Table 1.
Analysis of variants in PRORP in four families with distinct clinical presentations
| Family | F1 | F2 | F3 | F4 | ||
|---|---|---|---|---|---|---|
| Family details | ||||||
| Family details | three affected female siblings | one affected male | one affected male | two affected siblings and their affected mother | ||
| Phenotype | Perrault syndrome | SNHL | developmental delay, SNHL, lactic acidosis, and white matter changes | white matter changes | ||
| Variant details | ||||||
| Variant | PRORP: c.1454C>T (p.Ala485Val) | PRORP: c.1235A>G (p.Asn412Ser) | PRORP: c.1301C>A (p.Ala434Asp) | PRORP: c.1334G>A (p.Arg445Gln) | PRORP: c.1197dupA (p.Ser400IlefsX6) | PRORP: c.1261C>T (p.Arg421Cys) |
| Location | Chr14(GRCh37): g.35739636C>T | Chr14(GRCh37): g.35649943A>G | Chr14(GRCh37): g.35735958C>A | Chr14(GRCh37): g.35735991G>A | Chr14(GRCh37): g.35649905dup | Chr14(GRCh37): g.35649969C>T |
| dbSNP | not present | rs148259590 | rs144536804 | rs777185638 | rs764714439 | rs147065101 |
| Zygosity | homozygous | heterozygous | heterozygous | heterozygous | heterozygous | homozygous |
| Inheritance | N/A | maternal | paternal | maternal | paternal | N/A |
| gnomAD MAF (count) | not present | 0.0001382 (39 heterozygotes, 0 homozygotes) | 0.0008385 (237 heterozygotes, 0 homozygotes) | 0.00002475 (7 heterozygotes, 0 homozygotes) | 0.00003593 (9 heterozygotes, 0 homozygotes) | 0.0001279 (36 heterozygotes, 0 homozygotes) |
| Prediction tools | ||||||
| SIFT | deleterious (0.0) | deleterious (0.0) | deleterious (0.03) | deleterious (0.0) | N/A | deleterious (0.03) |
| PolyPhen | probably damaging (1.0) | probably damaging (1.0) | benign (0.443) | probably damaging (1.0) | N/A | probably damaging (1.0) |
| MutationTaster | disease causing (1.0) | disease causing (1.0) | disease causing (0.811) | disease causing (1.0) | N/A | disease causing (1.0) |
| VarCards | 0.91 (extreme) | 0.74(extreme) | 0.39 | 0.83 (extreme) | N/A | 0.57 (extreme) |
| CADD | 34 | 26.4 | 28.2 | 34 | N/A | 35 |
| Conservation | highly conserved | highly conserved | moderately conserved | highly conserved | N/A | highly conserved |
| Effect on protein | ||||||
| Variant prediction | may distort the active site | may interfere with the shape of the active site | reduce the stability of the protein | directly impact nuclease function | loss of function | this region is disordered in the structure so was not modeled |
| FOLDX change | reduces stability (ΔΔG 3.97 kcal/mol) | slightly reduces stability (ΔΔG 1.61 kcal/mol) | slightly reduces stability (ΔΔG 1.66 kcal/mol) | slightly reduces stability (ΔΔG 2.32 kcal/mol) | N/A | N/A |
| tRNA processing (approximate % of wild-type) | 82% | 13% | 86% | 25% | N/A | 81% |
All variants mapped to the PRORP transcript GenBank: NM_014672.3. SNHL, sensorineural hearing loss; MAF, minor allele frequency.