APC – Cenani-Lenz Syndactyly Syndrome

Cenani-Lenz syndactyly syndrome (MONDO:0008931) is an autosomal recessive disorder characterized by complex syndactyly, facial dysmorphism, and variable renal anomalies. While most cases are explained by biallelic LRP4 variants, a single consanguineous Saudi family has established APC as a second locus. In this pedigree, three affected siblings homozygous for an intronic APC splice-site deletion (c.423-4_423-2del) presented with classic syndactyly and scoliosis, mapping to 5q22.2 and segregating with disease status (PMID:25676610).

The APC c.423-4_423-2del variant abolishes normal splicing, reducing wild-type transcript levels by ~80% and producing a truncated protein; patient-derived cells show upregulated Wnt/β-catenin signalling analogous to LRP4 defects, supporting a loss-of-function mechanism (PMID:25676610). A subsequent review identified additional APC truncating alleles in Cenani-Lenz–like cases without polyposis, further implicating APC in the Wnt antagonistic pathway in limb development (PMID:30569497).

No conflicting data have been reported for APC in Cenani-Lenz syndrome to date. However, evidence is limited to a single family and a small number of probands. Additional unrelated families and functional studies are needed to meet higher ClinGen criteria for clinical validity.

Key Take-home: APC should be included in gene panels for autosomal recessive Cenani-Lenz syndrome, as loss-of-function APC variants can mimic LRP4-related syndactyly syndromes.

References

• Journal of medical genetics • 2015 • A novel APC mutation defines a second locus for Cenani-Lenz syndrome. PMID:25676610
• American journal of medical genetics. Part A • 2019 • Cenani-Lenz syndrome and other related syndactyly disorders due to variants in LRP4, GREM1/FMN1, and APC: Insight into the pathogenesis and the relationship to polyposis through the WNT and BMP antagonistic pathways. PMID:30569497

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