Coffin-Siris Syndrome Should be Included in the Differential Diagnosis of Angelman Syndrome, Case Study Says

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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Coffin-Siris syndrome, mutation, Angelman

Coffin-Siris syndrome (CSS) should be included in the differential diagnosis of Angelman syndrome, say researchers, after describing the case of a 14-year-old boy who harbored a genetic mutation associated with CSS and experienced typical symptoms of Angelman syndrome.

The findings were reported in the study, “Identification of a de novo splicing variant in the Coffin-Siris gene, SMARCE1, in a patient with Angelman‐like syndrome,” in the journal Molecular Genetics & Genomic Medicine.

Angelman syndrome is a genetic neurodevelopmental disorder usually associated with severe intellectual disability, difficulty speaking, loss of movement control (ataxia) and epileptic seizures. It is caused by the loss or malfunction of the maternal copy of the ubiquitin protein ligase E3A (UBE3A) gene in neurons from specific regions of the brain.

However, in approximately 10% of the patients with a clinical diagnosis of Angelman, the molecular defects underlying the disease are unknown. According to researchers, this happens because “some of these patients [may] harbor alternative genetic defects that present overlapping features with AS [Angelman syndrome].”

Recent advances in gene sequencing “have already been useful to identify alternative genes responsible for other heterogeneous genetic diseases such as Rett, Kleefstra, and Smith-Magenis syndromes.”

Researchers from the Universitat Autònoma de Barcelona in Spain have found a new genetic variant of SMARCE1, the gene involved in CSS — a condition characterised by mild to severe intellectual disability or delayed development of speech and motor skills — in a patient with typical Angelman symptoms, using a technique called whole-exome sequencing (WES). This technique examines the DNA sequence of all genes encoding for proteins (exome) on a given sample.

After extracting DNA from blood samples of the patient and his parents, researchers used WES to look for genetic defects that might explain the boy’s Angelman-like symptoms.

Genetic analysis identified a new SMARCE1 splicing variant that lacks an entire exon (the coding sequence of a gene that provides instructions to make proteins) of the gene, leading to the production of a shorter protein lacking 27 amino acids (protein building blocks). A splicing variant of a gene can be obtained when a region of the gene is removed or shifted, generating different proteins.

Since missense (a single nucleotide mutation that alters protein composition) mutations in SMARCE1 are directly associated with CSS, researchers re-evaluated the patient to look for typical CSS symptoms. Clinical re-evaluation of the boy confirmed the presence of CSS symptoms, many of which overlapped with those of Angelman.

“Taking into account these results, we believe that CSS should be added to the expanding list of differential diagnoses for AS, probably accounting for some of the molecularly undiagnosed AS‐like patients,” the researchers wrote.

“The increasing use of exome sequencing in diagnostic laboratories will allow the analysis of all those genes that are involved in severe neurodevelopment disorders in patients who present AS clinical features, improving the diagnostic rate, and providing knowledge of the phenotypic [symptoms shown] spectrum of AS‐like causative genes, among them those responsible for Coffin–Siris syndrome,” they concluded.