The association of neurodevelopmental abnormalities, congenital heart and renal defects in a Tuberous Sclerosis Complex patient cohort

Robinson, Jessica, Uzun, Orhan, Ron Loh, Ne, Harris, Isabelle Rose, Woolley, Thomas E. ORCID: https://orcid.org/0000-0001-6225-5365, Harwood, Adrian ORCID: https://orcid.org/0000-0003-3124-5169, Gardner, Jennifer Frances and Syed, Yasir Ahmed ORCID: https://orcid.org/0000-0001-9495-307X 2022. The association of neurodevelopmental abnormalities, congenital heart and renal defects in a Tuberous Sclerosis Complex patient cohort. BMC Medicine 20 , 123. 10.1186/s12916-022-02325-0

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Abstract

Background: Tuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterised by the presence of benign tumours throughout multiple organs including the brain, kidneys, heart, liver, eyes, lungs and skin, in addition to neurological and neuropsychiatric complications. Intracardiac tumour (rhabdomyoma), neurodevelopmental disorders (NDDs) and kidney disorders (KD) are common manifestations of TSC and have been linked with TSC1 and TSC2 loss-of-function mutations independently, but the dynamic relationship between these organ manifestations remains unexplored. Therefore, this study aims to characterise the nature of the relationship specifically between these three organs' manifestations in TSC1 and TSC2 mutation patients. Methods: Clinical data gathered from TSC patients across South Wales registered with Cardiff and Vale University Health Board (CAV UHB) between 1990 and 2020 were analysed retrospectively to evaluate abnormalities in the heart, brain and kidney development. TSC-related abnormalities such as tumour prevalence, location and size were analysed for each organ in addition to neuropsychiatric involvement and were compared between TSC1 and TSC2 mutant genotypes. Lastly, statistical co-occurrence between organ manifestations co-morbidity was quantified, and trajectories of disease progression throughout organs were modelled. Results: This study found a significantly greater mutational frequency at the TSC2 locus in the cohort in comparison to TSC1. An equal proportion of male and female patients were observed in this group and by meta-analysis of previous studies. No significant difference in characterisation of heart involvement was observed between TSC1 and TSC2 patients. Brain involvement was seen with increased severity in TSC2 patients, characterised by a greater prevalence of cortical tubers and communication disorders. Renal pathology was further enhanced in TSC2 patients, marked by increased bilateral angiomyolipoma prevalence. Furthermore, co-occurrence of NDDs and KDs was the most positively correlated out of investigated manifestations, regardless of genotype. Analysis of disease trajectories revealed a more diverse clinical outcome for TSC2 patients: however, a chronological association of rhabdomyoma, NDD and KD was most frequently observed for TSC1 patients. Conclusions: This study marks the first empirical investigation of the co-morbidity between congenital heart defects (CHD), NDDs, and KDs in TSC1 and TSC2 patients. This remains a unique first step towards the characterisation of the dynamic role between genetics, heart function, brain function and kidney function during the early development in the context of TSC.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Additional Information:	This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made.
Publisher:	BioMed Central
ISSN:	1741-7015
Date of First Compliant Deposit:	21 March 2022
Date of Acceptance:	7 March 2022
Last Modified:	12 May 2023 17:13
URI:	https://orca.cardiff.ac.uk/id/eprint/148267

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