TABLE III.
Genotypes and associated SCID subtypes
| SCID subtype | ||||
|---|---|---|---|---|
| Genotype | Overall frequency* | Typical SCID (69% of total) | Leaky/atypical SCID (26% of total) | Omenn syndrome (5% of total) |
| IL2RG † | ~30% | Most common (42%)‡ | Common | |
| RAG1 | ~17% | Common | Most common (26%) | Most common (79%) |
| ADA | ~12% | Common | Common | |
| IL7R | ~7% | Common | Very rare | |
| DCLRE1C | ~7% | Common | Rare | |
| JAK3 | ~5% | Common | Unusual | |
| RAG2 | ~4% | Unusual | Common | Common |
| RMRP | <4% | Very rare | Common | Possible |
| CD3D | <2% | Unusual | Rare | |
| AK2 | <2% | Unusual | Very rare | |
| PNP | <1% | Very rare | Rare | |
| MSN † | <1% | Very rare | Very rare | |
| LIG4 | <1% | Rare | ||
| NHEJ1 | <1% | Rare | ||
| BCL11B † | <1% | Very rare | ||
| MAN2B2 | <1% | Very rare | ||
| RAC2 † | <1% | Very rare | ||
| TTC7A | <1% | Very rare | ||
Of all SCIDs, including 7% without identified pathogenic variant(s). Data derived from 346 patients (diagnosed 2010–2021) from the PIDTC 6901 prospective natural history study (see accompanying article by Dvorak et al8). Other rare genotypes that might produce a phenotype overlapping with SCID include CD3E, CD3Z, CORO1A, DIAPH1, DOCK2, EPG5, EXTL3, FCHO1, ICOSLG, IKBKB, ITPKB, LAT, LCK, LIG1, MYSM1, POLE1, POLE2, PRKDC, SLP76, SMARCAL1, TRAC, and ZAP70.
IL2RG and MSN mutations are X-linked recessive; BCL11B and RAC2 are autosomal- dominant; all others are autosomal-recessive. A hemizygous pathogenic variant in a gene on the X chromosome is required for male patients. A heterozygous variant with dominant function is required for autosomal-dominant genes. Autosomal-recessive genes require 2 compound heterozygous variants or a single homozygous pathogenic variant. Abnormal adenosine deaminase or purine nucleoside phosphorylase enzyme activity is also acceptable.
Frequency of genotypes within a particular SCID subtype. Common genotypes are those found in >5% of cases within that subtype; unusual genotypes are those found in 2%−5% of cases; rare genotypes are those found in more than 1 patient; very rare genotypes are those seen in only a single patient; possible genotypes have been reported in the literature, but not found among PIDTC 6901 prospective natural history cases.