Likely inborn error of metabolism

Gene: TMEM251

Green List (high evidence)

Added new-gene-name tag, new approved HGNC gene symbol for TMEM251 is LYSET.

Created: 10 Jul 2026, 3:19 p.m. | Last Modified: 10 Jul 2026, 3:19 p.m.

Panel Version: 9.24

Comment on list classification: There are now four unrelated families reported where probands harboured biallelic TMEM251 (new name LYSET) variants and presented with severe skeletal dysplasia, stemming from abnormal lysosomal enzyme activity. Hence, this gene can be promoted to Green at the next update.

Created: 10 Jul 2026, 3:15 p.m. | Last Modified: 10 Jul 2026, 3:15 p.m.

Panel Version: 9.23

PMID: 41858182 Sperb-Ludwig et al., 2026
Report of a 3yo patient with a homozygous variant NM_001098621.4:c.112C>T (p.Gln38Ter) in LYSET. Method: WGS. Consanguineous Brazilian parents. The patient presented with contractures, facial dysmorphism, cardiac abnormalities, and severe skeletal dysplasia (osteopenia, brachycephaly, sella turcica J, hip subluxation, hypodevelopment of L2, and more).

PMID: 40171858 Kariminejad et al., 2025
Report of two Iranian brothers with homozygous pathogenic variants in LYSET (c.197dupA, p.Tyr66Ter) and LYSET-related mucolipidosis. Clinical features: dysmorphic features, hepatomegaly, contractures, developmental delay, radiographs showed skeletal dysplasia (dysostosis multiplex - scapular hypoplasia, paddle-shaped ribs, ovoid vertebrae, widening of long bones. Elevated lysosomal hydrolase activity was noted in plasma, and reduced activity in blood of P1 - characteristic of ML1. Both brothers had short stature noted at 18 months: -2.67SD and -2SD.

PMID:33252156 Ain et al., 2021
Report of two unrelated families (from Pakistan and Iran) with individuals presenting with a severe skeletal disorder. WES identified two homozygous variants (missense and nonsense) in TMEM251. The candidate variants segregated with 5 affected members of the first family. In the second family there was only 1 affected individual who was homozygous for the variant, 22 other unaffected members were either heterozygous or and wild type alleles. P2 had developmental delay and craniosynostosis in addition to skeletal abnormalities.
Abnormal activities of three lysosomal enzymes detected from the sample of the patient from one family suggest that TMEM251 may have a metabolic role. (It was not possible to perform these tests in affected individuals in the other family).
Some functional data: p.Arg45Trp mutant TMEM251 protein was targeted less efficiently and the localization was punctate in Golgi in osteosarcoma cells, and Tmem251 knockdown by small interfering RNA induced dedifferentiation of rat primary chondrocytes).
Sources: Literature

Created: 10 Jul 2026, 3:13 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Dysostosis multiplex, Ain-Naz type, OMIM:619345; dysostosis multiplex, Ain-Naz type, MONDO:0859156; lysosomal storage disease with skeletal involvement, MONDO:0800088

Publications

• 33252156
• 40171858
• 41858182