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Primary lymphoedema v4.10 UNC45A Ida Ertmanska edited their review of gene: UNC45A: Changed phenotypes to: Aagenaes syndrome, MONDO:0008966
Primary lymphoedema v4.10 UNC45A Arina Puzriakova Publications for gene: UNC45A were set to PMID: 37328071; PMID: 39887522
Primary lymphoedema v4.9 UNC45A Arina Puzriakova Phenotypes for gene: UNC45A were changed from lymphedema in the lower and upper limbs; cholestasis; hyperbilirubinemia; increased concentrations of bile acids in blood to Aagenaes syndrome, MONDO:0008966
Primary lymphoedema v4.8 UNC45A Arina Puzriakova Classified gene: UNC45A as Amber List (moderate evidence)
Primary lymphoedema v4.8 UNC45A Arina Puzriakova Gene: unc45a has been classified as Amber List (Moderate Evidence).
Primary lymphoedema v4.7 UNC45A Arina Puzriakova Tag Q3_25_promote_green tag was added to gene: UNC45A.
Tag Q3_25_NHS_review tag was added to gene: UNC45A.
Primary lymphoedema v4.7 UNC45A Ida Ertmanska changed review comment from: 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 - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).

; to: 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).
Primary lymphoedema v4.7 UNC45A Ida Ertmanska commented on gene: UNC45A: 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.
Primary lymphoedema v4.7 UNC45A Ida Ertmanska edited their review of gene: UNC45A: Changed publications to: 37328071, 39887522
Primary lymphoedema v4.7 UNC45A Ida Ertmanska changed review comment from: PMID: 37328071 Almaas et al., 2023
Aagenaes syndrome is a condition characterized by neonatal cholestasis, lymphedema, and giant cell hepatitis.
26 patients from 24 different families. 19 individuals homozygous for c.-98G>T (5' UTR region) in UNC45A & 7 individuals compound heterozygous for c.-98G>T 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
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 + CRISPR/Cas9-created cell model.; to: 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 - hypothesised to be a separate disease entity, characterised by bone fragility, hearing loss, cholestasis, and congenital diarrhea (PMID: 29429573 Esteve et al., 2018).
Primary lymphoedema v4.7 UNC45A Ida Ertmanska edited their review of gene: UNC45A: Changed phenotypes to: Osteootohepatoenteric syndrome, OMIM:619377, Aagenaes syndrome, MONDO:0008966
Primary lymphoedema v4.7 UNC45A Ida Ertmanska reviewed gene: UNC45A: Rating: GREEN; Mode of pathogenicity: None; Publications: 37328071; Phenotypes: Osteootohepatoenteric syndrome 619377; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary lymphoedema v4.7 UNC45A Matthew Edwards gene: UNC45A was added
gene: UNC45A was added to Primary lymphoedema. Sources: Expert Review
Mode of inheritance for gene: UNC45A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UNC45A were set to PMID: 37328071; PMID: 39887522
Phenotypes for gene: UNC45A were set to lymphedema in the lower and upper limbs; cholestasis; hyperbilirubinemia; increased concentrations of bile acids in blood
Penetrance for gene: UNC45A were set to unknown
Review for gene: UNC45A was set to GREEN
Added comment: Confirmed cause of Aagenaes syndrome/lymphedema cholestasis syndrome 1. 4. Primary lymphoedema may be presenting feature
Sources: Expert Review