A six-attribute classification of geneticmosaicism

Martínez‐Glez, Víctor; Tenorio, Jair; Nevado, Julián; Gordo, Gema; Rodríguez‐Laguna, Lara; Feito, Marta; Lucas, R. de; Pérez-Jurado, Luís A.; Pérez, Víctor L.; Torrelo, Antonio; Spinner, Nancy B.; Happle, Rudolf; Biesecker, Leslie G.; Lapunzina, Pablo

doi:10.1038/s41436-020-0877-3

Cited by 43 publications

(49 citation statements)

References 144 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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.…”

Section: Discussionmentioning

confidence: 63%

“…While typical SKS is caused by pathogenic germinal MTOR variants, mosaicism confined to the brain usually results in isolated focal cortical dysplasia (FCD) without additional SKS features 4,5 . Only five patients with disseminated mosaicism (i.e., presence of two or more lesions in the body) 6 have been described so far (Patient 2 from Gordo et al, 1 patient 1 from Handoko et al 7 and patients LR 13–310, LR 14–326 and LR 15–044 from Mirzaa et al 8 ). Patients with disseminated mosaic variants can display some SKS features, but usually present features consistent with mosaicism, such as patchy hypopigmentation of the skin, hemimegalencephaly, and FCD/polymicrogyria.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Carli¹,

Fusillo²,

Coppo³

et al. 2021

Clinical Genetics

View full text Add to dashboard Cite

Smith‐Kingsmore syndrome (SKS) is a rare autosomal dominant disorder caused by heterozygous germline activating pathogenic variants in mammalian target of rapamycin (MTOR) on chromosome 1p36. A few patients with disseminated mosaicism have been described so far and they seem to display a different phenotype when compared to germline cases. Here we report the sixth case with a disseminated mosaic MTOR pathogenic variant, a 7‐year‐old boy with hemimegalencephaly, epilepsy, developmental delay, hypomelanosis of Ito, and lateralized overgrowth. Genetic testing revealed a pathogenic variant (c.4448G > A, p.Cys1483Tyr) in MTOR with a frequency of 32% in the DNA extracted from a skin sample, 3% in saliva and 0.46% in blood. The clinical features observed in our patient further corroborate the existence of differences in phenotypic presentation of germline and mosaic SKS cases. Moreover, lateralized overgrowth, a finding never described so far in SKS, further expands the phenotypic spectrum of SKS and allows the inclusion of MTOR pathogenic variants among the several causes of asymmetric body overgrowth.

show abstract

Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

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

Carli¹,

Fusillo²,

Coppo³

et al. 2021

Clinical Genetics

View full text Add to dashboard Cite

show abstract

“…The results showed that twin A carried a mosaic variant with a fraction level of 13.35%, and that twin B was negative. The mosaicism in this affected fetus can be designated as A1B2C1D1E2F2: a somatic mosaicism (A1), according to a new six‐attribute classification of genetic mosaicism proposed by Martínez‐Glez et al 3 In addition, short tandem repeat polymorphism marker analysis also confirmed the monozygotic pregnancy.…”

Section: Figurementioning

confidence: 95%

Prenatal phenotypic discordance in monozygotic twins due to a postzygotic TSC2 variant

Guo²,

Jiang

et al. 2020

Prenatal Diagnosis

View full text Add to dashboard Cite

“…Somatic MTOR variants have been associated with a clinical presentation of asymmetric megalencephaly (including hemimegalencephaly), polymicrogyria, and cutaneous pigmentary mosaicism, while variants confined to subregions of the brain have been associated with focal cortical dysplasia (FCD) types 2a and 2b, which frequently result in epilepsy and other neurodevelopmental deficits [ 1 , 3 ]. Germline and somatic mosaic MTOR pathogenic variants [ 5 ] cause Smith-Kingsmore Syndrome (SKS), which is characterized by macrocephaly/megalencephaly, developmental delay, intellectual disability, hypotonia, and seizures [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity

et al. 2021

View full text Add to dashboard Cite

Smith-Kingsmore syndrome (SKS) is a rare neurodevelopmental disorder characterized by macrocephaly/megalencephaly, developmental delay, intellectual disability, hypotonia, and seizures. It is caused by dominant missense mutations in MTOR. The pathogenicity of novel variants in MTOR in patients with neurodevelopmental disorders can be difficult to determine and the mechanism by which variants cause disease remains poorly understood. We report 7 patients with SKS with 4 novel MTOR variants and describe their phenotypes. We perform in vitro functional analyses to confirm MTOR activation and interrogate disease mechanisms. We complete structural analyses to understand the 3D properties of pathogenic variants. We examine the accuracy of relative accessible surface area, a quantitative measure of amino acid side-chain accessibility, as a predictor of MTOR variant pathogenicity. We describe novel clinical features of patients with SKS. We confirm MTOR Complex 1 activation and identify MTOR Complex 2 activation as a new potential mechanism of disease in SKS. We find that pathogenic MTOR variants disproportionately cluster in hotspots in the core of the protein, where they disrupt alpha helix packing due to the insertion of bulky amino acid side chains. We find that relative accessible surface area is significantly lower for SKS-associated variants compared to benign variants. We expand the phenotype of SKS and demonstrate that additional pathways of activation may contribute to disease. Incorporating 3D properties of MTOR variants may help in pathogenicity classification. We hope these findings may contribute to improving the precision of care and therapeutic development for individuals with SKS.

show abstract

A six-attribute classification of geneticmosaicism

Cited by 43 publications

References 144 publications

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

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

Prenatal phenotypic discordance in monozygotic twins due to a postzygotic TSC2 variant

Functional and structural analyses of novel Smith-Kingsmore Syndrome-Associated MTOR variants reveal potential new mechanisms and predictors of pathogenicity

Contact Info

Product

Resources

About