title: Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities.
abstract: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Ambry Genetics Corporation, Aliso Viejo, CA, 92656, USA. cmroske@ambrygen.com.
authors.forename: Cameron
authors.initials: C
authors.lastname: Mroske
authors.affiliation: Marshfield Clinic Research Foundation, Marshfield, WI, 54449, USA. rasmussen.kristen@marshfieldclinic.org.
authors.forename: Kristen
authors.initials: K
authors.lastname: Rasmussen
authors.affiliation: Ambry Genetics Corporation, Aliso Viejo, CA, 92656, USA. dshinde@ambrygen.com.
authors.forename: Deepali N
authors.initials: DN
authors.lastname: Shinde
authors.affiliation: Ambry Genetics Corporation, Aliso Viejo, CA, 92656, USA. rhuether@ambrygen.com.
authors.forename: Robert
authors.initials: R
authors.lastname: Huether
authors.affiliation: Ambry Genetics Corporation, Aliso Viejo, CA, 92656, USA. zpowis@ambrygen.com.
authors.forename: Zoe
authors.initials: Z
authors.lastname: Powis
authors.affiliation: Ambry Genetics Corporation, Aliso Viejo, CA, 92656, USA. hmlu@ambrygen.com.
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Lu
authors.affiliation: Ambry Genetics Corporation, Aliso Viejo, CA, 92656, USA. rbaxter@ambrygen.com.
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Baxter
authors.affiliation: Marshfield Clinic Research Foundation, Marshfield, WI, 54449, USA. mcpherson.elizabeth@marshfieldclinic.org.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McPherson
authors.affiliation: Ambry Genetics Corporation, Aliso Viejo, CA, 92656, USA. stang@ambrygen.com.
authors.forename: Sha
authors.initials: S
authors.lastname: Tang
mesh_terms: D001321:Autistic Disorder / Q000235:genetics; D002648:Child; D002658:Developmental Disabilities / Q000235:genetics; D059472:Exome; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D008297:Male; D058627:Megalencephaly / Q000235:genetics*; D009030:Mosaicism; D017422:Sequence Analysis, DNA / Q000379:methods; D035781:Siblings; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D013737:Testis / Q000473:pathology / Q000502:physiology*; D055815:Young Adult
chemical_list: C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases