Early onset or syndromic epilepsy

Gene: UFM1

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Green List (high evidence)

AR hypomyelinating loeukodystrophy 14 - characterised by hypotonia, almost complete lack of motor or cognitive skills and absent language development. Additional features include intractable seizures. Hamilton et al, 2017 - 16 children aged 3 months to 7 years - most patients of Roma descent - all patients over the age of 18 months developed severe intractable epilepsy - median survival 2 years - all had a hom 3 bp del in the promotor region - haplotype analysis showed a founder effect, in vitro expression studies done. Nahorski et al, 2108 - 4 children from 2 consang Sudanese families - developed intractable seizures in first few weeks/months if life - hom missense mutation, in vitro expression studies undertaken.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy hypomyelinating 14 617899

Publications

• 29868776
• 28931644

Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 3 variants reported in 3 unrelated cases in which seizures are a phenotypic feature.

Created: 27 Nov 2018, 2:54 p.m.

Green List (high evidence)

Biallelic UFM1 mutations cause Leukodystrophy hypomyelinating 14, MIM 617899.

PMID: 28931644 is the first report on 16 individuals from 14 families with shared Roma ethnic background. All subjects were found to harbor a UFM1 promoter 3 basepair deletion in the homozygous state.

All patients demonstrated a severe phenotype including lack of development and severe epileptic encephalopathy while their MRI images demonstrated hypomyelination with atrophy of the basal ganglia and the cerebellum.

The promoter deletion was detected by exome sequencing. Previously a 0.8 Mb homozygous region (encompassing UFM1) was identified to be shared by all the patients in whom a SNP array was performed. Alternative causes, notably TUBB4A mutations and deletions/duplications were excluded. 3 individuals had Sanger sequencing of all coding regions within the homozygous interval to rule out other - eventually missed - variants.

The deletion (rs747359907 - NC_000013.11:g.38349765_38349767delTCA or NM_001286704.1:c.-273_-271delTCA) was shown to be a founder mutation in the Roma population.

PMID: 29868776 reports 4 additional individuals from 2 consanguineous families (one from Ethiopia, for the other this was not specified). All 4 patients were homozygous for the c.241C>T (NM_016617.3) or p.(Arg81Cys) variant which was shown to be hypomorphic upon functional studies.

The phenotype consisted of developmental delay (4/4 or 20/20 including the patients from the previous report with which comparison is made in table 2 of the article) with microcephaly (4/4 or 20/20) and seizures (4/4 or 16/20) as well as MRI abnormalities. Failure to thrive and/or short stature were also among the most common features.

UFM1 (as well as UFC1 also discussed in the same article) participate in ufmylation, with mutations in other enzymes of the same process (notably UBA5 - gene rated Green in the ID and epilepsy panels) having already been described in neurodevelopmental disorders.

As a result, this gene can be considered for inclusion in this panel as green (or amber).

Created: 20 Nov 2018, 1:10 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy hypomyelinating 14, 617899

Publications

• 28931644
• 29868776