Clinical Characteristics and Outcome, According to the Type of Mutation of RPS19 Gene in DBA Patients
| Patient (sex) . | Age at Diagnosis of DBA (mo) . | Malformative Status . | Response at First Steroid Course . | Status at Last Follow- Up . | Genomic DNA Mutation . | Expected Protein Alteration . | Inheritance . | Mutation in Other Family Members* . |
|---|---|---|---|---|---|---|---|---|
| Nonsense mutations | ||||||||
| F23 (F) | 1 | Kidney hypoplasia/aplasia, low hair line, short stature | NR | Dead | 34 C → T | Gln12Stop | s | 0 |
| F49 (F) | 2 | Triphalangeal thumb, low implantation of thumbs | NR | TD | 144 C → A | Tyr48Stop | s | 0 |
| F44 (M) | 2 | Hydrocephaly, unique median cerebral ventricule, atrioventricular septal defect, modeling defect of long bones | NR | TD | 99 G → C | Trp33Stop | s | 0 |
| F16 (M) | 2 | None | CR | SD | 34 C → T | Gln12Stop | s | 0 |
| F69 (F) | 22 | Short stature | CR | SD | 166 C → G | Arg56Stop | s | 0 |
| G7 (F) | 2 | Short stature | CR | SD | 280 C → T | Arg94Stop | se | e: 2/3 |
| I6 (M) | 3 | None | CR | SD | 155 G → A | Trp52Stop | s | 0 |
| I7 (M) | 0 | None | NR | TD | 31 C → T | Gln11Stop | s | 0 |
| I8 (F) | 2 | None | NR | TD | 280 C → T | Arg94Stop | d | d: 1/1 |
| I9 (F) | 0 | Congenital bilateral glaucoma | CR | TD | 280 C → T | Arg94Stop | d | d: 2/2 |
| G27 (M) | NA | NA | NA | NA | 280 C → T | Arg94Stop | s | 0 |
| Missense mutations | ||||||||
| F42 (F) | 1 | Short stature | NR | TD | 380 G → A | Gly127Gln | s | 0 |
| F18 (F) | 2 | Triphalangeal thumb, anogenital fistula, interventricular septal defect | NR | TD | 184 C → T | Arg62Trp | s | 0 |
| F32 (F) | 1 | None | PR | TD | 167 G → A | Arg56Gln | s | 0 |
| F28 (M) | 1 | None | PR | TD | 167 G → A | Arg56Gln | s | 0 |
| F7 (M) | 3 | None | NR | TD | 167 G → A | Arg56Gln | se | e: 0/3 |
| G20 (F) | 2 | None | CR | SD | 43 G → T | Val15Phe | s | 0 |
| F70 (F) | 2 | None | NR | TD | 358 G → C | Gly120Ser | s | 0 |
| F12 (M) | 0 | None | CR | CRem | 184 C → T | Arg62Trp | d | d: 2/2 |
| F9 (M) | 0 | None | CR | NA | 1 A → G | Met1Val | d | d: 2/2 |
| G24 (M) | 2 | None | NR | BMT | 184 C → T | Arg62Trp | se | e: 1/1 |
| I10 (M) | 2 | Short stature | NR | Dead | 184 C → T | Arg62Trp | s | 0 |
| I11 (F) | 4 | Duplication of thumb | CR | CRem | 302 G → A | Arg101His | s | h: 1/1 |
| I53 (M) | 0 | Micrognathia, proximal implanted thumbs, short stature | NR | TD | 184 C → T | Arg62Trp | s | 0 |
| S1 | NA | NA | NA | NA | 154 T → C | Trp52Arg | s | 0 |
| E28 (F) | 2 | None | NA | CRem | 182 C → A | Ala61Ser | se | e: 0/1 h: 1/1 |
| S2 (F) | <12 | None | NR | TD | 184 C → T | Arg62Trp | d | d: 1/1 |
| Insertions and deletions | ||||||||
| F31 (M) | 2 | None | NR | TD | ins A between nt 14 and 15 | Frameshift at codon 5 stop at codon 50 | s | 0 |
| F4 (F) | 1 | Hypertelorism, epicanthus, low ear set, antimongoloid eye line | NR | CRem | del 295 bp 356 (+281-+576) | Deletion of exon 5 | de | d: 1/1 e: 1/1 |
| F19 (M) | 2 | Epicanthus, low hairline, short stature | CR | SD | del 1 bp nt 222 | Frameshift at codon 74 stop at codon 75 | s | 0 |
| F26 (M) | 2 | Dysplasia of mitral valve, short stature | NR | TD | ins A between nt 104 and 105 | Frameshift at codon 35 stop at codon 50 | s | 0 |
