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

Smith‐Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a variable intellectual disability, autism spectrum disorder, and MTOR gain of function variants. Only 30 patients with MTOR missense variants are published, including 14 (47%) with the MTOR c.5395G>A p.(Glu...

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Bibliographic Details
Published in:American journal of medical genetics. Part A 2021-08, Vol.185 (8), p.2445-2454
Main Authors: Poole, Rebecca L., Curry, Philippa D. K., Marcinkute, Ruta, Brewer, Carole, Coman, David, Hobson, Emma, Johnson, Diana, Lynch, Sally Ann, Saggar, Anand, Searle, Claire, Scurr, Ingrid, Turnpenny, Peter D., Vasudevan, Pradeep, Tatton‐Brown, Katrina
Format: Article
Language:English
Subjects:
Adolescent
Alleles
Amino Acid Substitution
Autism
Autism Spectrum Disorder - diagnosis
Autism Spectrum Disorder - genetics
Child
Child, Preschool
Facies
Female
Genetic Association Studies
Genetic Loci
Humans
Intellectual disabilities
Intellectual Disability - diagnosis
Intellectual Disability - genetics
Male
Megalencephaly
Megalencephaly - diagnosis
Megalencephaly - genetics
MTOR
Mutation, Missense
Patients
Phenotype
Phenotypes
Smith‐Kingsmore syndrome
Syndrome
TOR protein
TOR Serine-Threonine Kinases - genetics
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Summary:Smith‐Kingsmore Syndrome (SKS) is a rare genetic syndrome associated with megalencephaly, a variable intellectual disability, autism spectrum disorder, and MTOR gain of function variants. Only 30 patients with MTOR missense variants are published, including 14 (47%) with the MTOR c.5395G>A p.(Glu1799Lys) variant. Limited phenotypic data impacts the quality of information delivered to families and the robustness of interpretation of novel MTOR missense variation. This study aims to improve our understanding of the SKS phenotype through the investigation of 16 further patients with the MTOR c.5395G>A p.(Glu1799Lys) variant. Through the careful phenotypic evaluation of these 16 patients and integration with data from 14 previously reported patients, we have defined major (100% patients) and frequent (>15%) SKS clinical characteristics and, using these data, proposed guidance for evidence‐based management. In addition, in the absence of functional studies, we suggest that the combination of the SKS major clinical features of megalencephaly (where the head circumference is at least 3SD) and an intellectual disability with a de novo MTOR missense variant (absent from population databases) should be considered diagnostic for SKS.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.62350