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Novel variants in the LRP4 underlying Cenani-Lenz Syndactyly syndrome


Cenani-Lenz syndrome (CLS) is a rare autosomal-recessive congenital disorder affecting development of distal limbs. It is characterized mainly by syndactyly and/or oligodactyly, renal anomalies, and characteristic facial features. Mutations in the LRP4 gene, located on human chromosome 11p11.2–q13.1, causes the CLS. The gene LRP4 encodes a low-density lipoprotein receptor-related protein-4, which mediates SOST-dependent inhibition of bone formation and Wnt signaling. In the study, presented here, three families of Pakistani origin, segregating CLS in the autosomal recessive manner were clinically and genetically characterized. In two families (A and B), microsatellite-based homozygosity mapping followed by Sanger sequencing identified a novel homozygous missense variant [NM_002334.3: c.295G>C; p.(Asp99His)] in the LRP4 gene. In the third family C, exome sequencing revealed a second novel homozygous missense variant [NM_002334.3: c.1633C>T; p.(Arg545Trp)] in the same gene. To determine the functional relevance of these variants, we tested their ability to inhibit canonical WNT signaling in a luciferase assay. Wild type LRP4 was able to inhibit LRP6-dependent WNT signaling robustly. The two mutants p.(Asp99His) and p.(Arg545Trp) inhibited WNT signaling less effectively, suggesting they reduced LRP4 function.

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We highly appreciate participation of members of the families in the study presented here. Hammal Khan and Muhammad Bilal were supported by PhD fellowship awarded by Higher Education Commission (HEC), Islamabad, Pakistan. Angie Chong was supported by NUS Graduate Scholarship. Shifeng Xue was supported by NUS PYP.

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Hammal Khan and Muhammad Bilal performed the experimental work, analyzed the data, and prepared the manuscript. Shoaib Nawaz, Abdullah, Sanaullah Abbasi, Amir Hussain, and Shabir Hussain visited the families, drawn pedigrees, and collected blood samples. Angie Chong and Shifeng Xue performed the functional analysis. Imran Ullah and Wasim Ahmad designed the study, provided funds, and finalized the manuscript.

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Correspondence to Wasim Ahmad.

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Khan, H., Chong, A.E.Q., Bilal, M. et al. Novel variants in the LRP4 underlying Cenani-Lenz Syndactyly syndrome. J Hum Genet 67, 253–259 (2022).

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