April 23, 2024

Congenital Heart Defects in Patients with Molecularly Confirmed Sotos Syndrome

Giulio Calcagni, Federica Ferrigno, Alessio Franceschini, Maria Lisa Dentici, Rossella Capolino, Lorenzo Sinibaldi, Chiara Minotti, Alessia Micalizzi, Viola Alesi, Antonio Novelli, Anwar Baban, Giovanni Parlapiano, Domenico Coviello, Paolo Versacci, Carolina Putotto, Marcello Chinali, Fabrizio Drago, Andrea Bartuli, Bruno Marino, Maria Cristina Digilio

Sotos syndrome is a rare autosomal dominant disorder described by overgrowth, motor delays, learning challenges, and distinctive facial features, with an estimated prevalence of 1 in 14,000 newborns. It is primarily caused by heterozygous variants in the NSD1 gene on chromosome 5q35, with additional cases linked to 5q35 deletions. The NSD1 gene, comprising 23 exons, has over 400 reported mutations associated with Sotos syndrome. While NSD1 gene’s role in transcription stays elusive, its connection to cardiac complications like congenital heart defects (CHDs) is significant, with a prevalence of 15-40% in Sotos patients, including septal defects, patent ductus arteriosus, and complex malformations.

From June 2011 to December 2022, this study assessed 39 Sotos syndrome cases with causative NSD1 gene variants (Group 1) and 6 with 5q35 deletions (Group 2). Genomic DNA was extracted and analyzed for NSD1 mutations using sequencing platforms. Variants were prioritized and annotated utilizing the Geneyx Analysis platform.  Patients underwent thorough cardiac assessments including echocardiography.

Patients in Group 1 exhibited various cardiac anomalies. The frequency of cardiac deficiencies differed based on mutation types, with a mildly higher occurrence in patients with missense variants. Group 2 patients, all male, displayed CHDs with further extracardiac features.

In conclusion, the authors noted a higher frequency of CHDs at 58.9% in the study’s Sotos syndrome patients with causative NSD1 gene variants compared to the literature’s 15-40%. This elevated rate may be influenced by the author’s expertise in cardiology and genetic analysis, attracting patients seeking specialized cardiac care. Notably, genetic correlations showed diverse cardiac phenotypes even with the same mutation, emphasizing the complexity of CHD in Sotos syndrome. Finally, the authors advocated for thorough cardiac evaluations and specialized follow-ups for improved management and understanding of these cardiac conditions.


Interesting Publication in PubMed: Biallelic Truncating Variants in Children with Titinopathy Represent a Recognizable Condition with Distinctive Muscular and Cardiac Characteristics: A Report on Five Patients


Abbreviations from the text:

**Sotos syndrome (SS)** – A rare autosomal dominant disorder.

**NSD1 gene** – Nuclear Receptor Binding SET Domain Protein 1 gene.

**Chromosome 5q35** – A specific location on chromosome 5.

**Congenital heart defects (CHDs)** – Structural problems with the heart present at birth.

**Genomic DNA (gDNA)** – The complete set of DNA in an organism.

**Echocardiography (ECHO)** – An ultrasound test for the heart.

**Missense variants** – Mutations resulting in a different amino acid in a protein.

**Geneyx Analysis platform** – A tool used for prioritizing and annotating genetic variants.

**Septal defects** – Abnormal openings in the heart’s septum.

**Patent ductus arteriosus (PDA)** – A persistent opening between two major blood vessels leading from the heart.

**Extracardiac features** – Symptoms or conditions outside of the heart.

**Exons** – Sections of a gene that code for proteins.






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