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

Abstract

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.

Constitutional mosaicism in RASA1‐related capillary malformation‐arteriovenous malformation

“…The presence of somatic mutations, without previous germline mutations, has also been described in conditions such as the unifocal venous malformations, the PIK3CA ‐related overgrowth spectrum or in several Rasopathies, including NF1 . However, constitutional mosaicism, which is a pathogenic variant present constitutionally but at the same time in mosaic, therefore in mosaic in all cell types, seems to be an under‐recognized and rarely described mechanism . Here, we report constitutional mosaic pathogenic variants in the RASA1 gene in two unrelated patients with CM‐AVM.…”

“…8,11 However, constitutional mosaicism, which is a pathogenic variant present constitutionally but at the same time in mosaic, therefore in mosaic in all cell types, seems to be an under-recognized and rarely described mechanism. 12 Here, we report constitutional mosaic pathogenic variants in the RASA1 gene in two unrelated patients with CM-AVM. previously described in-house bioinformatics pipeline for somatic mosaicism detection.…”

Further definition of the proximal 19p13.3 microdeletion/microduplication syndrome and implication of PIAS4 as the major contributor

“…Other genes of interest in the microdeletion include CSNK1G2 which encodes for a protein with transferase activity that is involved in brain development, vesicular trafficking and neurotransmitter releasing from small synaptic vesicles . GNA15, GNG7 and GNA11 are members of the G‐protein family, where GNA15 is also involved in PI3K‐AKT signaling pathway through its interaction with PRKCA, a well‐known gene included in some pathways of constitutive and partial overgrowth disorders …”

“…34 GNA15, GNG7 and GNA11 are members of the G-protein family, where GNA15 is also involved in PI3K-AKT signaling pathway through its interaction with PRKCA, a well-known gene included in some pathways of constitutive and partial overgrowth disorders. 35,36 PIAS4 participates in the sumoylation of several proteins including CEBPA, PARK7, HERC2, MYB, TCF4 and RNF168. [12][13][14][15] PIAS4 acts as a potent inhibitor of the androgen receptor (AR) in prostate cancer cells.…”

Smith-Kingsmore syndrome: The first report of a Korean patient with the MTOR germline mutation c.5395G>A p.(Glu1799Lys)

“…Also known as macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (MINDS; ORPHA 457485), it is caused by a heterozygous germline mutation in MTOR (OMIM 601231) on chromosome 1p36 [1]. SKS is characterized by intellectual disability; macrocephaly/hemicephaly/ megalencephaly; seizures; and facial dysmorphic features such as curly/wavy hair, frontal bossing, midface hypoplasia, small chin, and hypertelorism [2]. The prevalence of SKS remains unknown.…”