title: Smith-Kingsmore syndrome: A third family with the MTOR mutation c.5395G>A p.(Glu1799Lys) and evidence for paternal gonadal mosaicism.
abstract: 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. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Shahida
authors.initials: S
authors.lastname: Moosa
authors.affiliation: Genetikum, Neu-Ulm, Germany.
authors.forename: Helena
authors.initials: H
authors.lastname: Böhrer-Rabel
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Institute of Human Genetics, University Hospital Düsseldorf, Düsseldorf, Germany.
authors.forename: Filippo
authors.initials: F
authors.lastname: Beleggia
authors.affiliation: Cologne Center for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Yun
authors.initials: Y
authors.lastname: Li
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Gökhan
authors.initials: G
authors.lastname: Yigit
authors.affiliation: Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D002675:Child, Preschool; D003062:Codon; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D009030:Mosaicism; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA; D035781:Siblings; D013577:Syndrome; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D003062:Codon; D058570:TOR Serine-Threonine Kinases
keywords: MTOR; Smith-Kingsmore syndrome; macrocephaly; p.Glu1799 somatic hotspot