Germline Mosaicism Linked to Angelman Syndrome in 2 Siblings for 1st Time, Researchers Say

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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For the first time, the occurrence of germline mosaicism — a phenomenon in which a mutation is present only in a progenitors’ sperm or eggs and is passed on to an individual from otherwise healthy parents — has been associated with Angelman syndrome in two Chinese siblings, researchers report.

Their findings appeared in a short communication, titled “Apparent germline mosaicism for a 15q11-q13 deletion causing recurrent Angelman syndrome in a Chinese family,” published in the European Journal of Obstetrics & Gynecology and Reproductive Biology.

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.

In approximately 80% of patients, the disorder is caused by a deletion in a specific region of chromosome 15 (chr15q11-q13) that contains a set of imprinted genes, including UBE3A. Imprinted genes are those in which one of the copies, either the maternal or paternal copy, is silenced by chemical DNA modifications.

“Almost all of 15q11-q13 deletions arise de novo [appear for the first time in a individual, instead of being inherited from the parents], being present in affected patients, but not in their parents nor in healthy siblings,” the investigators wrote.

In this short report, the researchers described the case of a Chinese family in which two siblings carried a large chromosomal deletion (15q11.2-q13.1) associated with Angelman syndrome, providing the first evidence of germline mosaicism associated with this disorder.

Germline mosaicism occurs when parents who appear to be normal on genetic testing can have children who are affected with a certain genetic disorder. In short, it means that a mutation occurs only in the egg or sperm of an individual and not in other cells of the body. These individuals can then pass on these mutations to their children.

The couple had already given birth to a healthy girl before having their first affected child. The now 2.5-year-old girl had microcephaly (abnormally small head), developmental delays, and speech and motor impairments.

Genetic analysis showed the girl had a large deletion in chromosome 15 (15q11.2-q13.1), confirming an Angelman diagnosis. Subsequent analysis revealed that neither of the parents carried the same mutation.

One year later, during the first trimester of her third pregnancy, the mother requested an invasive procedure for prenatal diagnosis due to concerns about having previously given birth to an affected child. Unexpectedly, the results showed the fetus carried the same chromosomic deletion that had been found in her younger daughter. Based on these findings, the parents decided to terminate the pregnancy.

Analysis of the haplotypes — a group of alleles (variant forms of the same gene) located in the same chromosomic region — performed afterward confirmed the occurrence of germline mosaicism in the family.

“To our knowledge the present case is the first documentation of germline mosaicism for an interstitial 15q11-q13 deletion [a deletion within a chromosome]. This has important implications for genetic counseling. For apparently an isolated case of AS [Angelman syndrome] where the mother has been fully investigated, including molecular analysis of genomic DNA directly extracted from peripheral blood leukocytes [white blood cells], and appears unaffected, she is still at risk of another affected child,” the scientists concluded.