Singleton-Merten Syndrome 1
In affected individuals from 3 unrelated families with early and extreme aortic and valvular calcification, dental anomalies, osteopenia, and acroosteolysis (SGMRT1; 182250), previously reported by Feigenbaum et al. (1988), Rutsch et al. (2005), and Valverde et al. (2010), respectively, Rutsch et al. (2015) performed whole-exome sequencing and identified heterozygosity for a c.2465G-A transition in the IFIH1 gene, resulting in an arg822-to-gln (R822Q) substitution at a highly conserved residue in 1 of 2 core helicase domains. The mutation, which segregated with disease in each family, was not found in any unaffected family members; analysis of 17 additional family members from the largest family showed that all but 1 individual with dental anomalies carried the mutation, and 1 individual with only psoriasis carried the mutation, whereas 3 others with only psoriasis did not. The authors noted that the IFIH1 c.2465G-A variant has been reported as a SNP (rs376048533) in 1 individual with 'cardiac and pulmonary phenotypes' from among 6,517 individuals in the NHLBI Exome Variant Server database, and is listed in the Exome Aggregation Consortium Browser with an allele frequency of 0.00002481. In vitro functional analysis revealed that the R822Q mutant enhanced MDA5 function in interferon-beta (IFNB1; 147640) induction, and interferon signature genes were upregulated in patient blood and dental cells. Rutsch et al. (2015) concluded that R822Q is a gain-of-function substitution that causes Singleton-Merten syndrome through dysregulation of the human innate immune response.
In a 10-year-old boy with Singleton-Merten syndrome, Riou et al. (2022) identified heterozygosity for the recurrent R822Q mutation (c.2465G-A, NM_022168.4) in the IFIH1 gene. The mutation arose de novo.
Aicardi-Goutieres Syndrome 7
In a 6-year-old boy with bilateral spasticity, developmental delay, and basal ganglia calcification (AGS7; 615846), Buers et al. (2017) identified heterozygosity for the R822Q mutation in the IFIH1 gene. The mutation was not present in parental DNA and was considered to have arisen de novo.
