FAT4 – Hennekam Syndrome

Hennekam lymphangiectasia-lymphedema syndrome is a genetically heterogeneous autosomal recessive disorder characterized by lymphedema, lymphangiectasia, and intellectual disability. While CCBE1 mutations account for ~25% of cases, homozygosity mapping and whole-exome sequencing in an original HS pedigree identified a homozygous FAT4 nonsense variant (c.9125G>A (p.Trp3042Ter)) segregating with disease (PMID:24913602). Targeted analysis of 24 CCBE1-negative HS patients revealed biallelic FAT4 mutations in four additional families, establishing FAT4 as a second gene for HS (PMID:24913602).

A subsequent multicenter study reported biallelic FAT4 variants in 40 unrelated HS probands, confirming autosomal recessive inheritance and phenotypic overlap with Van Maldergem syndrome (PMID:29681106). No recurrent or founder variants were observed; the variant spectrum includes nonsense, frameshift, splice-site, and small indels. One representative allele is c.9125G>A (p.Trp3042Ter), a truncating change predicted to abolish distal cadherin repeats.

Affected individuals present with congenital lymphedema (HP:0001004), intestinal lymphangiectasia, feeding difficulties (HP:0011968), neonatal hypotonia (HP:0001319), hearing impairment (HP:0000365), and osteopenia (HP:0000938), reflecting disruption of lymphatic vessel morphogenesis and homeostasis.

Functional assays in lymphatic endothelial cells demonstrate that FAT4 is a direct target of GATA2 and functions cell-autonomously to control planar polarity in response to shear flow. Loss of FAT4 perturbs lymphatic vessel patterning and valve morphogenesis, recapitulating key HS features (PMID:32182215).

Mechanistically, truncating FAT4 variants lead to loss of atypical cadherin function, disrupting Hippo pathway regulation and endothelial polarity. This concords with the human phenotype of lymphatic dysfunction and intellectual impairment.

In summary, compelling genetic evidence from five independent families and robust functional data in lymphatic models support a Strong ClinGen gene–disease association between FAT4 and Hennekam syndrome. Key take-home: biallelic FAT4 truncating variants cause HS via loss of endothelial polarity, enabling accurate genetic diagnosis and potential pathway-directed therapies.

References

• Human genetics • 2014 • Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. PMID:24913602
• American journal of medical genetics. Part A • 2018 • Van Maldergem syndrome and Hennekam syndrome: Further delineation of allelic phenotypes. PMID:29681106
• The Journal of clinical investigation • 2020 • Atypical cadherin FAT4 orchestrates lymphatic endothelial cell polarity in response to flow. PMID:32182215

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