Rare syndromic craniosynostosis or isolated multisuture synostosis

Gene: TMEM251

I don't know

Comment on list classification: Updated rating to Amber as second patient reported in PMID:41858182 (brachycephaly).

Created: 10 Jul 2026, 3:09 p.m. | Last Modified: 10 Jul 2026, 3:09 p.m.

Panel Version: 6.12

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.

Created: 10 Jul 2026, 3:08 p.m. | Last Modified: 10 Jul 2026, 3:08 p.m.

Panel Version: 6.11

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Dysostosis multiplex, Ain-Naz type, OMIM:619345; craniosynostosis, MONDO:0015469

Publications

• 41858182
• 40171858

Red List (low evidence)

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

The OMIM entry for this gene is OMIM:619332, which has been cross-checked with Ensembl, HGNC and G2P. Hence, gene-checked tag has been added.

Created: 17 Oct 2023, 11:50 a.m. | Last Modified: 17 Oct 2023, 11:50 a.m.

Panel Version: 4.174

Whole-exome sequencing identified two homozygous variants c.133C>T/ p.Arg45Trp (absent from gnomAD) and c.215dupA/ p.Tyr72Ter (2 alleles in gnomAD, annotated as pathogenic in ClinVar), in two families. Immunofluorescence and confocal studies show that the p.Arg45Trp mutant TMEM251 protein was targeted less efficiently to the Golgi complex compared to wildtype protein (PMID:33252156).
Sources: Literature

Created: 23 Jul 2023, 7:46 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Dysostosis multiplex, Ain-Naz type, OMIM:619345; craniosynostosis, MONDO:0015469

Publications

• 33252156
• 36980886