Mosaic skin disorders - deep sequencing

Gene: TSC2

Green List (high evidence)

Comment on list classification: There are numerous individuals reported in literature diagnosed with Tuberous sclerosis complex, harbouring heterozygous mosaic TSC2 variants. Variants are sometimes detected in skin biopsy samples only - not in blood or saliva. Deep sequencing of multiple patient samples is advised, as the variants often occur at very low frequencies (down to <1%). Based on the available evidence, TSC2 should be promoted to Green for Mosaic skin disorders - deep sequencing.

Created: 5 Dec 2025, 4:14 p.m. | Last Modified: 5 Dec 2025, 4:14 p.m.

Panel Version: 3.16

Tuberous sclerosis complex present with hamartomatous tumors affecting multiple organs, including the skin: facial angiofibroma, ungual fibroma, and shagreen patch (PMID: 37141891).

PMID: 37356622 Blasco-Perez et al., 2023
Cohort of Tuberous sclerosis complex (TSC) patients. Seq method: deep coverage NGS seq of TSC1 and TSC2 - average coverage >400x. 8/29 variants were detected in mosaicism, 4 at extremely low levels ( <16%). Variants are sometimes detected in skin biopsy samples only - not in blood or saliva.
Patients with TSC2 variants:
6 mosaic heterozygous cases:
Patient 14: TSC2:c.482-1G>C, p.(Ala161Valfs∗22); variant detected in peripheral blood (1%) and oral swab (1%);
Patient 16: TSC2:c.1119G>A, p.Ala326_Gln373del - 35% in peripheral blood
Patient 17: TSC2:c.1283_1285del, p.Ser428del - 16% in peripheral blood and 10% in oral swab
Patient 18: TSC2:c.1397T>C, p.Leu466Pro - 19% in peripheral blood
Patient 21: TSC2:c.1716+1745_2546-58del; g.2117381_2125742del (8362 bp del), p.Thr573Leufs∗45 - <50% in peripheral blood
Patient 25: TSC2:c.4398delinsTT, p.Ala1467Cysfs∗57 - 7% in peripheral blood

PMID: 37141891 Klonowska et al., 2023
Cohort of 95 individuals with TSC and confirmed mosaicism. Method: Deep massively parallel sequencing (MPS) (median read depth ≥ 500×). 9/95 individuals had variants in TSC1, and 86/95 patients had variants detected in TCS2.
The cohort included patients previously reported in PMID: 26540169 Tyburczy et al., 2015, as well as PMID: 31160751 Giannikou et al., 2019; PMID: 31114024 Treichel et al., 2019; PMID: 32461669 Ogorek et al., 2020.

PMID: 26540169 Tyburczy et al., 2015
Cohort of 53 patients with TSC and no mutation identified in previous testing. Median read depth was ≥ 5,000x for long-range PCR, and ≥ 500x in hybrid capture method. All 53 TSC patients had skin involvement. Reported 22 patients with mosaic heterozygous TSC2 variants (allele freq 0.21-34%).

This gene is associated with AD Tuberous sclerosis-2, MIM: 613254 in OMIM (accessed 5th Dec 2025).

Created: 5 Dec 2025, 4:12 p.m. | Last Modified: 5 Dec 2025, 4:12 p.m.

Panel Version: 3.16

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Tuberous sclerosis-2, OMIM: 613254

Publications

• 26540169
• 31160751
• 31114024
• 32461669
• 37141891
• 37356622

Green List (high evidence)

Mosaic, potential for transmission to offspring in germline
Sources: Expert Review

Created: 31 Oct 2025, 2:14 p.m.

Mode of inheritance
Other

Phenotypes
Cutaneous pigmentary abnormalities, and/or other aspects of germline TSC disease

Publications

• PMID: 37356622