| F25 (F) | 1 | Short stature | CR | SD | del 31bp (274-314) | Deletion of 31 nt of exon 4, frameshift at codon 92 stop at codon 100 | s | 0 |
| F64 (F) | 11 | Microcephaly, short stature | CR | CRem | del 2 bp (390-391) | Frameshift at codon 130 stop at codon 151 | s | 0 |
| G22 (F) | 3 | None | NA | NA | del 2 bp (293-294) | Frameshift at codon 98 stop at codon 152 | s | 0 |
| I1 (M) | 2 | Short stature | NR | CRem | deletion of a complete allele | s | 0 | |
| I2 (M) | 1 | None | NR | TD | del A 341 | Frameshift at codon 115 stop at codon 123 | s | 0 |
| I4 (M) | 1 | None | CR | CRem | Ins G between nt 238 and 239 | Frameshift at codon 80 stop at codon 153 | s | 0 |
| I5 (F) | 0 | Bilateral congenital glaucoma, short stature, left eyelid ptosis, atrial septal defect | NR | TD | Ins AGA between nt 53 and 54 | Insertion E at codon 19 no frameshift | s | 0 |
| E10 (M) | 3 | None | CR | SD | del 2 bp (383-384) | Frameshift at codon 128 stop at codon 153 | se | e: 2/2 |
| E13 (M) | 3 | High arch palate, facial asymetry | CR | SD | del 2 bp (250-251) | Frameshift at codon 84 stop at codon 153 | s | 0 |
| S10 (F) | 1 | Left kidney aplasia/hypoplasia, short stature | PR | TD | t(X;19) | s | ||
| S11 (M) | 2 | Macrocephaly, mental retardation, short broad bones, extra ribs, malformations of the spine, short stature | PR | TD | deletion of a complete allele | s | 0 | |
| I24 (F) | 2 | Mental retardation, short stature | CR | TD | 46, XX, t(8;19)(q35;q13) | s | 0 | |
| Splice sites defects | ||||||||
| F21 (M) | 2 | Short stature | NR | TD | 173 (−2) agCTT → tgCTT | Acceptor splice site IVSA | s | 0 |
| F66 (F) | 2 | None | CR | SD | del 4 bp 71 (+3-+6) Aagtgagtttgg → Agtttggg | Donor splice site defect IISD | de | d: 2/2 e: 1/ 1 te: 1/1 |
| F77 (M) | 2 | None | NR | BMT | 356 (+2) T → A ATGGgt → ATGGga | Donor splice site defect IVSD | s | 0 |
| I3 (M) | 0 | None | NR | TD | del G 173(−1) agCTT → aCTT | Acceptor splice site defect IVSA | s | 0 |
| E3 (M) | 13 | None | NR | CRem | 1 (−1) agATG → atATG | Acceptor splice site defect ISA | de | d: 1/1 e: 0/1 |
| Exon 1 (non-coding) | ||||||||
| F21 (M) | 2 | Short stature | NR | TD | del 4 bp (−629-−625) | s | 0 | |
| F25 (F) | 1 | Short stature | CR | SD | del 4 bp (−629-−625) | s | 0 | |
| F1 (M) | 0 | None | NR | TD | del 4 bp (−629-−625) | se | e: 2/3 h: 1/15 | |
| Mutations in intronic regions | ||||||||
| F11 (M) | 3 | None | NR | TD | intron 1 −460 G → T | se | e: 0/2 h: 1/2 | |
| F5 (M) | 2 | None | NR | TD | intron 5 6 pp downstream of exon 5 G → C | d | d: 0/3 | |
| F53 (F) | 0 | None | NR | TD | intron 1 −460 G → T | s | 0 | |
| F74 (F) | 2 | None | CR | SD | intron 4 18 bpdownstream of exon 4 G → C | s | 0 | |
| F15 (M) | NA | None | NR | TD | intron 1 −460 G → T | s | 0 | |
| G28 (M) | NA | None | CR | SD | intron 1 −460 G → T | s | 0 | |
| F58 (M) | 4 | None | CR | SD | −836 G → C | d | NA | |
| Patient (sex) . | Age at Diagnosis of DBA (mo) . | Malformative Status . | Response at First Steroid Course . | Status at Last Follow- Up . | Genomic DNA Mutation . | Expected Protein Alteration . | Inheritance . | Mutation in Other Family Members* . |
|---|---|---|---|---|---|---|---|---|
| Nonsense mutations | ||||||||
