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29 Oct 2025	Primary lymphoedema v4.14	MDFIC	Ida Ertmanska changed review comment from: PMID: 35235341 Byrne et al., 2022 Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops. 3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs3) variant. The parents were confirmed heterozygous in 2 families. 1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124) variant - absent from gnomAD, parents heterozygous. Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63) variant - parents heterozygous, variant absent from gnomAD. In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38. In addition, 4 unrelated individuals presented with hydrops, 3 of them fetal and 1 at birth. PMID: 39386015 Weidner et al., 2024 13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified. This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).; to: PMID: 35235341 Byrne et al., 2022 Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops. 3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs3) variant. The parents were confirmed heterozygous in 2 families. 1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124) variant - absent from gnomAD, parents heterozygous. Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63) variant - parents heterozygous, variant absent from gnomAD. In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38. 4 of the probands presented with hydrops - 3 of them fetal (19-22 weeks) and 1 at birth. PMID: 39386015 Weidner et al., 2024 13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified. This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
29 Oct 2025	Primary lymphoedema v4.14	MDFIC	Ida Ertmanska changed review comment from: PMID: 35235341 Byrne et al., 2022 Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema. 3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs3) variant. The parents were confirmed heterozygous in 2 families. 1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124) variant - absent from gnomAD, parents heterozygous. Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63) variant - parents heterozygous, variant absent from gnomAD. In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38. In addition, 4 unrelated individuals presented with hydrops, 3 of them fetal and 1 at birth. PMID: 39386015 Weidner et al., 2024 13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified. This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).; to: PMID: 35235341 Byrne et al., 2022 Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema, pleural effusions, and hydrops. 3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs3) variant. The parents were confirmed heterozygous in 2 families. 1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124) variant - absent from gnomAD, parents heterozygous. Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63) variant - parents heterozygous, variant absent from gnomAD. In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38. In addition, 4 unrelated individuals presented with hydrops, 3 of them fetal and 1 at birth. PMID: 39386015 Weidner et al., 2024 13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified. This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
29 Oct 2025	Primary lymphoedema v4.14	MDFIC	Ida Ertmanska changed review comment from: PMID: 35235341 Byrne et al., 2022 Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema. 3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs3) variant. The parents were confirmed heterozygous in 2 families. 1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124) variant - absent from gnomAD, parents heterozygous. Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63) variant - parents heterozygous, variant absent from gnomAD. In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38. In addition, 4 unrelated individuals presented with hydrops, 3 of them fetal and 1 at birth. This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).; to: PMID: 35235341 Byrne et al., 2022 Reported 5 families (4 of them consanguineous - Arabic, Kurdish, Iranian ancestry; 1 non-consanguineous, European ancestry) with homozygous truncating variants in MDFIC in probands who displayed phenotypes consistent with CCLA - Central conducting lymphatic anomaly, including lymphoedema. 3 probands were homozygous for the NM_001166345.1:c.391dup, p.(Met131Asnfs3) variant. The parents were confirmed heterozygous in 2 families. 1 proband was homozygous for a NM_001166345.1: c.371del, p.(Ser124) variant - absent from gnomAD, parents heterozygous. Last proband was homozygous for a NM_001166345.1:c.187G>T, p.(Gly63) variant - parents heterozygous, variant absent from gnomAD. In a Chinese, non-consanguineous family (LE-452), two siblings presented with nonimmune hydrops fetalis (no lymphoedema) - compound het for c.391dup, p.(Met131Asnfs3) and c.732 T>G; p.(Phe244Leu). Variants confirmed in trans. p.(Phe244Leu) is present in gnomAD v4 (28/44850 in East Asian population, MAF = 0.0006243, no homozygotes); Revel score = 0.38. In addition, 4 unrelated individuals presented with hydrops, 3 of them fetal and 1 at birth. PMID: 39386015 Weidner et al., 2024 13-year-old female patient with central conducting lymphatic anomaly and a homozygous MDFIC mutation - variant not specified. This gene is associated with AR Lymphatic malformation 12, MIM:620014 (OMIM accessed 29th Oct 2025).
10 Oct 2025	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.Lys368Serfs53; c.1572_1573insAT, p.Asp525Metfs16; c.1646_1647delTT, p.Phe549Cysfs37; 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.Lys368Serfs53; c.1572_1573insAT, p.Asp525Metfs16; c.1646_1647delTT, p.Phe549Cysfs37; 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).
10 Oct 2025	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.Lys368Serfs53; c.1572_1573insAT, p.Asp525Metfs16; c.1646_1647delTT, p.Phe549Cysfs37; 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.Lys368Serfs53; c.1572_1573insAT, p.Asp525Metfs16; c.1646_1647delTT, p.Phe549Cysfs37; 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).
24 Jul 2019	Primary lymphoedema v1.94	MET	Sarah Leigh Publications for gene: MET were set to
24 Jul 2019	Primary lymphoedema v1.88	MET	Sahar Mansour reviewed gene: MET: Rating: RED; Mode of pathogenicity: ; Publications: 18564920; Phenotypes: Primary and Secondary Lymphedema; Mode of inheritance: Unknown
24 Jul 2019	Primary lymphoedema v1.87	MET	Sarah Leigh commented on gene: MET
23 Jul 2019	Primary lymphoedema v1.83	MET	Sarah Leigh gene: MET was added gene: MET was added to Primary lymphoedema. Sources: Expert list Mode of inheritance for gene: MET was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
24 Sep 2018	Primary lymphoedema v1.26	PTPN14	Rebecca Foulger commented on gene: PTPN14: Au et al (2010, PMID:20826270) provide a mouse model of PTPN14 deficiency where 14% of mutant animals showed swelling of limb extremeties.