We have recently described a family with a condition (Santos syndrome (SS; MIM 613005)) characterized by fibular agenesis/hypoplasia, hypoplastic femora and grossly malformed/deformed clubfeet with severe oligodactyly, ungual hypoplasia/anonychia, sometimes associated with mild brachydactyly and occasional pre-axial polydactyly. Autosomal dominant inheritance with incomplete penetrance was suggested, but autosomal recessive inheritance could not be ruled out, due to the high frequency of consanguineous matings in the region where the family lived. This report deals with linkage studies and exome sequencing, disclosing a novel variant in WNT7A, c.934G>A (p.Gly312Ser), as the cause of this syndrome. This variant was present in homozygous state in five individuals typically affected by the SS syndrome, and in heterozygous state in the son of one affected homozygous individual. The heterozygous boy presented only unilateral complex polysyndactyly and we hypothesize that he either presents a distinct defect or that his phenotype results from a rare, mild clinical manifestation of the variant in heterozygous state. Variants in WNT7A are known to cause at least two other limb defect disorders, the syndromes of Fuhrmann and Al-Awadi/Raas-Rothschild. Despite their variable degree of expressivity and overlap, the three related conditions can be differentiated phenotypically in most instances.
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We thank Mr Guilherme Yamamoto for assistance in bioinformatics; Dr Carla Rosenberg and Silvia S Costa for array-CGH experiments and exome library preparation; Dr Angela M Vianna-Morgante and Dr Bernd Wollnik (from Universitätsmedizin Göttingen, Göttingen, Germany) for helpful discussions. We also thank CEPID-FAPESP (Centro de Estudos do Genoma humano e Células-tronco, 2013/08028-1) and CAPES for the financial support, and the patients for their cooperation.
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on Journal of Human Genetics website
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Alves, L., Santos, S., Musso, C. et al. Santos syndrome is caused by mutation in the WNT7A gene. J Hum Genet 62, 1073–1078 (2017). https://doi.org/10.1038/jhg.2017.86
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