UFM1

Inheritance Pattern: AR

Disease ID:MONDO:0033486

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0033486

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0033486

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0012905

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0033486

Submitter: ClinGen

UFM1 was first reported in relation to autosomal recessive hypomyelinating leukodystrophy in 2017 (Hamilton et al., PMID: 28931644). The authors described the disorder as a recessive variant of hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), and the entity was catalogued in OMIM as hypomyelinating leukodystrophy 14. The UFM1 gene encodes for the ubiquitin-like protein Ubiquitin-fold modifier 1 (UFM1). UFM1 has been reported to be involved in processes such as managing ER function, including selective autophagy of the ER, and the maintenance of p53 stability (Komatsu et al. 2024, PMID: 38141606). Affected individuals have global developmental delay, intellectual disability, microcephaly, growth impairments including short stature, drug resistant seizures, cerebellar hypoplasia, delayed CNS myelination and/or hypomyelination, and basal ganglia anomalies (PMID: 35189806). Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Two unique variants, 1 promoter region deletion variant and 1 missense variant, have been reported in the homozygous state in 30 probands across 6 publications and are included in this curation (PMID: 28931644, 29868776, 34573312, 35189806, 36082649, 33807868). Both variants have supporting functional data. The recurrent promoter region deletion variant NM_001286704.1: c.-273_-271delTCA has been reported to be a founder variant in the Roma population. Variants in this gene have segregated with disease across multiple relatives across multiple families (PMID: 28931644, 29868776). The mechanism of pathogenicity is still being researched, but these variants have been reported to cause disease through a hypomorphic effect (PMID: 28931644, 29868776). This gene-disease relationship is also supported by experimental evidence including protein interaction evidence, a mouse model, and a drosophila model (28931644, 29868776, 27545674, 31914610). Hamilton et al. used a luciferase activity assay to show that the founder mutation significantly reduced promoter and transcriptional activity in neuronal cell lines (SY5Y neuroblastoma and U373 astroglioma), but not in HeLa and HOG-F2 oligodendroglioma cell lines (PMID: 28931644). Nahorski et al. performed various assays that illustrated a hypomorphic effect of the founder mutation on the ability of UFM1 to interact with its conjugates, including its E1 enzyme (UBA5) and E2 enzyme (UFC1) (PMID: 29868776). Muona et al. generated CNS-specific Ufm1 knockout mice to show that impaired UFM1 function results in similar effects of conjugate formation disruption, as well as neonatal death, microcephaly, and apoptosis in specific neurons (PMID: 27545674). Yu et al. used RNA interference of UFM1 as well as other proteins in the UFM1 cascade to discover that dysfunction of the cascade in Drosophila results in overall decreased brain volume, a reduced number of neuroblasts, disruption of cell cycle progression/processes (PMID: 31914610). In summary, there is definitive evidence supporting the relationship between UFM1 variants and leukodystrophy, hypomyelinating, 14 (MONDO:0033486), also known as UFM1-related hypomyelinating leukodystrophy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Leukodystrophy and Leukoencephalopathy gene curation expert panel on the meeting date 3/22/2026 (SOP Version 12).