Pigmentary skin disorders

Gene: SNAI2

I don't know

Comment on mode of inheritance: There are three unrelated patients reported with monoallelic SNAI2 variants (excluding the family from Celia Moss, who has later been identified with KIT variant) and piebaldism (mild in the patient reported in PMID:24443330, who also had EDA1 variant). However, all three families reported with heterozygous variants in the recent literature (PMIDs: 30936914; 41073431) presented with Waardenburg syndrome (variants from two cases from PMID:30936914 had higher frequencies in population databases) and did not have any phenotype relevant to pigmentary skin disorders.

There are two unrelated patients reported with homozygous SNAI2 deletions and with Waardenburg syndrome. These patients presented with hearing loss and heterochromia iridis and not with any skin pigmentation phenotypes.

The MOI should therefore be updated from 'BIALLELIC, autosomal or pseudoautosomal' to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' as the patients with biallelic variants did not present with any skin pigmentation phenotypes.

The rating should remain amber as none of the recent monoallelic cases had piebaldism and the earlier cases with piebaldism were identified with SNAI2 deletion/variants via Southern blots/ single gene sequencing. The 'watchlist' tag has been added for reviewing this gene with new evidence in the future.

Created: 29 Apr 2026, 4:51 p.m. | Last Modified: 29 Apr 2026, 4:51 p.m.

Panel Version: 4.21

PMID:12444107 (2002) reported the identification of homozygous deletions in SNAI2 gene (previous gene name: SLUG) in two unrelated patients with Waardenburg syndrome type 2 (WS2). The first patient was reported with profound bilateral sensorineural hearing loss and heterochromia iridis, while the second patient presented with 60 dB hearing loss and unilateral heterochromia. Neither of the patients were reported with any pigmentary abnormalities of the skin.

PMID:12955764 (2003) reported Southern blot analysis of the SNAI2 (SLUG) gene in 17 unrelated patients with piebaldism, who lacked apparent KIT mutations. Three patients had evident heterozygous deletions of the SNAI2 gene encompassing the entire coding region. However, Celia Moss (one of the co-authors of this publication) reviewed below that one of the reported patients was from her and it was identified from further investigation that this patient had a KIT mutation and not SNAI2.

PMID:24443330 (2014) reported a female patient of Chinese descent with a SNAI2 5'UTR variant and a recurrent EDA1 variant. The patient presented with a mild form of piebaldism and a severe form of X-linked hypohidrotic ectodermal dysplasia.

PMID:30936914 (2019) reported a 90-patient WS cohort from which two novel heterozygous variants in SNAI2 gene were identified in one patient each. One of these patients were reported with WS2 and other with WS4, and both presented with heterochromia irides and hearing loss. Both the detected SNAI2 variants (c.230C>G and c.365C>T) were not considered causative due to their frequency (>1/10000) in the population database.

PMID:41073431 (2025) reported a family of Chinese descent with WS and with a pathogenic heterozygous SNAI2 variant (c.230C>G). All four adolescents from the family (third generation) presented moderate to severe ID, along with severe anxiety, mild level of depression, and serious social dysfunction. But they did not show any signs of hearing loss or heterochromia iris, which are considered features of WS.

This gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 29 April 2026), but recessive variants are associated with 'limited' rating by Hearing Loss GCEP in ClinGen.

Created: 29 Apr 2026, 3:43 p.m. | Last Modified: 29 Apr 2026, 4:59 p.m.

Panel Version: 4.21

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Waardenburg syndrome type 2, MONDO:0019517; piebaldism, MONDO:0008244

Publications

• 12444107
• 12955764
• 24443330
• 30936914
• 41073431

Green List (high evidence)

Well established as a cause of Waardenburg.

Created: 22 Mar 2026, 1:31 p.m. | Last Modified: 22 Mar 2026, 1:31 p.m.

Panel Version: 4.13

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Waardenburg syndrome

Publications

• 12444107
• 12955764
• 30936914

I don't know

The initial report included a patient of mine who on further investigation had a KIT mutation not SNA12, correction to be published

Created: 12 Dec 2019, 12:27 p.m. | Last Modified: 12 Dec 2019, 12:27 p.m.

Panel Version: 0.26

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
PIEBALD TRAIT; PBT, WAARDENBURG SYNDROME, TYPE 2D; WS2D

Publications

• 12955764
• 12444107

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
PIEBALD TRAIT; PBT, WAARDENBURG SYNDROME, TYPE 2D; WS2D

Publications

• 12955764
• 12444107

I don't know

For Waardenburg syndrome, type 2D, PMID: 30561083 Only 2 cases reported that resulted from homozygous SNAI2 deletions. Both had sensorineural hearing loss and heterochromia, without any cutaneous or dysmorphic manifestations. Since the initial publication in 2002, no additional confirmatory cases have been reported.
SNAI2 in Piebaldism advised to rate as Amber based on review by Celia Moss.

Created: 12 Dec 2019, 12:20 p.m. | Last Modified: 12 Dec 2019, 12:20 p.m.

Panel Version: 0.23

Green List (high evidence)

This gene was part of an initial gene list collated by Thomas Cullup, GOSH and Veronica Kinsler, UCL, 25.Jan.2019 on behalf of the GMS Skin Specialist Test Group. Gene Symbol submitted: SNAI2; Suggested initial gene rating: Green; Evidence for inclusion: none provided; Evidence for exclusion: none provided; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none provided.

Created: 31 Jan 2019, 11:31 a.m.