Recurrent rhinovirus infections in a child with inherited MDA5 deficiency

Lamborn, Ian T.; Jing, Huie; Zhang, Yu; Drutman, Scott B.; Abbott, Jordan K.; Munir, Shirin; Bade, Sangeeta; Murdock, Heardley M.; Santos, Celia P.; Brock, Linda G.; Masutani, Evan; Fordjour, Emmanuel Y.; McElwee, Joshua J.; Hughes, Jason D.; Nichols, Dave P.; Belkadi, Aziz; Oler, Andrew J.; Happel, Corinne S.; Matthews, Helen F.; Abel, Laurent; Collins, Peter L.; Subbarao, Kanta; Gelfand, Erwin W.; Ciancanelli, Michael J.; Casanova, Jean-Laurent; Su, Helen C.

Because the patient was from an isolated small people group of Burma (Myanmar), we hypothesized an autosomal recessive inheritance with a probable founder effect. Whole exome sequencing (WES) was performed on the patient and her healthy immediate relatives, which revealed 1.8% homozygosity in the patient, 2.7% in the mother, and 2.0% in the father. These values were within the upper range of eight previously sequenced exomes from nonconsanguineous individuals (unpublished data) and were consistent with the lack of known consanguinity in this family. When suitable filtering on the variants was performed, a single homozygous missense mutation in IFIH1 NM_022168.3: c.1093A>G, p.K365E was identified in the patient and confirmed by Sanger dideoxy sequencing (Fig. 2 B; and Tables S1 and S2). This variant (rs117608083) was extremely rare, with an average minor allele frequency (MAF) in the Exome Aggregation Consor-tium (ExAC) database of 0.06%, where it was found mainly in East and South Asian populations, although no homozygotes were observed. The patient's missense mutation occurred at a location that was conserved across species (PhastCons, 1) and under evolutionary constraint (GERP, 3.96). Substitution of glutamate for lysine resulted in loss of physicochemical conservation (Grantham score, 56) and was predicted to have deleterious effects on protein structure and function (Poly-Phen2, 0.998). The patient also carried 14 other homozygous missense mutations, 2 compound heterozygous missense mutations, and 3 de-novo missense mutations, but of these, the IFIH1 mutation was computationally predicted to be most deleterious (CADD score of 25, surpassing mutation significance cutoff threshold for IFIH1 of 19.3; Itan et al., 2016) , with its normal gene product being highly expressed in immune cells and lung (Table S2) . For these reasons, we focused our attention on this variant. Both parents and a brother were carriers of this mutation (Fig. 2 A) .