Introduction
Materials and methods
Ethical compliance and data collection
Whole-exome sequencing and Sanger sequencing
Pathogenicity analysis
Literature review
Results
Case series
Patient 1
Patient | P1 | P2 | P3 | P4 |
---|---|---|---|---|
Gender | M | F | M | M |
Age of onset | 7 months | 4 months | 4 months | 23 months |
Initial visit | 9 months | 5 months | 5 months | 23 months |
Onset symptoms | Fever, cough, and convulsion | Diarrhea, vomit | Cough, diarrhea, and convulsion | Urethral stones |
Family history | + | + | − | − |
Growth retardation | + | − | − | − |
Proteinuria | + | − | + / − | − |
Hematuria | − | − | + | − |
Scr (15.4–90.4 umol/L) | 844.6 | 454 | 616.6 | 118 |
BUN (2.42–6.72 mmol/L) | 33.49 | 24.45 | 14.53 | 5.4 |
eGFR ml/(min.1.73m2) | 3.7 | 6.8 | 5.2 | 91 |
Blood calcium (2.23–2.8 mmol/L) | 2.4 | 2.17 | 1.9 | 2.43 |
Blood phosphorus (1.3–2.1 mmol/L) | 4.2 | 2.93 | 2.87 | 1.68 |
PTH (10-69 pg/ml) | 62.3 | 188 | UA | 68.9 |
Nephrocalcinosis | + | + | + | + |
Urinary tract stones | − | − | − | + |
Prognosis | Die | Die | Die | Follow up |
Mutations | c.302 T > G (p.L101R) c.653C > T(p.S218L) | c.302 T > G(p.L101R) c.653C > T(p.S218L) | c.26delC(p.T9fs) c.32C > G (p.P11R) | c.33dupC(p.K12Qfs*) c.33dupC(p.K12Qfs*) |
Patient 2
Patient 3
Patient 4
Genetic sequencing and pathogenicity analysis
Nucleotide | PROVEAN | PolyPhen − 2 | M-CAP | CADD | MUTATION TASTER |
---|---|---|---|---|---|
c.302 T > G | −5.478 Pathogenic | 0.954 Possible pathogenic | 0.758 Possibly pathogenic | 26.9 Pathogenic | Disease-causing |
Literature review
Exon | Frequency | Nucleotide changes | Amino acid changes | Variant type | Single gene frequency |
---|---|---|---|---|---|
Exon 1 | 44/149 (29.6%) | c.2 T > C | p.M1T | Missense | 5/149 (3.4%) |
c.25_26 insC | p.T9Tfs | Frameshift | 1/149 (0.7%) | ||
c.26delC | p.T9fs | Frameshift | 1/149 (0.7%) | ||
c.26_27insC | p.T9fs | Frameshift | 2/149 (1.3%) | ||
c.28_29delCCinsA | p.P10Tfs | Frameshift | 1/149 (0.7%) | ||
c.32C > G | p.P11R | Missense | 9/149 (6.0%) | ||
c.33dupC | p.K12Qfs | Frameshift | 18/149 (12.0%) | ||
c.97C > A | p. Leu33Met | Missense | 1/149 (0.7%) | ||
c.107G > A | p. Arg36His | Missense | 1/149 (0.7%) | ||
c.121G > T | p. Gly41Trp | Missense | 1/149 (0.7%) | ||
c.145A > C | p.M49L | Missense | 4/149 (2.7%) | ||
Exon 2 | 20/149 (13.3%) | c.190A > T | p.I64F | Missense | 2/149 (1.3%) |
c.215A > T | p.N72I | Missense | 7/149 (4.7%) | ||
c.242C > A | p.Ser81X | Nonsense | 2/149 (1.3%) | ||
c.302 T > G | p.L101R | Missense | 2/149 (1.3%) | ||
c.331C > T | p. Arg111* | Nonsense | 1/149 (0.7%) | ||
c.332G > A | p.Arg111Gln | Missense | 2/149 (1.3%) | ||
c.346G > A | p.Gly116Arg | Missense | 4/149 (2.7%) | ||
Exon 3 | 2/149 (1.3%) | c.364C > T | p. Arg122* | Nonsense | 2/149 (1.3%) |
Exon 4 | 5/149 (3.3%) | c.466G > A | p.G156R | Missense | 1/149 (0.7%) |
c.473C > T | p.S158L | Missense | 2/149 (1.3%) | ||
c.517 T > c | p.Cys173Arg | Missense | 2/149 (1.3%) | ||
Exon 5 | 7/149 (4.6%) | c.551C > A | p.Ser184 | − | 1/149 (0.7%) |
c.557C > T | p.Ala186Val | Missense | 2/149 (1.3%) | ||
c.577delC | p.Leu193Phefs*19 | Frameshift | 2/149 (1.3%) | ||
c.590G > A | p.Arg197Gln | Missense | 2/149 (1.3%) | ||
Exon 6 | 27/149 (18.2%) | c.605 T > A | p.I202N | Missense | 5/149 (3.4%) |
c.614C > T | p.S205L | Missense | 4/149 (2.7%) | ||
c.638C > T | p.A213V | Missense | 1/149 (0.7%) | ||
c.653C > T | p.S218L | Missense | 2/149 (1.3%) | ||
c.667A > c | p.Ser223Arg | Missense | 2/149 (1.3%) | ||
c.672G > T | p.Lys209Asn | Missense | 1/149 (0.7%) | ||
c.679_680del | p.K228Efs | Frameshift | 7/149 (4.7%) | ||
679-(IVS6 + 2)delAAgt | − | Splice | 5/149 (3.4%) | ||
