Two new mutations at the adenosine deaminase (ADA) locus (Q254X and del nt1050-54) unusual for not being missense mutations

Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype.

“…This deletion shifts the reading frame and mutates codons 319-321 from EEE to GVX, eliminating the last 43 amino acids. This same 5-bp deletion has recently been found in a patient with early-onset SCID3 and in unrelated ADA-deficient patients (36). MJ lacks a polymorphism, Lys8O > Arg, found in one of these patients, suggesting an independent origin, consistent with the suggestion that the mutation is at a deletional hot spot.…”

Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a coronin-1A mutation and a chromosome 16p11.2 deletion

“…Our patient developed progressively worsening infections that necessitated HCT, which has been curative. Although the majority of SCID infants are diagnosed in the first year of life, delayed presentations have been described, some of which involve leaky genetic defects, such as hypomorphic mutations allowing residual activity of the ADA enzyme[10; 11]. In contrast, our patient carries null alleles of CORO1A .…”

Disease-Specific Induced Pluripotent Stem Cells

“…Sequence analysis of the ADA gene in the disease-associated ADA-iPS2 line revealed a compound heterozygote: a GGG to GAA transition mutation at exon 7, causing a G216R amino acid substitution (Figure 1B); the other allele is known to have a frame-shift deletion (-GAAGA) in exon 10 (Hirschhorn et al, 1993). The SBDS-iPS8 line harbors point mutations at the IV2+2T>C intron 2 splice donor site (Figure 1B) and IVS3-1G>A mutation (Austin et al, 2005).…”

“…Mutated alleles identical to the original specimens were verified by DNA sequencing. Adenosine deaminase deficiency line ADA-iPS2, a compound heterozygote: GGG to GAA double transition in exon 7 of one allele (G216R substitution); the second allele is an exon 10 frame-shift deletion (-GAAGA) (Hirschhorn et al, 1993). Shwachman-Bodian-Diamond syndrome line SBDS-iPS8 is also a compound heterozygote: point mutations at the IV2+2T>C intron 2 splice donor site and an IVS3-1G>A mutation of the SBDS gene (Austin et al, 2005).…”