A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore syndrome and Antiphospholipid syndrome

Abstract

We report the clinical, biochemical and genetic findings from a Spanish girl of Caucasian origin who presented with macrocephaly, dysmorphic facial features, developmental delay, hypotonia, combined oxidative phosphorylation (OxPhos) deficiency, epilepsy and anti-phospholipid antibodies (aPL). Whole-exome sequencing (WES) uncovered a heterozygous variant in the MTOR gene (NM_004958.3: c.7235A>T: p.(Asp2412Val)) that encodes for the Serine/threonine-protein kinase mTOR. The substrates phosphorylation experiments demonstrated that this variant exerts its effect by gain-offunction (GOF) and autosomal dominant mechanism. GOF variants in this protein have been associated with Smith-Kingsmore syndrome (SKS), a rare autosomal dominant disorder characterized by intellectual disability, macrocephaly, seizure, developmental delay and dysmorphic facial features. Furthermore, the mTOR pathway has been demonstrated previously to be involved in many types of endothelium injuries including the antiphospholipid syndrome (APS), a systemic autoimmune disease characterized by the production of aPL with recurrent vascular thrombosis. Therefore, our patient is the first one with an mTOR variant and diagnosed with SKS and APS. In conclusion, our data expand both the genetic and phenotypic spectrum associated with MTOR gene variants.

A new case of Smith‐Kingsmore syndrome with somatic MTOR pathogenic variant expands the phenotypic spectrum to lateralized overgrowth

“…Among them, the c.5395G > A p.Glu1799Lys variant was found in nearly half of the cases (14 of 34) and represents a mutational hotspot 15 . Among the patients reported, 29 carried germline pathogenic variants, either de novo or deriving from gonadal mosaicism, 1,11‐13 while five patients presented mosaic variants in at least two of the tissues tested (disseminated mosaicism) 1,6‐8 . The main clinical features of these patients are summarized in Table 1 and compared with our case.…”

“…Since SKS was first described, and to the best of our knowledge, 12 pathogenic MTOR variants in 34 patients have been reported in the medical literature, 1,7,11‐13 all of which were gain‐of‐function missense variants 1,2,12‐15 . Among them, the c.5395G > A p.Glu1799Lys variant was found in nearly half of the cases (14 of 34) and represents a mutational hotspot 15 .…”

Expanding the phenotype of MTOR -related disorders and the Smith-Kingsmore syndrome

“…6 A recently published article reported a de novo MTOR gain of function variant in a patient with SKS and antiphospholipid syndrome, expanding both the genetic and phenotypic spectra of MTOR-associated diseases. 7…”

Delineating the Smith‐Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G > A p.(Glu1799Lys) missense variant

“…In 2013, constitutional MTOR variants were reported to cause a new OGID syndrome, eponymously named Smith-Kingsmore Syndrome (SKS) (OMIM 616638) (Smith et al, 2013). Since this initial description, a total of 30 patients with constitutional MTOR variants have been described, with clinical features including megalencephaly, a variable intellectual disability, autism spectrum disorder, and seizures (Allen et al, 2013;Baynam et al, 2015;Elizondo-Plazas et al, 2020;Ghahramani et al, 2015;Gordo et al, 2018;Lee et al, 2019;Mirzaa et al, 2016;Møller et al, 2016;Moosa et al, 2017;Mroske et al, 2015;Rodríguez-García et al, 2019;Smith et al, 2013).…”

“…This variant has been shown to decrease the binding of the mTOR inhibitor Deptor, thereby upregulating the mTOR pathway and promoting growth (Baynam et al, 2015;Gordo et al, 2018). Ten additional MTOR missense variants, targeting amino acid residues within the FAT and kinase domains, have been described in the remaining 16 patients reported in the literature (Allen et al, 2013;Elizondo-Plazas et al, 2020;Ghahramani et al, 2015;Gordo et al, 2018;Møller et al, 2016;Rodríguez-García et al, 2019;Smith et al, 2013) (Figure 1). There are limited functional data available on these 10 other variants but a gain of function effect has been ascribed to the MTOR c.4448G>T p.(Cys1483Phe) variant (Gordo et al, 2018;Grabiner et al, 2014;Smith et al, 2013).…”