Primary lymphoedema

Gene: UNC45A

Green List (high evidence)

Comment on list classification: UNC45A has been linked to Aagenaes syndrome - a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis. There are at least 28 affected individuals from 25 different families who presented with neonatal cholestasis and lymphedema (PMIDs:37328071;39887522). Based on the reported evidence, this gene should be rated Green for Primary lymphoedema.

Created: 10 Oct 2025, 3:49 p.m. | Last Modified: 10 Oct 2025, 3:49 p.m.

Panel Version: 4.7

Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis.

PMID: 37328071 Almaas et al., 2023
26 patients with Aagenaes syndrome from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T (no homozygotes reported in gnomAD v4) and an exonic loss-of-function variant in UNC45A: c.1101delC, p.Lys368Serfs*53; c.1572_1573insAT, p.Asp525Metfs*16; c.1646_1647delTT, p.Phe549Cysfs*37; c.2028+1G>A (intron 18); c.2590C>T, p.Gln864*.
Method: WGS + Sanger in first family, Sanger seq in subsequent patients. Tested unaffected parents were heterozygous for either the 5'UTR c.-98G>T variant, or an exonic variant.
Phenotype: 26/26 patients presented with cholestasis in infancy and childhood. All patients, except two young infants, had lymphedema of the lower limbs (age of onset: birth - 15 years); 19/26 also had lymphedema of the upper limbs.

Confirmed lower expression of UNC45A mRNA and protein in mutant HEK293T cells than controls.
Levels of expression of UNC45A mRNA from whole blood (relative to WT controls): 50% for patients homozygous for c.-98G>T; 37% in compound heterozygotes; 79% in parents het for c.-98G>T; 50% in parents het for exonic LoF variants.
Similar trend seen in protein levels: 50% of control UNC45A levels in homozygotes, and 17% of control residual blood protein in compound hets.

PMID: 39887522 Tan et al., 2025
Two siblings, compound het for c.-88G>A and c.1591C>T, p.(Arg531Ter) in UNC45A. Method: WES
Phenotype: both siblings presented with neonatal cholestasis and lymphedema; one sibling developed severe liver failure.

This gene is associated with Osteootohepatoenteric syndrome, 619377 in OMIM (accessed 10th Oct 2025) - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).

Created: 10 Oct 2025, 3:29 p.m. | Last Modified: 10 Oct 2025, 3:53 p.m.

Panel Version: 4.7

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Aagenaes syndrome, MONDO:0008966

Publications

• 37328071
• 39887522

Green List (high evidence)

Confirmed cause of Aagenaes syndrome/lymphedema cholestasis syndrome 1. 4. Primary lymphoedema may be presenting feature
Sources: Expert Review

Created: 1 Sep 2025, 1:32 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
lymphedema in the lower and upper limbs; cholestasis; hyperbilirubinemia; increased concentrations of bile acids in blood

Publications

• PMID: 37328071
• PMID: 39887522