Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Jul;55(7):1075-1092.
doi: 10.1111/hepr.14203. Epub 2025 May 13.

Exome-based genotype-first reverse phenotyping using structured electronic health record data identifies novel SERPINA1 variants associated with liver markers and demonstrates a dominant effect for specific variants on liver phenotype

Maël Silva Rodriguez  1   2 , Margaux Mulot  1 , Céline Chéry  1   2   3 , Mouni Bensenane  4 , Rosa-Maria Guéant-Rodriguez  1   2   3 , Roland Jaussaud  5 , Aurélie Cobat  6   7   8 , François Feillet  2   3   9 , Jean-Pierre Bronowicki  2   3   4 , Farès Namour  1   2   3 , Jean-Louis Guéant  1   2   3 , Abderrahim Oussalah  1   2   3
Affiliations

Exome-based genotype-first reverse phenotyping using structured electronic health record data identifies novel SERPINA1 variants associated with liver markers and demonstrates a dominant effect for specific variants on liver phenotype

Maël Silva Rodriguez et al. Hepatol Res. 2025 Jul.

Abstract

Aim: Although several SERPINA1 genetic variants have been reported for their pathogenicity to induce liver disorders through phenotype-driven approaches, data regarding genotype-driven approaches of the SERPINA1 locus remain unavailable. This study aimed to characterize the clinical and liver biological profiles of patients harboring nonbenign SERPINA1 variants.

Methods: We conducted a retrospective, exome-based genotype-first reverse phenotyping study using structured electronic health record data from consecutive patients from January 1, 2015, to January 31, 2022. Statistical associations were assessed using frequentist and Bayesian models, with validation in the UK Biobank cohort.

Results: Among 1377 patients analyzed, 15 SERPINA1 variants classified as nonbenign were identified in 217 (15.7%) patients. Data were available for 126 patients (median age, 41.5 years; 52.4% male). Liver disease, hyperferritinemia, and pulmonary emphysema were observed in 32.5% (41/126), 23% (29/126), and 5.6% (7/126) of the patients, respectively. The median follow-up duration was 1.3 years and encompassed 1085 biological observations. We confirmed associations with well-documented variants of SERPINA1 (p.Glu366Lys, p.Pro393Ser, p.Ala308Ser, p.Glu288Val, and p.Phe76del). We identified three novel genetic associations with liver markers: c.*10G > A, c.1065 + 10C > T, and p.Arg63Cys. The UK Biobank data confirmed significant gene- and variant-level associations, notably for the variants identified in our study, which ranked in the top decile of statistical associations.

Conclusions: This study supports the utility of a genotype-first approach in characterizing hepatic manifestations of nonbenign SERPINA1 variants. The findings highlight novel genotype-biomarker associations and suggest a role for SERPINA1 genetic testing in patients with unexplained liver abnormalities.

Keywords: ACMG reclassification; SERPINA1; alpha‐1 antitrypsin deficiency; exome‐based genotype‐first reverse phenotyping; liver disease markers.

PubMed Disclaimer

References

REFERENCES

    1. Strnad P, McElvaney NG, Lomas DA. Alpha(1)‐antitrypsin deficiency. N Engl J Med. 2020;382(15):1443–1455. https://doi.org/10.1056/nejmra1910234
    1. Greene CM, Marciniak SJ, Teckman J, Ferrarotti I, Brantly ML, Lomas DA, et al. Alpha1‐antitrypsin deficiency. Nat Rev Dis Primers. 2016;2(1):16051. https://doi.org/10.1038/nrdp.2016.51
    1. Suri A, Patel D, Teckman J. Alpha‐1‐antitrypsin deficiency. Clin Liver Dis. 2022;19(3):89–92. https://doi.org/10.1002/cld.1147
    1. Sood V, Lee EJ, Raghu V, Reyes‐Mugica M, Salgado CM, Squires J, et al. Liver transplantation for alpha 1 antitrypsin deficiency (A1ATD) using a heterozygous donor: outcomes and review of the literature. Pediatr Transplant. 2023;27(4):e14488. https://doi.org/10.1111/petr.14488
    1. Townsend SA, Edgar RG, Ellis PR, Kantas D, Newsome PN, Turner AM. Systematic review: the natural history of alpha‐1 antitrypsin deficiency, and associated liver disease. Aliment Pharmacol Ther. 2018;47(7):877–885. https://doi.org/10.1111/apt.14537

LinkOut - more resources