The Clinical Utility of Determining the Allelic Background of Mutations Causing Alpha-1 Antitrypsin Deficiency: The Case with the Null Variant Q0(Mattawa)/Q0(Ourém).

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is caused by genetic variants in the SERPINA1 gene conferring risk of developing emphysema. The clinical expression of AATD-related emphysema mostly occurs in carriers of 2 deficient alleles. By DNA sequencing of SERPINA1, numerous rare variants have been identified. Clarifying whether 2 mutations observed in 1 patient are on the same or distinct alleles has obvious clinical implications.
METHODS: We studied 7 carriers of a rare variant, Leu353Phe_fsTer24, known to lead to undetectable serum levels of AAT. Two of them were also carriers of the S or Z allele. We developed an allele-specific DNA sequencing method to characterize the allelic background of the Leu353Phe_fsTer24 variant.
RESULTS: The Leu353Phe_fsTer24 variant was transmitted on the same allele as the M3 variant (E376D) in all patients. This mutation is thus named Q0Ourém on the conventional PI system. We demonstrated that individuals harboring the E264V (S) and E342K (Z) mutations had them on distinct alleles from Q0Ourém and are, thus, compound heterozygotes. The 7 Q0Ourém carriers had AAT levels ranging from 0.18g/l to 0.82g/l. The lowest AAT serum levels were observed in compound heterozygotes (S/Q0Ourém and Z/Q0Ourém) suggesting higher risk of developing emphysema.
CONCLUSION: For the 7 patients, Leu353Phe_fsTer24 is transmitted on the M3 background and they are, thus, carriers of the Q0Ourém allele. Allele-specific DNA sequencing was useful to distinguish 1 or 2 deficient alleles in carriers of 2 mutations. In rare cases, this method is important to understand the clinical significance of genetic variants found in SERPINA1. JCOPDF