Men without Rett in family can carry causative mutations in their sperm

Study finds MECP2 mutations in 28% of males with no history of syndrome

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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More than a quarter of men at large may carry mutations causing Rett syndrome in a portion of their sperm, a study suggests.

The study, “MECP2 germline mosaicism plays an important part in the inheritance of Rett syndrome: a study of MECP2 germline mosaicism in males,” was published in the journal BMC Medicine.

Mutations in the gene MECP2 is the main cause of Rett syndrome. Scientific thinking has long held that most of these mutations develop de novo — meaning that the mutation is not inherited, but occurs for a first time in the affected person. However, an emerging body of evidence suggests that many supposedly de novo mutations are actually more complicated, due to a process called mosaicism.

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The general concept behind mosaicism is that sometimes, a few cells in the body have mutations that aren’t shared by the other cells in the body. It’s sort of like having different colored tiles in a mosaic, which is how the term gets its name. In some cases, mosaicism can affect germ cells — the cells that develop into sperm or eggs — and it is referred to as germline mosaicism.

Since germ cells contain the genetic code that’s ultimately passed on to a person’s offspring, germline mosaicism can result in mutations being passed to a person’s children, even though that person does not carry the mutation in most of their cells.

These mutations were commonly known as de novo in the past. Prior research has established that MECP2 mosaicism is detectable in some fathers of children with Rett syndrome, but it’s not clear how this compares to rates in the general population.

“Further research on germline mosaic mutations will be of great significance to the understanding of the genetic mechanism and the prevention measures of disease,” the investigators wrote.

Scientists in China looked for signs of germline mosaicism for the MECP2 gene in 32 fathers of girls with Rett syndrome. Results showed nine of them (28.1%) had MECP2 mosaicism; the proportion of individual sperm cells carrying the mutation ranged from 0.05% to 7.55% in each patient.

The researchers also tested for the same type of mosaicism in 25 healthy adult men who had no family history of Rett syndrome. Germline mosaicism was identified in seven (28%) of these individuals, with 0.05% to 0.18% total sperm affected.

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“Germline MECP2 mosaicism could be found in not only fathers with [Rett] daughters but also healthy adult males without family history of [Rett],” the researchers concluded, adding that this finding “suggests that germline MECP2 mosaic mutations may occur randomly in the general population.”

Since the data suggest that it’s common for multiple sperm to carry this mutation, these findings call into question the long-held idea that most Rett-causing mutations are truly de novo, the scientists said.

The researchers noted that the specific types of MECP2 mutations varied somewhat between the two groups, though in both groups, the most common mutations detected are also known to be common causes of Rett syndrome.

Given the small numbers of people examined in this study, these differences may be attributable to random chance, so the scientists called for larger studies to investigate types of MECP2 mutations in germline mosaicism.