Intellectual disability
Gene: UFC1

UFC1 (ubiquitin-fold modifier conjugating enzyme 1)
EnsemblGeneIds (GRCh38): ENSG00000143222
EnsemblGeneIds (GRCh37): ENSG00000143222
OMIM: 610554, Gene2Phenotype
UFC1 is in 5 panels

3 reviews

Catherine Snow (Genomics England)

Comment on list classification: UFC1 identified in literature PMID:30914295 as missing in PanelApp compared to other curated gene list for ID genes. Concur with Rebecca's Amber rating, that there are currently only two distinct variants/cases UFC1.
Created: 23 May 2019, 3:03 p.m.

Created: 23 May 2019, 3:03 p.m.

Panel version: Imported from Intellectual disability update May 2019 panel version 0.75

Rebecca Foulger (Genomics England curator)

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_016406.3:c.317C>T:p.(Thr106Ile) variant in UFC1 in two cases with global DD and progressive microcephaly (17-3196 and 17-3892). Both of these cases were published in Nahorski et al, 2018 (PMID:29868776, Table 1).
Created: 16 May 2019, 11:04 a.m.

Added 'watchlist' tag.
Created: 14 May 2019, 4 p.m.

Comment on list classification: UFC1 was added to the ID panel and rated Green by Konstantinos Varvagiannis. Changed rating from Grey to Amber based on literature evidence: PMID:29868776 (Nahorski et al. 2018) identified a homozygous missense variant in the UFC1 gene (T106I) in 7 affected members of 3 consanguineous Saudi families. All members displayed Global Developmental delay. Two of the sisters were previously reported by Anazi et al. (2017, PMID:27431290). Although the Saudi families were said to be unrelated, the families shared a haplotype, suggesting a founder effect. An unrelated Swiss boy was found to have a different homozygous variant in the UFC1 gene (R23Q). There are therefore currently two distinct variants/cases. Based on the Founder effect of the three Saudi families, I have rated as Amber awaiting a further unrelated case.
Created: 14 May 2019, 3:58 p.m.

Created: 14 May 2019, 3:58 p.m.

Panel version: 2.839

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic UFC1 mutations cause Neurodevelopmental disorder with spasticity and poor growth, MIM 618076.

PMID: 29868776 describes 7 individuals (most) born to consanguineous Saudi families (in one case the parents were not consanguineous but originated from the same tribe) as well as a further individual born to distantly related Swiss parents. One of these patients was previously briefly published by the same authors (PMID: 27431290).

The phenotype consisted of developmental delay (8/8 - usually profound), failure to thrive (8/8), short stature and microcephaly (both observed in 7/8), seizures (4/8) and variable brain MRI anomalies in some of these subjects.

Overall, two UFC1 missense variants are reported [NM_016406.3:c.317C>T or p.(Thr106Ile) and c.68G>A or p.(Arg23Gln) the former in the Saudi individuals]. Functional studies demonstrated the hypomorphic nature of the variants.

UFC1 (as well as UFM1 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 the ID panel as green (or amber).
Sources: Literature, Expert Review
Created: 20 Nov 2018, 10:29 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodevelopmental disorder with spasticity and poor growth, 618076

Publications

29868776

Created: 20 Nov 2018, 10:29 a.m.

Panel version: 2.545

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Amber
Literature
Expert Review Amber

Phenotypes

global developmental delay with progressive microcephaly
Neurodevelopmental disorder with spasticity and poor growth, 618076

Tags

watchlist

OMIM

610554

Clinvar variants

Variants in UFC1

Penetrance

Complete

Publications

30914295

Panels with this gene

History Filter Activity

25 Jul 2019, Gel status: 2

Set Phenotypes, Set publications

Catherine Snow (Genomics England)

Added phenotypes Neurodevelopmental disorder with spasticity and poor growth, 618076 for gene: UFC1 Publications for gene UFC1 were changed from 29868776; 27431290; 30237576 to 30914295

16 May 2019, Gel status: 2