; aortic coarctation; bicuspid aortic valve; dual molecular diagnosis; exome sequencing
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MDPI and ACS Style

Priolo, M.; Radio, F.C.; Pizzi, S.; Pintomalli, L.; Pantaleoni, F.; Mancini, C.; Cordeddu, V.; Africa, E.; Mammì, C.; Dallapiccola, B.; Tartaglia, M. Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype. Genes 2021, 12, 1009. https://doi.org/10.3390/genes12071009

AMA Style

Priolo M, Radio FC, Pizzi S, Pintomalli L, Pantaleoni F, Mancini C, Cordeddu V, Africa E, Mammì C, Dallapiccola B, Tartaglia M. Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype. Genes. 2021; 12(7):1009. https://doi.org/10.3390/genes12071009

Chicago/Turabian Style

Priolo, Manuela, Francesca C. Radio, Simone Pizzi, Letizia Pintomalli, Francesca Pantaleoni, Cecilia Mancini, Viviana Cordeddu, Emilio Africa, Corrado Mammì, Bruno Dallapiccola, and Marco Tartaglia. 2021. "Co-Occurring Heterozygous CNOT3 and SMAD6 Truncating Variants: Unusual Presentation and Refinement of the IDDSADF Phenotype" Genes 12, no. 7: 1009. https://doi.org/10.3390/genes12071009

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