title: Exome analysis in clinical practice: expanding the phenotype of Bartsocas-Papas syndrome.
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.
authors.affiliation: Division of Medical Genetics, A. I. duPont Hospital for Children, Wilmington, DE 19803, USA. kgripp@nemours.org
authors.forename: Karen W
authors.initials: KW
authors.lastname: Gripp
authors.forename: Sara
authors.initials: S
authors.lastname: Ennis
authors.forename: Joseph
authors.initials: J
authors.lastname: Napoli
mesh_terms: D002971:Cleft Lip / Q000175:diagnosis / Q000235:genetics*; D002972:Cleft Palate / Q000175:diagnosis / Q000235:genetics*; D003937:Diagnosis, Differential; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics*; D005143:Eyelids / Q000002:abnormalities*; D005260:Female; D006720:Homozygote; D006801:Humans; D007717:Knee / Q000002:abnormalities*; D009154:Mutation; D010641:Phenotype; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D013576:Syndactyly / Q000175:diagnosis / Q000235:genetics*
chemical_list: C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases