TABLE 1.
Details of individual IFIH1 mutations identified in the families included in the present data set
| cDNA change | Protein change | Families (de novo inheritance; or, number of symptomatic and non- penetrant individuals where familial) |
Associated phenotypes (‘/’ within family)(‘;’ between families) |
Upregulation of interferon signalling |
Assessment by interferon reporter assay |
gnomAD | SIFT | Polyphen2 | CADD score |
Var- cards |
|---|---|---|---|---|---|---|---|---|---|---|
| c.992C>G | p.Thr331Arg | AGS674 (de novo); AGS1972 (2;0) | AGS-SMS; SMS | Yes | Yes (de Carvalho et al., 2017) | Novel | Deleterious 0 | Probably damaging 1.000 | 29.7 | 22:23 |
| c.992C>T | p.Thr331Ile | AGS1938 (3;0) | SMS | Yes | Yes (de Carvalho et al., 2017) | Novel | Deleterious 0 | Probably damaging 1.000 | 31 | 22:23 |
| c.1009A>G | p.Arg337Gly | AGS237 (de novo) | NR | Yes | Yes (Rice et al., 2014) | Novel | Tolerated 0.12 | Probably damaging 1.000 | 26.8 | 17:23 |
| c.1165G>A | p.Gly389Arg | AGS848 (2;1) | AGS/SP/CNP | Yes | Yes (this paper) | Novel | Tolerated 0.88 | Benign 0.108 | 5.325 | 01:23 |
| c.1178A>T | p.Asp393Val | AGS626 (de novo) | NR | Yes | Yes (Rice et al., 2014) | Novel | Deleterious 0.01 | Probably damaging 0.998 | 28.6 | 16:23 |
| c.1178A>C | p.Asp393Ala | AGS2586 (de novo) | AGS | Yes | No | Novel | Deleterious 0.03 | Possibly damaging 0.913 | 24.8 | 12:23 |
| c.1331A>G | p.Glu444Gly | AGS2669 (de novo) | AGS | Yes | Yes (this paper) | Novel | Deleterious 0 | Probably damaging 1 | 31 | 23.23 |
| c.1347C>G | p.Asn449Lys | AGS1001 (de novo) | SP | Yes | Yes (this paper) | Novel | Tolerated 0.64 | Benign 0.163 | 13.91 | 03:23 |
| c.1465G>A | p.Ala489Thr | AGS755 (3;0)a | CLL/AGS-SMS/SMS | Yes | Yes (Bursztejn et al., 2015) | Novel | Deleterious 0 | Probably damaging 1.000 | 32 | 21:23 |
| c.1483G>A | p.Gly495Arg | AGS524 (2;0)a | SP-LLD/SP | Yes | Yes (Rice et al., 2014) | Novel | Deleterious 0.01 | Probably damaging 0.982 | 23.3 | 14:23 |
| c.1747A>G | p.Ile583Val | AGS2369 (de novo) | AGS | Yes | Yes (this paper) | Novel | Tolerated 0.48 | Benign 0.00 | 0.573 | 5.23 |
| c.2156C>T | p.Ala719Val | Hm_1 (de novo) | AGS | Yes | No | Novel | Tolerated 0.07 | Possibly damaging 0.949 | 27.1 | 09:23 |
| c.2159G>A | p.Arg720Gln | AGS102 (de novo); AGS647 (de novo); AGS1504 (de novo); AGS2422 (NPDT); AGS2548 (de novo); LD_0982.0 (de novo) | AGS; SP | Yes | Yes (Rice et al., 2014) | Novel | Deleterious 0 | Probably damaging 0.992 | 34 | 17:23 |
| c.2317G>C | p.Glu773Gln | AGS2399 (de novo) | NR | NA | Yes (this paper) | Novel | Tolerated 0.27 | Possibly damaging 0.743 | 24.8 | 13:23 |
