Intellectual disability
Gene: EMC1
In view of the three unrelated cases with biallelic variants, I consider this to be sufficient evidence for inclusion as green. I would only recommend this is in the context of biallelic variants however. There is only one case reported with a de novo heterozygous variant, therefore I feel further information in terms of more cases or understanding the spectrum of variants / functional effect of these is needed prior to prioritising monoallelic variants in addition. I have therefore changed the MOI to biallelic only.Created: 19 Jul 2019, 11:14 a.m. | Last Modified: 19 Jul 2019, 11:14 a.m.
Panel Version: 0.202
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Comment on list classification: EMC1 identified in literature PMID:30914295 as missing in PanelApp compared to other curated gene list for ID genes.
EMC1 has also been reviewed Green by Konstantinos Varvagiannis and is in OMIM and G2P as "Disease: Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.".
Harel et al. (PMID: 26942288) describes 4 individual families. Family 1-3 has three different biallelic homozygous variants. Family 4 has monoallelic, de novo hetrozygous variants. However additional evidence of EMC1 comes from Geetha et al. (PMID: 29271071) who reported on an additional individual with biallelic homozygous intronic variant, affected the splice sight and resulted in the retention of intron 11.
It has been noted that the phenotype severity is broad from severe to moderate developmental delay and because of this the authors propose that both monoallelic and biallelic pathogenic variants may be causative of the specific phenotype, though the presentation may be more severe in case of biallelic variants.
As there are sufficient number of families and variants EMC1 can be classified as Green.
Created: 20 May 2019, 1:48 p.m. | Last Modified: 3 Jul 2019, 1:38 p.m.
Panel Version: 0.196
Harel et al. (PMID: 26942288) describe 7 individuals from 3 families with biallelic pathogenic variants in EMC1.
In the first family, a single individual (born to non-consanguineous parents) was found to harbor a homozygous frameshift variant in a small (approx. 100 kb) stretch of absence of heterozygosity. The patients in the other two families were homozygous for missense variants (private to each family) in the context of parental consanguinity.
The common phenotype was suggestive of a progressive neurodegenerative disorder and consisted of hypotonia, severe developmental delay with marked speech delay, diminished deep tendon reflexes, cerebellar atrophy, vision as well as skeletal problems. Seizures were a feature in one subject.
One further patient from an additional (fourth) family was found to have a similar but milder phenotype and was only found to harbor a de novo missense variant in EMC1 following trio exome sequencing. Sanger sequencing of the promoter region as well as CNV calling from the exome data failed to reveal other variants in this specific individual.
Similarly to what has been observed in other genes the authors propose that both monoallelic and biallelic pathogenic variants may be causative of the specific phenotype, though the presentation may be more severe in case of biallelic variants.
Altogether this study reports 1 homozygous frameshift and 3 missense variants (2 of the latter found in homozygous state and one as a de novo heterozygous mutation). //
Geetha et al. (PMID: 29271071) describe an individual born to consanguineous parents presenting with hypotonia, developmental delay, and cerebellar atrophy as well as early onset epilepsy. Exome sequencing demonstrated a homozygous splice variant in EMC1. This variant was demonstrated to result to retention of intron 11 upon RNA sequencing. This was predicted to lead to premature truncation of the protein. //
EMC1 is associated in OMIM with Cerebellar atrophy, visual impairment, and psychomotor retardation (MIM 616875) for which an autosomal recessive inheritance mode is retained. //
Apart from the variants reported in the previous studies [p.Pro874Argfs*21, p.Thr82Met, p.Gly868Arg, p.Gly471Arg, c.1212+1G>A - NM_015047.2] further variants have been submitted in ClinVar as likely pathogenic (Variation IDs : 521479, 445564). //
The gene has been included in intellectual disability gene panels offered by a few other diagnostic labs. //
As a result this gene can be considered for inclusion in the panel as green (or amber).
Sources: Expert Review, LiteratureCreated: 20 Oct 2018, 1:52 a.m.
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes
Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM 616875
Publications
Variants in this GENE are reported as part of current diagnostic practice
Mode of inheritance for gene EMC1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Source Expert Review Green was added to EMC1. Added phenotypes Cerebellar atrophy, visual impairment, and psychomotor retardation, 616875 for gene: EMC1 Publications for gene EMC1 were changed from 26942288; 29271071 to 29271071; 26942288; 30914295 Rating Changed from No List (delete) to Green List (high evidence)
gene: EMC1 was added gene: EMC1 was added to Intellectual disability. Sources: Expert Review,Literature Mode of inheritance for gene: EMC1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: EMC1 were set to 26942288; 29271071 Phenotypes for gene: EMC1 were set to Cerebellar atrophy, visual impairment, and psychomotor retardation, MIM 616875 Penetrance for gene: EMC1 were set to Complete Review for gene: EMC1 was set to GREEN gene: EMC1 was marked as current diagnostic