Mosaic skin disorders - deep sequencing

Gene: TP63

Green List (high evidence)

Comment on list classification: There is only one reported case of a confirmed mosaic TP63 variant in a parent, which has been passed on to offspring in an autosomal dominant manner (PMID:18792980). PMID: 34703865 reports another individual described as mosaic, but variant details are not specified. Both patients presented with linear hypopigmented patches following Blaschkoid lines - usually indicative of cutaneous mosaicism. In addition, 3 unrelated sets of siblings, harbouring the same rare 'de novo' TP63 mutations, have been described - suggestive of undetected mosaicism in parents (PMIDs: 22740388; 27351625; 28977327). Based on available evidence, this gene will be tagged for promotion to Green on Mosaic skin disorders - deep sequencing. Expert Review will be requested regarding the evidence for mosaicism in four cases (suspected but not confirmed through sequencing).

Created: 3 Dec 2025, 3:34 p.m. | Last Modified: 3 Dec 2025, 3:34 p.m.

Panel Version: 3.9

PMID: 34703865 Chen, Issa and Schmidt, 2021
Report of a 31 yo African American man harbouring a 'TP63 gene copy number variant' (not specified) with a mosaic distribution (ratio not given). Putative diagnosis: ectodermal dysplasia (ED). Phenotype: patterned skin hypopigmentation (including linear hypopigmented patches following Blaschkoid lines), alopecia, and dental anomaly (one hypoplastic, conical tooth). Variant identified through an ED-associated gene panel.

PMID: 28977327 Rosa et al., 2017
3 siblings with Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome, parents unaffected. Germline mosaicism hypothesised, but no DNA sequencing described.

PMID: 27351625 Enriquez et al., 2016
Report of two sibling fetuses with urogenital abnormalities, split hand and foot malformation, and bilateral cleft lip and palate. Both het for c.1051G > A; p.D351N in TP63. Both parents were unaffected. 'Parental lymphocyte DNA showed no evidence of the TP63 mutation but germline mosaicism in a parent is assumed' - only TP63 sequenced, parents are WT. Mosaicism presumed due to recurrence in the two siblings. The same missense mutation was reported de novo in other families (PMID: 21434540 Ergin et al., 2010 and PMID: 16691622 Rinne et al., 2006).

PMID: 22740388 Barbaro et al., 2012
Two sisters with Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. Both sisters were heterozygous for TP63 c.1568T>C p.L523P (NM_003722.5: c.1574T>C, p.Leu525Pro) - not in gnomAD v4.1.0. Parental DNA analysis (blood, father's seminal fluid and mother's buccal, vaginal, and cervical cells) did not reveal the mutation. Authors pose that the apparently de novo variant was actually inherited through very low grade somatic mosaicism or maternal gonadal mosaicism.

PMID: 18792980 Kosaki et al., 2008
Newborn with split hand/foot malformation with whorl-like pigmentary pattern following Blaschko lines, heterozygous for c.727C>T, p.R204W (NM_003722.5: c.727C>T, p.Arg243Trp) - germline, variant not present in gnomAD v4.1.0. Mosaicism confirmed in the father (sequencing of peripheral blood and hair). Father presented with ectrodactyly of the hands a whorl-like pigmentary pattern following Blaschko lines.

TP63 is associated with several AD conditions in OMIM, including Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 MIM:604292 (accessed 3rd Dec 2025).

Created: 3 Dec 2025, 3:01 p.m. | Last Modified: 3 Dec 2025, 3:22 p.m.

Panel Version: 3.9

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3, OMIM:604292

Publications

• 18792980
• 22740388
• 27351625
• 28977327
• 34703865

Green List (high evidence)

Mosaic, important to diagnose as literature evidence of passing on in germline to offspring

Created: 31 Oct 2025, 2:05 p.m. | Last Modified: 31 Oct 2025, 2:05 p.m.

Panel Version: 3.1

Phenotypes
Blaschkolinear hypopigmentation, with or without features of germline TP63 diseases

Publications

• PMID: 34703865
• PMID: 27351625
• PMID: 22740388

Comment on list classification: New gene added to this panel by Tom Cullup (GOSH). This gene is associated with a number of phenotypes, some of which lead to dermatologic abnormalities. Mosaicism is not common - there is only one paper confirming somatic mosaicism in one individual (PMID: 18792980), plus another case mentioned by Tom Cullup from Kinsler lab. There is also a report of suspected mosaicism (but not confirmed) in a patient due to the Blaschko distributions of hypopigmented patches on their skin and hair loss (PMID: 34703865).

The phenotype fits the scope and this is likely the only panel to pick up somatic cases. However, the evidence supporting somatic mosaicism is borderline. Only one case has been published since 2008, and at least one additional confirmed case is needed to corroborate the association. Leaving rating as Amber with watchlist tag to monitor for additional evidence.

Created: 31 Aug 2023, 3 p.m. | Last Modified: 31 Aug 2023, 3 p.m.

Panel Version: 2.31

Green List (high evidence)

Lots of evidence to support germline variation causing disease - 2x cases now identified as somatic mosaic with pigmentary anomalies (1x in literature, 1 x Kinsler lab). Gene can be rated green based on germline occurrences, and important to be able to detect somatic mosaics as a differential in cases of Blaschkolinear pigmentary anomalies.
Sources: Expert list

Created: 3 May 2023, 2:53 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Split hand foot malformation with whorl-like pigmentary pattern

Publications

• 18792980