Submission Details

The ALB gene encodes albumin, which is predominantly expressed in the liver. Albumin accounts for approximately 60-65% of the total protein in plasma and plays multiple roles. It maintains oncotic pressure in blood circulation, transports and sequesters metabolites, contributes to endothelial stabilization and normal capillary permeability, and functions as a circulating enzyme and antioxidant. Analbuminemia has been recognized as a recessively transmitted disease since the 1950s. Patients typically present with absent or significantly reduced albumin in serum, along with elevated cholesterol and triglycerides. Clinically, adult patients may be asymptomatic or exhibit lower limb edema, fatigue, and hypotension, largely due to the compensatory mechanism of globulins in the circulation (PMID: 7937781, 32181025, 30842957, 23176518, 15976105, 29214768). Clinical manifestations are more severe in children, with symptoms potentially starting prenatally, such as pleural effusions, excessive fluid retention, intrauterine growth retardation, premature birth, small for gestational age, recurrent respiratory infections, and even early death (PMID: 29981851, 20638375, 26543026, 23176518, 27346974, 24627724, 181542732, 15300429, 23730173). Variants in the ALB gene began to be reported in the 1990s with the advancement of molecular technology. The earliest article included in this curation described the homozygous p.Arg138Ter variant identified in an American female with analbuminemia, who has been extensively studied and followed up since the 1950s (PMID: 7937781). Additionally, eleven unique variants, including nonsense, frameshift, and splicing variants, reported in eleven unrelated probands (PMIDs: 32181025, 15613718, 30842957, 15976105, 29214768, 29981851, 20638375, 26543026, 23176518, 27346974, 24627724) have been included in this curation. The pathogenicity mechanism is loss-of-function. This gene-disease association is supported by animal models. Null mice and rats with undetectable albumin in serum were healthy and grew normally. The biochemical profile demonstrated elevated cholesterol, LDL, and triglycerides, along with decreased calcium, which are consistent with observations in human patients (PMID: 25654695, 7400127, 21187011). Further studies in null rats demonstrated that the accumulation of triglycerides was not caused by increased liver lipogenesis and secretion. Instead, hypertriglyceridemia and decreased fatty acid levels in serum resulted from the failure of lipolysis without albumin as a fatty acid carrier (PMID: 21187011). In summary, ALB is definitively associated with autosomal recessive analbuminemia. This association has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date [May 9, 2025] (SOP Version 11).