Genetic and clinical characteristics of patients with heterozygous ITPR3 mutations
| PATIENT . | P1 . | P2 . | P3 . | P4 . | P5 . | |
|---|---|---|---|---|---|---|
| Variant annotation | ||||||
| Inheritance | het, de novo | het, de novo | het, maternal | het, de novo | het, de novo | het, ? de novo |
| Nt change | c.586G>A | c.7517T>A | c.5549G>A | c.7571G>A | c.7570C>T | c.7570C>T |
| AA change | p.A196T | p.I2506N | p.R1850Q | p.R2524H | p.R2524C | p.R2524C |
| GNOMAD, DBSNP151, 1000G | No | No | gnomAD freq = 0.082 6079 hom | No | No | No |
| CADD (95% CI MSC = 16) | 32 | 33 | 21.5 | 32 | 30 | 30 |
| SIFT | Deleterious | Deleterious | Tolerated | Deleterious | Deleterious | Deleterious |
| Polyphen2 | Probably damaging | Probably damaging | Benign | Probably damaging | Probably damaging | Probably damaging |
| Clinical presentation | ||||||
| Age at presentation | 7 yo | 3 mo | Infancy | 4 mo | 14 mo | |
| Age now | 24 yo | 6 yo | 33 yo | 18 yo | 13 yo | |
| Combined immunodeficiency | Yes | Yes | Yes | Yes | Yes | |
| Viral infections | Cutaneous (severe HPV, resistant molluscum); EBV | Respiratory (RSV); GI (adenovirus) | Respiratory; cutaneous (severe VZV); EBV | Respiratory (VZV, adenovirus, RSV); cutaneous (HPV) | Respiratory; EBV | |
| Bacterial infections | Impetigo | LRTI (H. influenzae) | LRTI | P. aeruginosa resp. colonization | LRTI (H. influenzae, S. pneumoniae) | |
| T cell lymphopenia | Yes | Yes | Yes | Yes | Yes | |
| B cell lymphopenia | No | No | Yes | Yes | Yes | |
| Hypogammaglobulinemia | No | Yes | Yes | No | No | |
| Other | ITP, eczema | Atopy, lymphoma | ITP, lymphoma | |||
| ED | No | Yes | Yes | Yes | Yes | |
| Dental anomalies | No | Small, peg-shaped lower incisors | Hypo- and microdontia | Peg-shaped lower incisors, hypodontia | Peg-shaped lower incisors, enamel discoloration | |
| Hair anomalies | No | Thin hair | Thin hair | Thin, light hair | Thin, light hair | |
| Nail anomalies | No | No | No | Thin nails | Slow nail growth | |
| Hypohidrosis | No | No | No | Yes | No | |
| Other system disease | No | Yes | No | Yes | Yes | |
| Neurology | Unsafe swallow, chronic motor neuronopathy | Demyelinating motor and sensory neuropathy | ||||
| Gastroenterology | Chronic constipation | |||||
| Respiratory | Bronchiectasis | Bronchiectasis | ||||
| Other | Atrial septal defect | Growth restriction, developmental delay, dysmorphism | ||||
| Current treatment | Post-HCT, Abx, IgRT | Post-HCT, CSA, Abx, IgRT | Post-HCT | Abx, DNAse nebulizers | Post-HCT, Abx, IgRT | |
| PATIENT . | P1 . | P2 . | P3 . | P4 . | P5 . | |
|---|---|---|---|---|---|---|
| Variant annotation | ||||||
| Inheritance | het, de novo | het, de novo | het, maternal | het, de novo | het, de novo | het, ? de novo |
| Nt change | c.586G>A | c.7517T>A | c.5549G>A | c.7571G>A | c.7570C>T | c.7570C>T |
| AA change | p.A196T | p.I2506N | p.R1850Q | p.R2524H | p.R2524C | p.R2524C |
| GNOMAD, DBSNP151, 1000G | No | No | gnomAD freq = 0.082 6079 hom | No | No | No |
| CADD (95% CI MSC = 16) | 32 | 33 | 21.5 | 32 | 30 | 30 |
| SIFT | Deleterious | Deleterious | Tolerated | Deleterious | Deleterious | Deleterious |
| Polyphen2 | Probably damaging | Probably damaging | Benign | Probably damaging | Probably damaging | Probably damaging |
| Clinical presentation | ||||||
| Age at presentation | 7 yo | 3 mo | Infancy | 4 mo | 14 mo | |
| Age now | 24 yo | 6 yo | 33 yo | 18 yo | 13 yo | |
| Combined immunodeficiency | Yes | Yes | Yes | Yes | Yes | |
| Viral infections | Cutaneous (severe HPV, resistant molluscum); EBV | Respiratory (RSV); GI (adenovirus) | Respiratory; cutaneous (severe VZV); EBV | Respiratory (VZV, adenovirus, RSV); cutaneous (HPV) | Respiratory; EBV | |
| Bacterial infections | Impetigo | LRTI (H. influenzae) | LRTI | P. aeruginosa resp. colonization | LRTI (H. influenzae, S. pneumoniae) | |
| T cell lymphopenia | Yes | Yes | Yes | Yes | Yes | |
| B cell lymphopenia | No | No | Yes | Yes | Yes | |
| Hypogammaglobulinemia | No | Yes | Yes | No | No | |
| Other | ITP, eczema | Atopy, lymphoma | ITP, lymphoma | |||
| ED | No | Yes | Yes | Yes | Yes | |
| Dental anomalies | No | Small, peg-shaped lower incisors | Hypo- and microdontia | Peg-shaped lower incisors, hypodontia | Peg-shaped lower incisors, enamel discoloration | |
| Hair anomalies | No | Thin hair | Thin hair | Thin, light hair | Thin, light hair | |
| Nail anomalies | No | No | No | Thin nails | Slow nail growth | |
| Hypohidrosis | No | No | No | Yes | No | |
| Other system disease | No | Yes | No | Yes | Yes | |
| Neurology | Unsafe swallow, chronic motor neuronopathy | Demyelinating motor and sensory neuropathy | ||||
| Gastroenterology | Chronic constipation | |||||
| Respiratory | Bronchiectasis | Bronchiectasis | ||||
| Other | Atrial septal defect | Growth restriction, developmental delay, dysmorphism | ||||
| Current treatment | Post-HCT, Abx, IgRT | Post-HCT, CSA, Abx, IgRT | Post-HCT | Abx, DNAse nebulizers | Post-HCT, Abx, IgRT | |
95% CI MSC, 95% confidence interval MSC; Abx, antibiotics; CSA, cyclosporin; GI, gastrointestinal; het, heterozygous; hom, homozygous; HPV, human papilloma virus; IgRT, immunoglobulin replacement therapy; LRTI, lower respiratory tract infection; mo, months old; Nt, nucleotide; Resp, respiratory; RSV, respiratory syncytial virus; VZV, varicella zoster virus; yo, years old.