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Keywords:

  • cleft lip/palate;
  • ankyloblepharon–ectodermal defects–cleft lip/palate syndrome;
  • Bartsocas–Papas syndrome;
  • autosomal recessive popliteal pterygium syndrome;
  • RIPK4

Abstract

Exome analysis has had a dramatic impact on genetic research. We present the application of such newly generated information to patient care. The patient was a female, born with normal growth parameters to nonconsanguineous parents after an uneventful pregnancy. She had bilateral cleft lip/palate and ankyloblepharon. Sparse hair, dysplastic nails and hypohidrosis were subsequently noted. With exception of speech related issues, her development was normal. A clinical diagnosis of ankyloblepharon–ectodermal defects-cleft lip/palate or Hay–Wells syndrome resulted in TP63 sequence analysis. TP63 sequence and deletion/duplication analysis of all coding exons had a normal result, as did chromosome and SNP array analysis. Diagnostic exome analysis revealed a heterozygous nonsense mutation in KRT83 categorized as deleterious and associated with monilethrix. In addition, a homozygous missense variant of unknown clinical significance was reported in RIPK4. Using research based exome analysis, RIPK4 had just a few months prior been identified as pathogenic for Bartsocas–Papas syndrome. While the clinical diagnostic report implied the KRT83 mutation as a more likely cause for the patient's phenotype, clinical correlation, literature review and use of computerized mutation analysis programs allowed us to identify the homozygous RIPK4 (c.488G > A; p.Gly163Asp) mutation as the underlying pathogenic change. Consequently, we expand the phenotype of Bartsocas–Papas syndrome to an attenuated presentation resembling Hay–Wells syndrome, lacking lethality and pterygia. In contrast to the autosomal dominant Hay–Wells syndrome, Bartsocas–Papas syndrome is autosomal recessive, implying a 25% recurrence risk. © 2013 Wiley Periodicals, Inc.