Exon 7 | 1/149 (0.7%) | c.740 T > G | p.Leu247Arg | Missense | 1/149 (0.7%) |
Exon 8 | 25/149 (16.9%) | c.815_816insGA | p.L272fs | Frameshift | 15/149 (10.1%) |
c817insAG | p.S275Rfs | Frameshift | 1/149 (0.7%) | ||
c.823_824dupAG | p.Ser275Argfs*38 | Frameshift | 4/149 (2.7%) | ||
c.824G > A | p.S275N | Missense | 1/149 (0.7%) | ||
c.824_825insAG | p.S275Rfs | Frameshift | 2/149 (1.3%) | ||
c.829_830insA | p.Ala277fs | Frameshift | 1/149 (0.7%) | ||
c844C > T | p.Gln282* | Nonsense | 1/149 (0.7%) | ||
Exon 9 | 2/149 (1.4%) | c.864G > A | p.Trp288X | Nonsense | 1/149 (0.7%) |
c.909delG | p.Q303fs | Frameshift | 1/149 (0.7%) | ||
Exon 10 | 6/149 (4.0%) | c.997A > T | p.R333* | Nonsense | 3/149 (2.0%) |
c.1015delG | p.V339Sfs*2 | Frameshift | 1/149 (0.7%) | ||
c.1049G > A | p. Gly350Asp | Missense | 2/149 (1.3%) | ||
Exon 11 | 10/149 (6.7%) | c.1072–2A > G | − | Splice | 1/149 (0.7%) |
c. 1079G > A | p. Arg360Gln | Missense | 6/149 (4.0%) | ||
c.1161C > A | p.C387X | Nonsense | 3/149 (2.0%) |
Parameters | Frequency (n,%) |
---|---|
The most common variants | Number of variants (n = 149) |
c.33dupC | 18/149 (12.0) |
c.815_816insGA | 15/149 (10.1) |
c.32C > G | 9/149 (6.0) |
c.679_680del | 7/149 (4.7) |
c.215A > T | 7/149 (4.7) |
Mutation type | Total number of allelesa (n = 148) |
Missense | 72/148 (48.6) |
Frameshift | 57/148 (38.5) |
Nonsense | 13/148 (8.8) |
Splice | 6/148 (4.1) |
Gene function category | Total number of PH1 patientsb (n = 47) |
Truncation/truncation | 19/47 (40.4) |
Missense/missense | 14/47 (29.8) |
Truncation/ missense | 11/47 (23.4) |
Truncation/splice | 2/47 (4.3) |
Missense/ splice | 1/47 (2.1) |
Gene function category | Patients with ESRD/PH1 patients with renal function outcome |
Truncation/truncation | 7/19 (36.8) |
Missense/missense | 9/14 (64.3) |
Truncation/missense | 6/10 (60.0) |
Truncation/splice | 1/2 (50.0) |
Missense/splice | 1/1 (100.0) |
Gene function category | Dead patients/patients with the outcome |
Missense/missense | 4/12 (33.3) |
Truncation/ missense | 3/8 (37.5) |
Truncation/truncation | 2/12 (16.7) |
Truncation/splice | 1/1 (100.0) |
Missense/splice | 0/1 (0.0) |
Exon location of the variant gene | The proportion of patients with ESRDc |
Exon 1 | 15/32 (46.9) |
Exon 2 | 10/12 (83.3) |
Exon 6 | 6/13 (46.2) |
Exon 8 | 10/19 (52.6) |
Exon location of the variant gene | The proportion of patients who diedd |
Exon 1 | 7/24 (29.2) |
Exon 2 | 4/11 (36.4) |
Exon 6 | 5/11 (45.5) |
Exon 8 | 1/12 (8.3) |
Chinese patients of PH1 | Total pediatric patients | Pediatric patients | Adult patients | Mandrile et al., 2014 [7] | M'Dimegh et al., 2017 [39] | Hopp et al., 2015 [16] | Abid et al., 2023 [40] | Wannous et al., 2023 [41] | ||
---|---|---|---|---|---|---|---|---|---|---|
< 1 year old | ≥ 1 year old | |||||||||
Gender (male/female) | 35/13 | 30/11 | 7/2 | 22/10 | 5/2 | 300/226 | 94/52 | NA | 141/64 | 20/20 |
The median age of onset | 51 months | 38 months | 4 months | 55 months | 28 years old | NA | NA | 5.2 years old | Under 5 years old | 3 years old |
Region | China | Europe | Tunisia | America | South Asia | Syria | ||||
Main clinical manifestations (n,%) | ||||||||||
Urolithiasis | 41/48, 85.4 | 34/41, 82.9 | 2/9, 22.2 | 32/32,100.0 | 7/7,100.0 | 316/526, 60.1 | 74/146, 51.0 | 49/160, 30.6 | 41.3% | 28/40, 70.0 |
Renal insufficiency | 7/48, 14.5 | 7/41, 17.1 | 7/9, 77.8 | 0/32, 0.0 | 0/7, 0.0 | NA | NA | NA | 67.2% | 29/40, 72.5 |
Outcomesa (n, %) | ||||||||||
ESRD | 24/47, 51.1 | 18/40, 45.0 | 7/8, 87.5 | 11/31, 35.5 | 6/7, 85.7 | 267/458, 58.0 | 89/146, 61.0 | NA | 50% | NA |
Deathb | 14/36, 38.9 | 8/29, 27.6 | 6/8, 75.0 | 1/20, 5.0 | 3/6, 50.0 | 67/477, 14.0 | NA | NA | NA | 13/28, 46.4 |