Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings.

Creator(s)

R C Caylor, Children's Mercy Hospital
L Grote, Children's Mercy Hospital
Isabelle Thiffault, Children's Mercy HospitalFollow
Emily G. Farrow, Children's Mercy HospitalFollow
Laurel K. Willig, Children's Mercy HospitalFollow
Sarah E. Soden, Children's Mercy HospitalFollow
Shivarajan Manickavasagam Amudhavalli, Children's Mercy HospitalFollow
Amy J. Nopper, Children's Mercy HospitalFollow
Kimberly A. Horii, Children's Mercy HospitalFollow
Emily Fleming, Children's Mercy HospitalFollow
Janda L. Jenkins, Children's Mercy HospitalFollow
Holly Welsh, Children's Mercy HospitalFollow
Mohammed Ilyas, Children's Mercy HospitalFollow
Kendra Engleman, Children's Mercy HospitalFollow
Ahmed Abdelmoity, Children's Mercy HospitalFollow
Carol J. Saunders, Children's Mercy HospitalFollow

Document Type

Article

Publication Date

8-2018

Identifier

DOI: 10.1007/s10048-018-0551-y

Abstract

Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disorder characterized by lesions and benign tumors in multiple organ systems including the brain, skin, heart, eyes, kidneys, and lungs. The phenotype is highly variable, although penetrance is reportedly complete. We report the molecular diagnosis of TSC in individuals exhibiting extreme intra-familial variability, including the incidental diagnosis of asymptomatic family members. Exome sequencing was performed in three families, with probands referred for epilepsy, autism, and absent speech (Family 1); epileptic spasms (Family 2); and connective tissue disorders (Family 3.) Pathogenic variants in TSC1 or TSC2 were identified in nine individuals, including relatives with limited or no medical concerns at the time of testing. Of the nine individuals reported here, six had post-diagnosis examinations and three met clinical diagnostic criteria for TSC. One did not meet clinical criteria for a possible or definite diagnosis of TSC, and two had only a possible clinical diagnosis following post-diagnosis workup. These individuals as well as their mothers demonstrated limited features that would not raise concern for TSC in the absence of molecular results. In addition, three individuals exhibited epilepsy with normal brain MRIs, and two without seizures or intellectual disability had MRI findings fulfilling major criteria for TSC highlighting the difficulty providers face when relying on clinical criteria to guide genetic testing. Given the importance of a timely TSC diagnosis for clinical management, such cases demonstrate a potential benefit for clinical criteria to include seizures and an unbiased molecular approach to genetic testing.

Journal Title

Neurogenetics

Volume

19

Issue

3

First Page

205

Last Page

213

MeSH Keywords

Adolescent; Adult; Asymptomatic Diseases; Child; Family; Female; Humans; Incidental Findings; Infant; Male; Middle Aged; Pakistan; Phenotype; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Whole Exome Sequencing; Young Adult

Keywords

Asymptomatic; Atypical phenotype; Exome sequencing; Genetic counseling; Incidental finding; Molecular diagnosis; TSC1; TSC2; Tuberous sclerosis complex

Comments

Erratum in

• Correction to: Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings. Caylor RC, Grote L, Thiffault I, Farrow EG, Willig L, Soden S, Amudhavalli SM, Nopper AJ, Horii KA, Fleming E, Jenkins J, Welsh H, Ilyas M, Engleman K, Abdelmoity A, Saunders CJ.Neurogenetics. 2018 Dec;19(4):261-262. doi: 10.1007/s10048-018-0554-8.PMID: 29992365

Recommended Citation

Caylor RC, Grote L, Thiffault I, et al. Incidental diagnosis of tuberous sclerosis complex by exome sequencing in three families with subclinical findings [published correction appears in Neurogenetics. 2018 Jul 11;:]. Neurogenetics. 2018;19(3):205-213. doi:10.1007/s10048-018-0551-y