Table 1 Pathogenic or likely pathogenic variants detected in this study
Patient | Pathogenic or likely pathogenic variants in the responsible genes for SRS | Pathogenic variants in causative genes for known genetic syndromes presenting with growth failure | |||||||
|---|---|---|---|---|---|---|---|---|---|
Patient 1 [12] | Patient 2 [12] | Patient 3 | Patient 4 | Patient 5 | Patient 6 | Patient 7 | Patient 8 | Patient 9 | |
Gene | IGF2 | IGF2 | CDKN1C | PLAG1 | IGF1R | PIK3R1 | SRCAP | TCF4 | PTPN11 |
Variant | c.209G>A | c.211T>C | c.947G>A | c.589C>T | c.1457delC | c.1892G>A | c.7376delC | c.1102_1103delCA | c.844A>G |
p.(Cys70Tyr) | p.(Cys71Arg) | p.(Arg316Gln) | p.(Arg197*) | p.(Ser487Profs*21) | p.(Arg631Gln) | p.(Pro2459Leufs*16) | p.(Gln368Glyfs*6) | p.(Ile282Val) | |
Genetic diagnosis | SRS | SRS | SRS | SRS | IGF1R abnormality | SHORT syndrome | Floating-Harbor syndrome | Pitt-Hopkins syndrome | Noonan syndrome |
Inheritance | De novo | De novo or paternal | Mother (carrier) | Mother (affected) | Father (carrier) | De novo | De novo | De novo | De novo |
Allele | Paternal | Paternal | Maternal | Maternal | Paternal | NE | NE | NE | NE |
Karyotype | 46,XY | 46,XY | 46,XX | 46,XX | NE | 46,XY | 46,XY | 46,XX | 46,XY |
Allele frequency | |||||||||
 gnomAD [13] | None | None | None | None | None | None | None | None | None |
 HGVD [14] | None | None | None | None | None | None | None | None | None |
 4.7KJPN [15] | None | None | None | None | None | None | None | None | None |
In silico pathogenicity prediction | |||||||||
 CADD [16] | 1% most deleterious | 1% most deleterious | 1% most deleterious | 1% most deleterious | 1% most deleterious | 1% most deleterious | 1% most deleterious | 1% most deleterious | 1% most deleterious |
 (PHRED score) | 27.4 | 27.2 | 32.0 | 37.0 | 35.0 | 33.0 | 27.2 | 35.0 | 23.6 |
 MutationTaster [17] (score) | Disease causing | Disease causing | Disease causing | Disease causing | Disease causing | Disease causing | Disease causing | Disease causing | Disease causing |
1.000 | 1.000 | 0.662 | 1.000 | 1.000 | 1.000 | 1.000 | 1.000 | 1.000 | |
 SIFT [18] (score) | Damaging | Damaging | Damaging | – | – | Damaging | – | – | Damaging |
0.000 | 0.000 | 0.000 | Â | Â | 0.000 | Â | Â | 0.000 | |
 PP2_HVAR [19] (score) | Probably damaging | Probably damaging | Probably damaging | – | – | Probably damaging | – | – | Benign |
0.975 | 0.933 | 0.982 | Â | Â | 0.941 | Â | Â | 0.088 | |
 M-CAP [20] (score) | Possibly pathogenic | Possibly pathogenic | Possibly pathogenic | – | – | Possible pathogenic | – | – | Possibly pathogenic |
0.867 | 0.887 | 0.964 | Â | Â | 0.568 | Â | Â | 0.033 | |
ACMG classification [11] criteria | Pathogenic | Likely pathogenic | Likely pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic | Pathogenic |
PS2, PM1, PM2, PP3, PP4 | PM1, PM2, PP3, PP4 | PS3, PM2, PM5a, PP3 | PVS1, PM2, PP1, PP3 | PVS1, PM2, PP3 | PS1, PS2, PM2, PP3 | PSV1, PS1, PS2, PM2, PP3 | PSV1, PS2, PM2, PP3, PP4 | PS1, PS2, PM2 | |