ALB

Inheritance Pattern: AD

Disease ID:MONDO:0014448

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014449

Submitter: ClinGen

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).

Inheritance Pattern: AR

Disease ID:MONDO:0014449

Submitter: PanelApp Australia

Inheritance Pattern: SD

Disease ID:MONDO:0014448

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0014448

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0014448

Submitter: ClinGen

Familial dysalbuminemic hyperthyroxinemia (FDH) was first reported in 1979 and has been confirmed as an autosomal dominant benign trait characterized by elevated total thyroxine (T4) and normal thyroid-stimulating hormone (TSH) levels in serum. Serum free T4, as well as total and free triiodothyronine (T3), may also be elevated. Although individuals with FDH typically do not exhibit thyrotoxic symptoms, there is a risk of inappropriate treatment being offered to these individuals. Therefore, the identification of FDH through serum and genetic testing is clinically important to avoid unnecessary therapies. The molecular basis of FDH was elucidated with the identification of the most common variant, ALB c.725G>A (p.Arg242His), reported in 1994 (Petersen et al., PMID: 8064810). The ALB gene encodes albumin, which is responsible for the transport and sequestration of metabolites, including hormones, in the circulation. Four missense variants (c.725G>A, p.Arg242His; c.724C>A, p.Arg242Ser; c.725G>C, p.Arg242Pro; and c.737G>T, p.Arg246Ile) that have been identified in 25 probands were curated. These variants co-segregated with abnormal thyroid functional tests within families (PMID: 8064810, 12099390, 27834068, 29676214, 33728390, 38557642, 36864842, 32665066, 9329347, 32669045, 27904073, 24646103, 24494774, 27081329, 31582975). Notably, the level of total T4 was higher in homozygotes compared to heterozygotes (PMID: 29676214). The disease mechanism is a gain of function. Studies on the affinity between albumin and T4 in patient serum samples have demonstrated a high affinity of T4 to mutant albumin carrying either the Arg242His or Arg242Pro alteration (PMID: 8064810, 29676214, 9329347, 27904073). This increased affinity was also observed in experiments using recombinant human albumin (PMID: 26777880). In summary, there is moderate evidence supporting the gene-disease relationship for FDH. While additional evidence is needed to establish a causal role definitively, no convincing evidence has emerged to contradict this gene-disease relationship. This classification was approved by the ClinGen General Inborn Errors of Metabolism GCEP on the meeting date [May 9, 2025] (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0014449

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014449

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0014449

Submitter: Orphanet