mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review

Smith-Kingsmore syndrome (SKS) OMIM #616638, also known as MINDS syndrome (ORPHA 457485), is a rare autosomal dominant disorder reported so far in 23 patients. SKS is characterized by intellectual disability, macrocephaly/hemi/megalencephaly, and seizures. It is also associated with a pattern of facial dysmorphology and other non-neurological features. Germline or mosaic mutations of the mTOR gene have been detected in all patients. The mTOR gene is a key regulator of cell growth, cell proliferation, protein synthesis and synaptic plasticity, and the mTOR pathway (PI3K-AKT-mTOR) is highly regulated and critical for cell survival and apoptosis. Mutations in different genes in this pathway result in known rare diseases implicated in hemi/megalencephaly with epilepsy, as the tuberous sclerosis complex caused by mutations in TSC1 and TSC2, or the PIK3CA-related overgrowth spectrum (PROS). We here present 4 new cases of SKS, review all clinical and molecular aspects of this disorder, as well as some characteristics of the patients with only brain mTOR somatic mutations.This research was supported by the project IP-17 from the call “Todos Somos Raros” (Telemaraton TVE promoted by Fundación Isabel Gemio, Federación ASEM, and Federación Española de Enfermedades Raras), and co-financed by ISCIII, FEDER FUNDS FIS PI15/ 0148

Expansion and further delineation of the SETD5 phenotype leading to global developmental delay, variable dysmorphic features, and reduced penetrance

Diagnostic exome sequencing (DES) has aided delineation of the phenotypic spectrum of rare genetic etiologies of intellectual disability (ID). A SET domain containing 5 gene (SETD5) phenotype of ID and dysmorphic features has been previously described in relation to patients with 3p25.3 deletions and in a few individuals with de novo sequence alterations. Herein, we present additional patients with pathogenic SETD5 sequence alterations. The majority of patients in this cohort and previously reported have developmental delay, behavioral/psychiatric issues, and variable hand and skeletal abnormalities. We also present an apparently unaffected carrier mother of an affected individual and a carrier mother with normal intelligence and affected twin sons. We suggest that the phenotype of SETD5 is more complex and variable than previously presented. Therefore, many features and presentations need to be considered when evaluating a patient for SETD5 alterations through DES

Characterization of prostaglandin endoperoxide H synthase-1 enzyme expression during the differentiation of the megakaryocytic cell line, MEG-01.

The specific objectives of my Master's project have been two-fold: to characterize the expression of prostaglandin endoperoxide synthase-1 (PGHS-1) protein and mRNA within the context of megakaryopoiesis, and to identify growth factors capable of inducing such expression. We induced MEG-01 cells to differentiate into platelet-like structures by treating them with TPA (12-0-tetradecanoylphorbol-13-acetate). We found that PGHS-1 protein levels were him in the platelet like population whereas PGHS-1 mRNA levels were greatest in the adherent population. We screened a number of recombinant hematopoietic factors for the ability to induce PGHS-1 protein expression in MEG-01 cells. We found that the combinations IL-3/IL-11/GM-CSF/SCF/TPO, IL-11/GM-CSF/SCF/TPO, IL-11/GM-CSF/TPO, IL-6/IL-11/GM-CSF/SCF, IL-6/IL-11, IL-3/IL-6, and IL 6/GM-CSF could induce PGHS-1 protein expression, but only when incubated with MEG-01 cultures that consisted solely of adherent cells. In conclusion, we have revealed that PGHS-1 protein and mRNA expression correlate strongly with megakaryocyte differentiation, and that certain cytokines can act in concert to stimulate adherent MEG-01 cells to increase their expression of PGHS-1 protein. The combination of IL-6 and -11 not only stimulates MEG-01 cells to increase their expression of PGHS-1 protein, but also PGHS-1 mRNA. (Abstract shortened by UMI.

Smith-Kingsmore Syndrome: A Third Family with the MTOR Mutation C.5395G > A p.(Glu1799Lys) and Evidence for Paternal Gonadal Mosaicism

Heterozygous germline mutations in MTOR have been shown to underlie Smith-Kingsmore syndrome, a rare autosomal dominant syndrome characterized by macrocephaly, developmental delay, and dysmorphic facial features. Recently, two unrelated families with the MTOR mutation, c.5395G>A p.(Glu1799Lys), were reported. Here, we describe siblings from a non-consanguineous German family in whom we identified the same heterozygous missense mutation in MTOR. Remarkably, in all reported families with Smith-Kingsmore syndrome and the MTOR c.5395G>A mutation, including the family described herein, healthy parents of recurrently affected children do not have detectable levels of the mutation in tested tissues, lending credence to gonadal mosaicism as the underlying mechanism. Furthermore, the glutamic acid at position 1799 was shown to present a recurrent somatic mutation site in several cancers, including colon cancer, pointing to a somatic mutational hotspot in MTOR. Importantly, we highlight the occurrence of multiple intestinal polyps in the older sibling. Further patients are required to establish definitively whether polyp formation forms part of the SKS clinical spectrum. (C) 2016 Wiley Periodicals, Inc

Additional file 3: Table S3. of Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities

Variant Filtering Based on Inheritance Modeling & Interpretation. (PPTX 66.7 kb

Additional file 2: Table S2. of Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities

Bioinformatic Variant Filtering. (PPTX 54.9 kb

Additional file 1: Table S1. of Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities

Illumina Hiseq Run Metrics for family trio. (PPTX 75.6 kb