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Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities

Overview of attention for article published in BMC Medical Genetics, November 2015
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Title
Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities
Published in
BMC Medical Genetics, November 2015
DOI 10.1186/s12881-015-0240-8
Pubmed ID
Authors

Cameron Mroske, Kristen Rasmussen, Deepali N. Shinde, Robert Huether, Zoe Powis, Hsiao-Mei Lu, Ruth M. Baxter, Elizabeth McPherson, Sha Tang

Abstract

In humans, Mammalian Target of Rapamycin (MTOR) encodes a 300 kDa serine/ threonine protein kinase that is ubiquitously expressed, particularly at high levels in brain. MTOR functions as an integrator of multiple cellular processes, and in so doing either directly or indirectly regulates the phosphorylation of at least 800 proteins. While somatic MTOR mutations have been recognized in tumors for many years, and more recently in hemimegalencephaly, germline MTOR mutations have rarely been described. We report the successful application of family-trio Diagnostic Exome Sequencing (DES) to identify the underlying molecular etiology in two brothers with multiple neurological and developmental lesions, and for whom previous testing was non-diagnostic. The affected brothers, who were 6 and 23 years of age at the time of DES, presented symptoms including but not limited to mild Autism Spectrum Disorder (ASD), megalencephaly, gross motor skill delay, cryptorchidism and bilateral iris coloboma. Importantly, we determined that each affected brother harbored the MTOR missense alteration p.E1799K (c.5395G>A). This exact variant has been previously identified in multiple independent human somatic cancer samples and has been shown to result in increased MTOR activation. Further, recent independent reports describe two unrelated families in whom p.E1799K co-segregated with megalencephaly and intellectual disability (ID); in both cases, p.E1799K was shown to have originated due to germline mosaicism. In the case of the family reported herein, the absence of p.E1799K in genomic DNA extracted from the blood of either parent suggests that this alteration most likely arose due to gonadal mosaicism. Further, the p.E1799K variant exerts its effect by a gain-of-function (GOF), autosomal dominant mechanism. Herein, we describe the use of DES to uncover an activating MTOR missense alteration of gonadal mosaic origin that is likely to be the causative mutation in two brothers who present multiple neurological and developmental abnormalities. Our report brings the total number of families who harbor MTOR p.E1799K in association with megalencephaly and ID to three. In each case, evidence suggests that p.E1799K arose in the affected individuals due to gonadal mosaicism. Thus, MTOR p.E1799K can now be classified as a pathogenic GOF mutation that causes megalencephaly and cognitive impairment in humans.

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Mendeley readers

The data shown below were compiled from readership statistics for 65 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Netherlands 1 2%
Unknown 64 98%

Demographic breakdown

Readers by professional status Count As %
Researcher 12 18%
Student > Bachelor 11 17%
Student > Ph. D. Student 10 15%
Student > Master 10 15%
Student > Doctoral Student 5 8%
Other 13 20%
Unknown 4 6%
Readers by discipline Count As %
Psychology 14 22%
Medicine and Dentistry 11 17%
Biochemistry, Genetics and Molecular Biology 10 15%
Agricultural and Biological Sciences 7 11%
Nursing and Health Professions 5 8%
Other 12 18%
Unknown 6 9%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 07 November 2015.
All research outputs
#14,583,849
of 16,534,657 outputs
Outputs from BMC Medical Genetics
#768
of 999 outputs
Outputs of similar age
#238,030
of 288,758 outputs
Outputs of similar age from BMC Medical Genetics
#77
of 97 outputs
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So far Altmetric has tracked 999 research outputs from this source. They receive a mean Attention Score of 3.3. This one is in the 1st percentile – i.e., 1% of its peers scored the same or lower than it.
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We're also able to compare this research output to 97 others from the same source and published within six weeks on either side of this one. This one is in the 1st percentile – i.e., 1% of its contemporaries scored the same or lower than it.