| F23 (F) | 1 | Kidney hypoplasia/aplasia, low hair line, short stature | NR | Dead | 34 C → T | Gln12Stop | s | 0 |
| F49 (F) | 2 | Triphalangeal thumb, low implantation of thumbs | NR | TD | 144 C → A | Tyr48Stop | s | 0 |
| F44 (M) | 2 | Hydrocephaly, unique median cerebral ventricule, atrioventricular septal defect, modeling defect of long bones | NR | TD | 99 G → C | Trp33Stop | s | 0 |
| F16 (M) | 2 | None | CR | SD | 34 C → T | Gln12Stop | s | 0 |
| F69 (F) | 22 | Short stature | CR | SD | 166 C → G | Arg56Stop | s | 0 |
| G7 (F) | 2 | Short stature | CR | SD | 280 C → T | Arg94Stop | se | e: 2/3 |
| I6 (M) | 3 | None | CR | SD | 155 G → A | Trp52Stop | s | 0 |
| I7 (M) | 0 | None | NR | TD | 31 C → T | Gln11Stop | s | 0 |
| I8 (F) | 2 | None | NR | TD | 280 C → T | Arg94Stop | d | d: 1/1 |
| I9 (F) | 0 | Congenital bilateral glaucoma | CR | TD | 280 C → T | Arg94Stop | d | d: 2/2 |
| G27 (M) | NA | NA | NA | NA | 280 C → T | Arg94Stop | s | 0 |
| Missense mutations | ||||||||
| F42 (F) | 1 | Short stature | NR | TD | 380 G → A | Gly127Gln | s | 0 |
| F18 (F) | 2 | Triphalangeal thumb, anogenital fistula, interventricular septal defect | NR | TD | 184 C → T | Arg62Trp | s | 0 |
| F32 (F) | 1 | None | PR | TD | 167 G → A | Arg56Gln | s | 0 |
| F28 (M) | 1 | None | PR | TD | 167 G → A | Arg56Gln | s | 0 |
| F7 (M) | 3 | None | NR | TD | 167 G → A | Arg56Gln | se | e: 0/3 |
| G20 (F) | 2 | None | CR | SD | 43 G → T | Val15Phe | s | 0 |
| F70 (F) | 2 | None | NR | TD | 358 G → C | Gly120Ser | s | 0 |
| F12 (M) | 0 | None | CR | CRem | 184 C → T | Arg62Trp | d | d: 2/2 |
| F9 (M) | 0 | None | CR | NA | 1 A → G | Met1Val | d | d: 2/2 |
| G24 (M) | 2 | None | NR | BMT | 184 C → T | Arg62Trp | se | e: 1/1 |
| I10 (M) | 2 | Short stature | NR | Dead | 184 C → T | Arg62Trp | s | 0 |
| I11 (F) | 4 | Duplication of thumb | CR | CRem | 302 G → A | Arg101His | s | h: 1/1 |
| I53 (M) | 0 | Micrognathia, proximal implanted thumbs, short stature | NR | TD | 184 C → T | Arg62Trp | s | 0 |
| S1 | NA | NA | NA | NA | 154 T → C | Trp52Arg | s | 0 |
| E28 (F) | 2 | None | NA | CRem | 182 C → A | Ala61Ser | se | e: 0/1 h: 1/1 |
| S2 (F) | <12 | None | NR | TD | 184 C → T | Arg62Trp | d | d: 1/1 |
| Insertions and deletions | ||||||||
| F31 (M) | 2 | None | NR | TD | ins A between nt 14 and 15 | Frameshift at codon 5 stop at codon 50 | s | 0 |
| F4 (F) | 1 | Hypertelorism, epicanthus, low ear set, antimongoloid eye line | NR | CRem | del 295 bp 356 (+281-+576) | Deletion of exon 5 | de | d: 1/1 e: 1/1 |
| F19 (M) | 2 | Epicanthus, low hairline, short stature | CR | SD | del 1 bp nt 222 | Frameshift at codon 74 stop at codon 75 | s | 0 |
| F26 (M) | 2 | Dysplasia of mitral valve, short stature | NR | TD | ins A between nt 104 and 105 | Frameshift at codon 35 stop at codon 50 | s | 0 |
| F25 (F) | 1 | Short stature | CR | SD | del 31bp (274-314) | Deletion of 31 nt of exon 4, frameshift at codon 92 stop at codon 100 | s | 0 |
| F64 (F) | 11 | Microcephaly, short stature | CR | CRem | del 2 bp (390-391) | Frameshift at codon 130 stop at codon 151 | s | 0 |
| G22 (F) | 3 | None | NA | NA | del 2 bp (293-294) | Frameshift at codon 98 stop at codon 152 | s | 0 |
| I1 (M) | 2 | Short stature | NR | CRem | deletion of a complete allele | s | 0 | |
