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

BMC Medical Genetics

Sha Tang¹  Elizabeth McPherson²  Ruth M. Baxter¹  Hsiao-Mei Lu¹  Zoe Powis¹  Robert Huether¹  Deepali N. Shinde¹  Kristen Rasmussen²  Cameron Mroske¹ 

[1] Ambry Genetics Corporation, Aliso Viejo 92656, CA, USA;Marshfield Clinic Research Foundation, Marshfield 54449, WI, USA

关键词: Missense alteration;    Gain-of-function;    Gonadal mosaicism;    Megalencephaly;    Macrocephaly;    ASD;    Autism;    MTOR;    Family-trio;    Diagnostic exome sequencing;   

Others  :  1230628
DOI  :  10.1186/s12881-015-0240-8

 received in 2015-07-03, accepted in 2015-10-03,  发布年份 2015

【 摘 要 】

Background

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.

Case presentation

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.

Conclusion

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.

【 授权许可】

   
2015 Mroske et al.

【 图 表 】

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