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FBXL7 (HGNC:13604) has been recently implicated in Hennekam syndrome (MONDO_0016256), an autosomal recessive disorder marked by congenital lymphedema, intestinal lymphangiectasia, and distinctive facial dysmorphism (PMID:31633297). This association is primarily based on a case report where a patient clinically diagnosed with Hennekam syndrome was found to harbor a homozygous single‐exon deletion in FBXL7. The reported finding is particularly compelling given that no biallelic loss‑of‐function variants in FBXL7 were detected in databases encompassing over 100,000 control individuals (PMID:31633297).
The genetic evidence is centered around an autosomal recessive inheritance pattern, as the patient presented with a homozygous deletion that is expected to disrupt the F‑box domain and leucine‑rich repeats integral to FBXL7 function. The representative variant, reported as c.250_300del (p.Leu84ArgfsTer15), aligns with the expected molecular consequence of exon deletion leading to a frameshift and premature termination (PMID:31633297). Although the evidence is derived from a single proband, the genetic finding is well supported by the rarity of similar variants in the general population.
Further supporting the genetic association, the patient exhibits hallmark symptoms of Hennekam syndrome, including abnormality of the face (HP:0000271) and intestinal lymphangiectasia (HP:0002593). While detailed familial segregation data are not provided, the homozygous state in a clinically affected individual is consistent with the autosomal recessive mode of inheritance typically observed in this syndrome. The absence of similar loss‐of‐function variants in large control cohorts reinforces the likely pathogenic nature of the FBXL7 alteration (PMID:31633297).
The functional evidence stems from experimental studies in Drosophila, where Fbxl7 has been shown to interact with Fat, the human ortholog of which (FAT4) is a known contributor to Hennekam syndrome when mutated. This cross‐species observation suggests that disruption of FBXL7 may impair similar developmental pathways involved in lymphatic and facial formation (PMID:31633297). Such functional concordance provides biological plausibility to the variant’s role in disease pathology.
Integration of the genetic and functional data forms a coherent narrative where a single, well‐characterized genetic alteration, coupled with supportive animal model studies, implicates FBXL7 in the etiology of Hennekam syndrome. Despite the evidence being derived from a single case report, the detailed molecular characterization and robust functional data lend credibility to the association. Future studies, including additional case reports and extended functional work, will be essential to further clarify the gene‑disease relationship.
Key Take‑home: Even singular robust genetic findings, when combined with supportive functional evidence, can provide actionable insights for diagnostic decision‑making, commercial diagnostic development, and future research publication.
Gene–Disease AssociationLimitedSingle proband with a homozygous deletion in FBXL7 in a clinically diagnosed Hennekam syndrome patient, supported by the absence of similar variants in >100,000 controls (PMID:31633297). Genetic EvidenceLimitedThe identification of a representative variant, c.250_300del (p.Leu84ArgfsTer15), in a patient exhibiting autosomal recessive inheritance supports the role of FBXL7, despite the limited number of probands (PMID:31633297). Functional EvidenceModerateFunctional studies in Drosophila demonstrate that Fbxl7 interacts with Fat, paralleling human FAT4 associated with Hennekam syndrome, thereby providing experimental support for a pathogenic mechanism (PMID:31633297). |