Pigmentary skin disorders

Gene: LZTR1

Green List (high evidence)

Recently PMIDs 39140257, 39258154 have reported additional LZTR1 variants which they have found in patients with isolated multiple café-au-lait macules with or without freckling. Both studies found incomplete penetrance of this phenotype within families carrying the LZTR1 variants.

Created: 8 Apr 2025, 10:50 a.m. | Last Modified: 8 Apr 2025, 10:50 a.m.

Panel Version: 3.15

Publications

• 39140257
• 39258154

Green List (high evidence)

LoF variants are associated with isolated multiple café au lait macules with or without freckling.
PubMed 39258154 (Horn et al 2024) identified 4 heterozygous LoF variants in LZTR1 in 4 families with multiple isolated café au lait macules, and one family also had axillar freckling. Two unaffected family members were heterozygous for a LoF LZTR1 variant, indicating reduced penetrance.
PubMed 39140257 (Mastromoro et al 2024) Identified 52 variants in LZTR1, of which 21 (29%) were frameshift, 20 (28%) were nonsense and 14 (19%) affected splicing, in a cohort of 71 index patients with multiple café au lait macules (>6). 29% of relatives heterozygous for an LZTR1 LoF variant had café au lait macules, indicating reduced penetrance. Functional characterization showed accelerated protein degradation or mis-localization, and failure to downregulate mitogen-activated protein kinase signalling.

Created: 24 Feb 2025, 2:17 p.m. | Last Modified: 24 Feb 2025, 2:17 p.m.

Panel Version: 3.14

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Multiple café au lait macules

Publications

• 35361920
• 39140257
• 39258154

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mastromoro et al., reports: "Heterozygosity for loss-of-function variants in LZTR1 is associated with isolated multiple café-au-lait macules" with "Analysis revealed heterozygous LZTR1 variants in 6.0% (51/849) of participants, exceeding the general population prevalence. LZTR1-related CaLMs varied in number, displayed sharp or irregular borders, and were generally isolated, but occasionally associated with features recurring in RASopathies. In two families, CaLMs and schwannomas co-occurred. The molecular spectrum mainly consisted of truncating variants, indicating LoF"

Created: 24 Aug 2024, 1:36 p.m. | Last Modified: 24 Aug 2024, 1:36 p.m.

Panel Version: 3.12

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• https://doi.org/10.1016/j.gim.2024.101241

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
NOONAN SYNDROME 10; NS10, NOONAN SYNDROME 2; NS2

Publications

• 29469822
• 25795793

Following discussion with members of the Skin Specialist Group at the Webex call on 25.04.19, it was agreed that genes associated with RASopathies should be included on this panel. Therefore added to panel as a Green gene.

Created: 17 Sep 2019, 5:07 p.m. | Last Modified: 17 Sep 2019, 5:07 p.m.

Panel Version: 0.13