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Clin Genet. 2018 Apr;93(4):762-775. doi: 10.1111/cge.13135. Epub 2018 Feb 13.

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

Author information

1
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
2
Molecular Endocrinology Section, Overgrowth Syndromes Laboratory, Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
3
Vascular Malformations Section, Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
4
Clinical Genetics Section, Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
5
Structural and Functional Genomics Section, Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
6
Bioinformatics Section, Instituto de Genética Médica y Molecular (INGEMM), IdiPAZ, Hospital Universitario la Paz, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
7
IIB, Instituto de Investigación "Alberto Sols", Universidad Autónoma de Madrid (UAM), Madrid, Spain.

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.

KEYWORDS:

MINDS syndrome; Smith-Kingsmore syndrome; constitutive mosaicism; germline mosaicism; gonadal mosaicism; mTOR; macrocephaly; megalencephaly; somatic mosaicism

PMID:
28892148
DOI:
10.1111/cge.13135
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