Researchers Encourage Screening for New Mutations Linked to Angelman

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Screenings should be conducted for novel mutations in people with Angelman syndrome-like disease — those with clinical features of Angelman but whose genetic cause remains unknown — say researchers who recently identified 10 new variants.

“A high rate of diagnosis is essential since it contributes to more appropriate clinical patient surveillance as well as family genetic counseling,” they wrote.

Their study, “New genes involved in Angelman syndrome-like: Expanding the genetic spectrum,” was published in PLOS One.

The vast majority of cases of Angelman syndrome are caused by mutations in a gene called UBE3AHowever, as many as 15% of patients who show clinical features of Angelman have no abnormalities in the UBE3A gene. In such cases, it’s likely that other mutations contribute to the development of Angelman syndrome, but these are rare and not well-understood.

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In the study, a team of scientists in Spain conducted genetic analyses on 14 people with Angelman-like disease. The patients were first diagnosed with Angelman-like disease between ages 11 months and 8 years, and disease features persisted to the time of most recent data collection, when they were 9 to 38 years old.

All of the patients showed symptoms typical of Angelman, “including severe global developmental delay, speech impairment and a behavioral phenotype that included apparent happy disposition as the most remarkable feature,” the researchers reported.

The patients were analyzed using whole-exome sequencing, which determines the sequence of the exome — the roughly 2% of a person’s total genetic code, or genome, that provides instructions for making proteins.

For all but one of the patients, their biological parents were also analyzed, which allowed the researchers to check whether mutations were inherited or developed de novo (that is, only in the affected individual).

Results identified a pathogenic (disease-causing) or likely pathogenic mutation in 11 of the 14 patients, a diagnostic yield of 78.5%.

“The global yield diagnostic of [whole-exome sequencing] … is higher to what has been reported in the literature for other neurodevelopmental disorders,” the scientists wrote.

Ten of these patients had de novo mutations in genes known to affect neurological development. The specific affected genes were: SYNGAP1VAMP2TBL1XR1ASXL3SATB2SMARCE1SPTAN1KCNQ3, and SLC6A1.

The other patients had an X-linked mutation in the gene LAS1L, which has also been linked to neurological disease.

X-linked mutations are carried on the X chromosome, which is one of the two sex-determining chromosomes: females have two X chromosomes, and males have one (and also one Y chromosome). As such, X-linked mutations are more likely to cause disease in males, because females usually have a healthy version of the gene on their other X-chromosome that can compensate for the mutation.

For some of the identified mutations, the clinical features were consistent with what has been described in prior reports of people with mutations in the same genes. For example, patients with SYNGAP1 or SATB2 displayed aggressive behavior, which has been reported previously in other individuals with these mutations.

However, this wasn’t always the case. For instance, SYNGAP1 mutations have previously been linked to unsteady gait and low muscle tone, which weren’t present in the patient with this mutation in the study.

“Not all patients presented all the clinical features associated with the genes identified,” the researchers wrote. “This clinical variability, possibly due to the different pathogenicity [disease-causing] strength of the genetic variants, differences in genetic background and to non-genetic environmental factors, makes the clinical diagnosis challenging.”

They added that none of the genes except SYNGAP1 have previously been linked with Angelman.

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“We propose the genes identified in this study should be included in the AS [Angelman syndrome] differential diagnosis,” the team wrote. (Differential diagnosis is the process of determining what condition a patient has, and ruling out conditions that they don’t have.)

In addition to the mutations in genes with known associations to neurological disease, the results also identified a patient with a mutation in the gene HSF2, which has not been linked with neurological problems.

“Although HSF2 has not been previously associated with any human disease, the gene is highly expressed in the brain. … Furthermore, HSF2 knockout mice show defects in the development of the central nervous system,” the researchers wrote.

They suggested that HSF2 could be a new candidate gene for Angelman-like disease, but noted a need for further research into this gene.

“The identification of additional patients with loss of function variants in HSF2 and functional studies in neural cells will contribute to elucidate the role of HSF2,” they wrote.