Primary lymphoedema

Gene: MDFIC

Green List (high evidence)

Comment on list classification: There are at least 5 probands reported with biallelic variants in MDFIC, who presented with central conducting lymphatic anomaly - including lymphoedema, pleural effusions, and hydrops. Based on the available evidence, this gene should be promoted to Green for Primary lymphoedema at the next GMS update.

Created: 29 Oct 2025, 9:10 a.m. | Last Modified: 29 Oct 2025, 9:10 a.m.

Panel Version: 4.14

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.(Met131Asnfs*3) 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.(Met131Asnfs*3) 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).

Created: 29 Oct 2025, 9:04 a.m. | Last Modified: 29 Oct 2025, 9:11 a.m.

Panel Version: 4.14

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Lymphatic malformation 12, OMIM:620014; lymphatic malformation 12, MONDO:0031043

Publications

• 35235341
• 39386015

Green List (high evidence)

Sources: Literature

Created: 23 Oct 2025, 10:49 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
primary lymphoedema; central conducting lymphatic anomaly

Publications

• PMID: 35235341