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Am J Med Genet A. 2017 Jan;173(1):264-267. doi: 10.1002/ajmg.a.37999. Epub 2016 Oct 18.

Smith-Kingsmore syndrome: A third family with the MTOR mutation c.5395G>A p.(Glu1799Lys) and evidence for paternal gonadal mosaicism.

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Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
Genetikum, Neu-Ulm, Germany.
Cologne Center for Genomics, University of Cologne, Cologne, Germany.
Institute of Human Genetics, University of Cologne, Cologne, Germany.
Institute of Human Genetics, University Hospital Düsseldorf, Düsseldorf, Germany.


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.


MTOR; Smith-Kingsmore syndrome; macrocephaly; p.Glu1799 somatic hotspot

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