Intellectual disability - microarray and sequencing
Gene: UFM1Comment on list classification: Following advice from Genomics England Clinical Team UFM1 will be classified as Green. Advice was "There are two founder variants in this gene in two different populations. This gives increased confidence in the gene, rather than something else in linkage disequilibrium. The phenotype is relevant. There is some work to suggest reduced expression in CNS cell lines for example. It is borderline but I think overall worth including as green."Created: 24 Jun 2019, 9:32 a.m. | Last Modified: 24 Jun 2019, 9:32 a.m.
Panel Version: 0.191
Comment on list classification: UFM1 identified in literature PMID:30914295 as missing in PanelApp compared to other curated gene list for ID genes. Concur with Rebecca's Amber rating on current ID panel.Created: 10 Jun 2019, 3:30 p.m.
Comment on list classification: UFM1 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Updated rating from Grey to Amber based on literature evidence. Although 20 patients have been reported so far (16 from a Roma population in PMID:28931644 and 4 from 2 Sudanese families in PMID:29868776), the Sudanese families share a haplotype and the variant is suggested to be a Founder variant. The variant in the Roma population (PMID:28931644) is also suggested to be a Founder variant. Therefore only two distinct cases to date. Have added 'watchlist' tag awaiting a further unrelated case.Created: 16 May 2019, 10:58 a.m.
Maddirevula et al 2019 (PMID:30237576) searched their database on exomes in search of homozygous variants that could be linked to diseases. They identified the NM_016617.3:c.241C>T:p.(Arg81Cys) variant in one case with global DD and progressive microcephaly (10DG0945). This case was published in Nahorski et al, 2018 (PMID:29868776, Table 1) so does not offer an additional case.Created: 16 May 2019, 10:55 a.m.
Comment on mode of inheritance: Although the original MOI was set to 'BOTH monoallelic and biallelic', I changed the MOI to 'biallelic only' to match OMIM, literature and Konstantinos Varvagiannis' review.Created: 16 May 2019, 10:46 a.m.
In 4 patients with profound global developmental delay from 2 Sudanese families, Nahorski et al, 2018 (PMID:29868776) identified a homozygous misense variant in the UFM1 gene (R81C). Functional assays showed the mutated protein had decreased ability to form a complex with UBA5 and UFC1, and suggested that a complete LOF allele would be embryonic lethal. Although the Sudanese families were not known to be related, they originate from the same village in Sudan, and families shared a haplotype, suggesting a founder effect. Nahorski et al, 2018 included a comparison of the phenotypes and UFM1 variants from the Hamilton et al., 2017 (PMID:28931644) in Table 2.Created: 16 May 2019, 10:38 a.m.
Hamilton et al., 2017 (PMID:28931644) identified a homozygous 3bp deletion in the promotor of UFM1 in 16 patients of Roma descent with hypomyelinating leukodystrophy-14 (MIM:617899). Haplotype analysis revealed a founder effect. All patients had severe developmental delay.Created: 16 May 2019, 10:37 a.m.
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, 1:09 p.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Leukodystrophy hypomyelinating 14, 617899
Publications
Tag watchlist was removed from gene: UFM1.
Tag de novo tag was added to gene: UFM1.
Source Expert Review Green was added to UFM1. Added phenotypes Leukodystrophy, hypomyelinating, 14, 617899 for gene: UFM1 Publications for gene UFM1 were changed from 28931644; 29868776; 30237576 to 28931644; 29868776; 30914295 Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Tag watchlist tag was added to gene: UFM1.
Phenotypes for gene: UFM1 were changed from Leukodystrophy hypomyelinating 14, 617899; global developmental delay to Leukodystrophy hypomyelinating 14, 617899; global developmental delay with progressive microcephaly
Publications for gene: UFM1 were set to 28931644; 29868776
Gene: ufm1 has been classified as Amber List (Moderate Evidence).
Mode of inheritance for gene: UFM1 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: UFM1 were changed from Leukodystrophy hypomyelinating 14, 617899 to Leukodystrophy hypomyelinating 14, 617899; global developmental delay
gene: UFM1 was added gene: UFM1 was added to Intellectual disability. Sources: Literature,Expert Review Mode of inheritance for gene: UFM1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: UFM1 were set to 28931644; 29868776 Phenotypes for gene: UFM1 were set to Leukodystrophy hypomyelinating 14, 617899 Penetrance for gene: UFM1 were set to Complete Review for gene: UFM1 was set to GREEN