| c.2335C>T | p.Arg779Cys | AGS376 (NPDT); AGS723 (NPDT); AGS1004 (de novo); AGS1156 (de novo); AGS2154 (1;1); AGS2180 (de novo); AGS2507 (de novo); LD_1030.0 (de novo) |
AGS-LLD; SP-ICC; NR; unilateral white matter disease/CNP; AGS |
Yes | Yes (Rice et al., 2014) | Novel | Deleterious 0.01 | Probably damaging 1.000 | 34 | 21:23 |
| c.2336G>A | p.Arg779His | AGS163 (de novo); AGS259 (3;2); AGS1351 (de novo); AGS1509 (de novo); AGS2177 (1;2); Berg_1 (de novo); Orc_0098 (de novo); LD_1199.0 (de novo); LD_1381 (3;1); LD_1585.0 (de novo) | AGS; CNP; NR; SP | Yes | Yes (Rice et al., 2014) | 1/244230 | Tolerated 0.05 | Probably damaging 0.994 | 28.9 | 19:23 |
| c.2336G>T | p.Arg779Leu | LD_1067.0 (de novo) | AGS | Yes | No | Novel | Tolerated 0.06 | Probably damaging 1.000 | 35 | 21:23 |
| c.2342G>A | p.Gly781Glu | LD_0940.0 (de novo); LD_0943.0 (de novo) | NR; SP | Yes | No | Novel | Deleterious 0 | Probably damaging 1.000 | 32 | 19:23 |
| c.2404A>G | p.Asn802Asp | AGS2662 (de novo) | NR | Yes | No | Novel | Tolerated 0.22 | Probably damaging 1.000 | 28.1 | 18:23 |
| c.2407A>T | p.Ile803Phe | LD_1488.0 (de novo) | AGS | Yes | Yes (this paper) | Novel | Tolerated 0.24 | Benign 0.043 | 11.8 | 04:23 |
| c.2465G>A | p.Arg822Gln | AGS1514 (de novo) | SD-ICC | Yes | Yes (Rutsch et al., 2015) | 6/244096 | Deleterious 0 | Probably damaging 1.000 | 35 | 23:23 |
| c.2471G>A | p.Arg824Lys | AGS735 (de novo); AGS2222 (de novo) | NR; Isolated liver disease | Yes | No | Novel | Deleterious 0 | Probably damaging 1.000 | 34 | 22:23 |
| c.2486C>G | p.Thr829Ser | AGS1290 (2 siblings and NPDT) | AGS | Yes | No | Novel | Tolerated 0.73 | Possibly damaging 0.512 | 16.61 | 12:23 |
| c.2544T>G | p.Asp848Glu | AGS531 (3;2) | SP-ICC/CNP | Yes | Yes (Ruaud et al., 2018) | Novel | Tolerated 0.4 | Benign 0.004 | 10.08 | 02:23 |
| c.2561T>A | p.Met854Lys | AGS2081 (de novo) | AGS/SMS | Yes | No | Novel | Deleterious 0 | Probably damaging 1.000 | 31 | 18:23 |
| c.2866A>G | p.Ile956Val | AGS1430 (2;1) | SP-ICC/CNP | Yes | Yes (this paper) | Novel | Tolerated 0.77 | Benign 0.004 | 3.576 | 06:23 |
| c.2936T>G | p.Leu979Trp | LD_1346.0 (de novo) | AGS | Yes | Yes (this paper) | Novel | Deleterious 0.01 | Probably damaging 1.000 | 26.6 | 16:23 |
Note: IFIH1 mutation annotation based on the reference complementary DNA sequence NM_022168.2.
Abbreviations: AGS, Aicardi–Goutières syndrome; CLL, Chilblain-like lesions; CNP, clinical nonpenetrance; ICC, Intracranial calcification; LLD, Lupus-like disease; NPDT, no parental DNA testing; NR, neuro-regression; SD, spastic dystonia; SP, spastic paraparesis; SMS, Singleton Merten syndrome.
a
This mutation was shown to have been paternally inherited by the proband and to have occurred de novo in the proband’s father.