A number sign (#) is used with this entry because of evidence that lymphatic malformation-14 (LMPHM14) is caused by heterozygous mutation in the ERG gene (165080) on chromosome 21q22.

Lymphatic malformation-14 (LMPHM14) is an autosomal dominant disorder characterized by primary lymphedema (Greene et al., 2023).

For a general phenotypic description and discussion of genetic heterogeneity of lymphatic malformation, see LMPHM1 (153100).

Greene et al. (2023) reported 5 affected individuals from 4 unrelated families with primary lymphedema and mutation in the ERG gene. Limited clinical information was published for the affected individuals, who were ascertained from a cohort of 77,539 participants, including 29,741 probands, tabulated in a relational database (Rareservoir) developed as part of the 100,000 Genomes Project (100KGP). One proband had a mildly affected father who developed lymphedema 2 decades later than his daughter; he was found to be mosaic for their ERG variant. In another family, the proband was enrolled in 100KGP for an unrelated condition, but chart review revealed that she exhibited additional features consistent with primary lymphedema.

The transmission pattern of LMPHM14 in the families reported by Greene et al. (2023) was consistent with autosomal dominant inheritance.

Using a Bayesian statistical method (BeviMed) to obtain a posterior probability of association between variation in 19,663 protein-coding genes and a case set of 94 probands with primary lymphedema, Greene et al. (2023) identified a dominant genetic association between primary lymphedema and frameshift variants in the ERG gene (see, e.g., 165080.0001-165080.0003) in 4 affected individuals from 3 unrelated families. A participant in a fourth family, enrolled in 100KGP for an unrelated condition, also carried a predicted ERG loss-of-function variant; manual chart review revealed that the proband had additional features consistent with primary lymphedema. Functional analysis demonstrated mislocalization of the mutant ERG in the cytosol rather than the nucleus, which would prevent it from binding to DNA and exerting its function as a transcription factor. The authors suggested that defective lymphangiogenesis in these ERG-associated primary lymphedema cases might result from reduced ERG availability in the nucleus, due to haploinsufficiency from nonsense-mediated decay or due to mislocalization.