WNT7A – Phocomelia, Schinzel Type (Al-Awadi-Raas-Rothschild Syndrome)

WNT7A encodes a secreted Wnt glycoprotein that directs limb bud patterning through dorsal-ventral signaling. Two unrelated patients with severe limb reduction consistent with phocomelia, Schinzel type (Al-Awadi-Raas-Rothschild syndrome) have been reported to carry homozygous missense WNT7A variants. The first case is a fetus with bilateral humeroradial synostosis, oligodactyly, fibular aplasia and uterine absence harboring c.304C>T (p.Arg102Trp) ([PMID:27638328]). The second is an Indian boy with classic limb aplasia, urogenital hypoplasia and novel dental anomalies who is homozygous for c.550A>C (p.Asn184Asp) ([PMID:28917830]). No other WNT7A variants have been definitively linked to this severe phenotype outside these reports, and a recent molecular review classified complete WNT7A loss-of-function as the driver of Al-Awadi-Raas-Rothschild syndrome ([PMID:23922166]).

Both missense changes segregate in an autosomal recessive pattern with heterozygous carriers showing no major limb defects. To date, no truncating or splice variants have been documented in this phenotype, suggesting that these specific missense substitutions abrogate essential WNT7A activity. Experimental evidence is limited to in situ expression studies and mechanistic review without dedicated in vivo models. Given this limited but concordant evidence, diagnostic WNT7A sequencing should be considered in fetuses and individuals presenting with phocomelia, particularly when accompanied by urogenital hypoplasia. Key Take-home: Biallelic WNT7A missense variants provide limited yet actionable evidence for autosomal recessive phocomelia, Schinzel type.

References

• European journal of medical genetics • 2016 • A novel missense mutation, p.(R102W) in WNT7A causes Al-Awadi Raas-Rothschild syndrome in a fetus. PMID:27638328
• European journal of medical genetics • 2017 • Al-Awadi-Raas-Rothschild syndrome with dental anomalies and a novel WNT7A mutation. PMID:28917830
• American journal of medical genetics. Part A • 2013 • Molecular basis of the clinical features of Al-Awadi-Raas-Rothschild (limb/pelvis/uterus-hypoplasia/aplasia) syndrome (AARRS) and Fuhrmann syndrome. PMID:23922166

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