| I2 (M) | 1 | None | NR | TD | del A 341 | Frameshift at codon 115 stop at codon 123 | s | 0 |
| I4 (M) | 1 | None | CR | CRem | Ins G between nt 238 and 239 | Frameshift at codon 80 stop at codon 153 | s | 0 |
| I5 (F) | 0 | Bilateral congenital glaucoma, short stature, left eyelid ptosis, atrial septal defect | NR | TD | Ins AGA between nt 53 and 54 | Insertion E at codon 19 no frameshift | s | 0 |
| E10 (M) | 3 | None | CR | SD | del 2 bp (383-384) | Frameshift at codon 128 stop at codon 153 | se | e: 2/2 |
| E13 (M) | 3 | High arch palate, facial asymetry | CR | SD | del 2 bp (250-251) | Frameshift at codon 84 stop at codon 153 | s | 0 |
| S10 (F) | 1 | Left kidney aplasia/hypoplasia, short stature | PR | TD | t(X;19) | s | ||
| S11 (M) | 2 | Macrocephaly, mental retardation, short broad bones, extra ribs, malformations of the spine, short stature | PR | TD | deletion of a complete allele | s | 0 | |
| I24 (F) | 2 | Mental retardation, short stature | CR | TD | 46, XX, t(8;19)(q35;q13) | s | 0 | |
| Splice sites defects | ||||||||
| F21 (M) | 2 | Short stature | NR | TD | 173 (−2) agCTT → tgCTT | Acceptor splice site IVSA | s | 0 |
| F66 (F) | 2 | None | CR | SD | del 4 bp 71 (+3-+6) Aagtgagtttgg → Agtttggg | Donor splice site defect IISD | de | d: 2/2 e: 1/ 1 te: 1/1 |
| F77 (M) | 2 | None | NR | BMT | 356 (+2) T → A ATGGgt → ATGGga | Donor splice site defect IVSD | s | 0 |
| I3 (M) | 0 | None | NR | TD | del G 173(−1) agCTT → aCTT | Acceptor splice site defect IVSA | s | 0 |
| E3 (M) | 13 | None | NR | CRem | 1 (−1) agATG → atATG | Acceptor splice site defect ISA | de | d: 1/1 e: 0/1 |
| Exon 1 (non-coding) | ||||||||
| F21 (M) | 2 | Short stature | NR | TD | del 4 bp (−629-−625) | s | 0 | |
| F25 (F) | 1 | Short stature | CR | SD | del 4 bp (−629-−625) | s | 0 | |
| F1 (M) | 0 | None | NR | TD | del 4 bp (−629-−625) | se | e: 2/3 h: 1/15 | |
| Mutations in intronic regions | ||||||||
| F11 (M) | 3 | None | NR | TD | intron 1 −460 G → T | se | e: 0/2 h: 1/2 | |
| F5 (M) | 2 | None | NR | TD | intron 5 6 pp downstream of exon 5 G → C | d | d: 0/3 | |
| F53 (F) | 0 | None | NR | TD | intron 1 −460 G → T | s | 0 | |
| F74 (F) | 2 | None | CR | SD | intron 4 18 bpdownstream of exon 4 G → C | s | 0 | |
| F15 (M) | NA | None | NR | TD | intron 1 −460 G → T | s | 0 | |
| G28 (M) | NA | None | CR | SD | intron 1 −460 G → T | s | 0 | |
| F58 (M) | 4 | None | CR | SD | −836 G → C | d | NA | |
Nucleotide number is based on the cDNA sequence data of RPS19 gene (Kondoh et al37), starting from the ATG. Mutations occurring upstream of ATG are numbered according to the genomic sequence, starting from the ATG (Draptchinskaia et al25). Amino acids are numbered from the first Methionine.
Abbreviations: TD, transfusion dependent; SD, steroid dependent; CRem, complete remission (free of treatment); BMT, treated with bone marrow transplantation; NA, not available; NR, no response; PR, partial response; CR, complete response; h, healthy; s, sporadic; d, dominant; e, occurrence of isolated high eADA phenotype in the family; te, transient erythroblastopenia; nt, nucleotide number; del, deletion; ins, insertion.
For each group of individuals is indicated the number sharing the same mutation than the DBA patient.