EMG1 (EMG1 N1-specific pseudouridine methyltransferase) is located on chromosome 12 at position 12p13.31. The protein is key in processing of pre-18S rRNA and small ribosomal subunit formation. EMG1 was first reported in relation to autosomal recessive Bowen-Conradi Syndrome (BCS) in 2009 (Armistead et al., PMID: 19463982). This condition is characterized by facial anomalies such as micrognathia and prominent nose, joint contractures, congenital microcephaly, rocker bottom foot/clubbed foot, and digit anomalies including camptodactyly. BCS is often lethal within the first year of life due to complications linked to motor issues and poor growth.
One variant (missense, p.(Asp86Gly)) that has been reported in 39 probands from 29 nuclear families in the highly consanguineous Hutteritte population, and in one publication, is included in this curation (PMID: 19463982). A founder effect is suspected. The mechanism of pathogenicity appears to be gain-of-function. This gene-disease relationship is also supported by experimental evidence including functional alteration, expression-level evidence, and mouse models (Liu & Thiele, 2001, PMID: 11694595; Eschrich et al., 2001, PMID: 11935223; Wu et al., 2010, PMID: 20858271; Armistead et al., 2015, PMID: 25708872). Functional alteration evidence shows that rRNA processing is inhibited when EMG1 is mutated. The protein localized to the nucleus in a yeast cell analysis. Mouse models show that the mutants exhibited early embryonic lethality, abnormal expression of early cell lineage markers, increased apoptosis, and neural tube defects.The impact of other variants in EMG1 is unknown; given the single position (p.Asp86Gly) involved to date, other variants would need very careful consideration.
In summary, the classification of this gene-disease relationship was upgraded from moderate to strong based on the strength of evidence, particularly the evidence from the mouse models and the restrictions in scoring founder variants through the framework. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date May 16th, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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