MTOR – macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome

Smith-Kingsmore syndrome (SKS), corresponding to MONDO:0014716, is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous gain-of-function variants in the MTOR gene (HGNC:3942). Clinically, SKS is defined by postnatal macrocephaly, global developmental delay, intellectual disability, seizures and distinctive dysmorphic facial features.

Clinical Validity

Genetic studies to date have identified SKS in over 50 unrelated probands with de novo MTOR missense mutations (PMID:28892148, PMID:34032352), including recurrent hotspot variants segregating in mosaic families. Gonadal mosaicism has been documented in at least three families, with multiple affected siblings lacking detectable parental blood mutation, supporting pathogenicity via a dominant gain-of-function mechanism (PMID:27753196). Concordant functional studies further reinforce a definitive gene–disease relationship.

Genetic Evidence

SKS exhibits an autosomal dominant inheritance mode with a preponderance of de novo events and occasional germline mosaicism. No additional segregation beyond sibling recurrence in mosaic families has been reported. To date, >50 probands harbor MTOR missense variants, predominantly within the kinase and FAT domains. The recurrent c.5395G>A (p.Glu1799Lys) variant is found in ~47% of reported cases and has been observed in three independent families (PMID:34032352). Other SKS-associated variants include c.4448G>A (p.Cys1483Tyr), c.7235A>T (p.Asp2412Val), c.7216G>A (p.Val2406Met) and c.5930C>T (p.Thr1977Ile).

Functional Evidence

In vitro assays demonstrate that SKS-associated MTOR variants induce hyperphosphorylation of downstream targets (p-S6K, p-4EBP1) consistent with mTORC1 and novel mTORC2 activation, confirming gain-of-function (PMID:34197453). Structural modeling indicates pathogenic variants cluster at key regulatory interfaces, disrupting helix packing and increasing catalytic activity. Rapamycin responsiveness varies by allele, informing potential targeted therapy.

Conflicting Evidence

No reports to date refute the MTOR–SKS association or assign alternative primary phenotypes, and absence of truncating or loss-of-function alleles in affected individuals further supports a specific gain-of-function mechanism.

Conclusion

Genetic and experimental data robustly support a definitive association between MTOR gain-of-function variants and SKS, with clear diagnostic and therapeutic implications. Routine sequencing of MTOR in patients with macrocephaly and developmental delay enables early diagnosis and informs mTOR-inhibitor intervention trials.

References

• American Journal of Medical Genetics. Part A | 2017 | Smith-Kingsmore syndrome: A third family with the MTOR mutation c.5395G>A p.(Glu1799Lys) and evidence for paternal gonadal mosaicism. PMID:27753196
• Clinical Genetics | 2018 | mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review. PMID:28892148
• American Journal of Medical Genetics. Part A | 2021 | Delineating the Smith-Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G>A p.(Glu1799Lys) missense variant. PMID:34032352
• PLoS Genetics | 2021 | Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity. PMID:34197453
• European Journal of Human Genetics | 2019 | A novel de novo MTOR gain-of-function variant in a patient with Smith-Kingsmore syndrome and Antiphospholipid syndrome. PMID:31053780

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