Rare familial TSC2 gene mutation associated with atypical phenotype presentation of Tuberous Sclerosis Complex

Abstract

Tuberous sclerosis complex (TSC) is a neurocutaneous disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. We describe an 18-month-old boy who presented with seizures and a single hypopigmented macule. He did not meet consensus criteria for the clinical diagnosis of TSC. Exome sequencing revealed a heterozygous TSC2 mutation (c.5138G>A (p.Arg1713His)) in the patient. This heterozygous alteration was detected in his mother as well as several other maternal family members. The mother and other family members with the mutation were asymptomatic except for the presence of hypopigmented macules. The phenotypic characteristics of the individuals in this family were not suggestive of a TSC2 mutation as none satisfied the clinical criteria for even a diagnosis of possible TSC. This case provides evidence for a unique TSC2 mutation that resulted in an atypical clinical presentation and indicates potential shortcomings of the current diagnostic criteria for TSC. These findings may have implications for genetic counseling and screening. © 2017 Wiley Periodicals, Inc.

Phacomatoses, genetic testing for personalisation of clinical management (part 2)

“…Mutations in the TSC1 gene are almost twice as frequent in hereditary cases as compared to the sporadic form. Penetration of the TSC1 and TSC2 mutations is complete, while expression of disease is variable [42]. Symptoms of the disease occur in people in whom the second copy of the gene is silenced due to changes in the DNA sequence (mutations) or epigenetic changes -in line with Knudson's two-hit theory [35].…”

“…If the TSC2 gene is deleted, the PKD1 (polycystin 1) gene is also deleted (3' ends of these genes overlap) causing a contiguous gene syndrome [41]. Interestingly, there are also reports of people / families with mutations in TSC2, who had a milder course of the disease, either mildly symptomatic or asymptomatic [42,43].…”

Impacting development in infants with tuberous sclerosis complex: Multidisciplinary research collaboration.

“…Farach et al (2017) examined six cases (descriptions ranging from birth to 15 years) of individuals with TSC2 c1864C>T, considered to be a pathogenic variant of the TSC2 gene. In general, individuals with TSC2 variants are thought to have more severe phenotypes than do those with TSC1 variants (e.g., Au et al, 2007; Kothare et al, 2014); however, there have been some reports that specific variants of TSC2 are associated with milder phenotypes (Fox et al, 2017; van Eeghen, Nellist, van Eeghen, & Thiele, 2013). Most of the six patients in this case report did not meet the clinical criteria for definite TSC, although they carried TSC2 c1864C>T. Developmental testing revealed cognitive and language functioning within the average range for one patient.…”

Identification of a novel heterozygous TSC2 splicing variant in a patient with Tuberous sclerosis complex

“…[ 6 ] The atypical clinical presentation indicates the potential shortcomings of the current diagnostic criteria for TSC. [ 7 ] A pathogenic variant of either TSC1 or TSC2 detected by genetic analysis represents a separate diagnostic criterion, regardless of clinical findings. [ 8 ] With advances in genomic DNA sequencing technology, it is now easy to analyze the entire sequence of TSC genes.…”

“…Even monozygotic twins with the same mutation can exhibit different clinical expressions [6] . The atypical clinical presentation indicates the potential shortcomings of the current diagnostic criteria for TSC [7] . A pathogenic variant of either TSC1 or TSC2 detected by genetic analysis represents a separate diagnostic criterion, regardless of clinical findings [8] .…”