title: Identification of a novel mutation in RIPK4 in a kindred with phenotypic features of Bartsocas-Papas and CHAND syndromes.
abstract: Three children from an expanded consanguineous Kuwaiti kindred presented with ankyloblepharon, sparse and curly hair, and hypoplastic nails, suggestive of CHAND syndrome (OMIM 214350) that belongs to the heterogeneous spectrum of ectodermal dysplasias. After exclusion of pathogenic mutations in TP63 we performed homozygosity mapping, followed by exome sequencing of one affected individual. We initially identified three homozygous mutations in the linked region, located in PWP2, MX2 and RIPK4. Recently, mutations in RIPK4 have been reported in Bartsocas-Papas syndrome (OMIM 263650) that shows overlapping clinical symptoms with the phenotype observed in the affected individuals studied here. Subsequent analysis of affected and non-affected family members showed that mutation c.850G>A (p.Glu284Lys) in RIPK4 was in complete segregation with the disease phenotype, in accordance with an autosomal recessive inheritance pattern, thus supporting pathogenicity of this variant. Interestingly, however, our patients did not have cleft lip/palate, a common feature encountered in Bartsocas-Papas syndrome. Whereas in Bartsocas-Papas syndromes missense mutations are usually located within the serin/threonin kinase of RIPK4, the mutation detected in our family resides just outside of the kinase domain, which could explain the milder phenotype. Our data raise the question if CHAND syndrome indeed is a distinct entity. Alternatively, CHAND and Bartsocas-Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. Our findings indicate that making an accurate diagnosis based only on the prevailing clinical symptoms is challenging.
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Gollasch
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Fitnat Buket
authors.initials: FB
authors.lastname: Basmanav
authors.affiliation: Genetic Skin Diseases Clinic, As'ad Al-Hamad Dermatology Center, Al-Sabah Hospital, Kuwait.
authors.forename: Arti
authors.initials: A
authors.lastname: Nanda
authors.affiliation: Department of Neuropathology, Neurozentrum, University of Freiburg, Freiburg, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Fritz
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Hassnaa
authors.initials: H
authors.lastname: Mahmoudi
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Wehner
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wolf
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Institute of Human Genetics, University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.|Cluster of Excellence on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Division of Dermatogenetics and Skin Cancer Center, Department of Dermatology, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Jorge
authors.initials: J
authors.lastname: Frank
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002971:Cleft Lip / Q000150:complications* / Q000235:genetics*; D002972:Cleft Palate / Q000150:complications* / Q000235:genetics*; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D019143:Evolution, Molecular; D059472:Exome / Q000235:genetics; D005124:Eye Abnormalities / Q000150:complications* / Q000235:genetics*; D005141:Eyelid Diseases / Q000150:complications* / Q000235:genetics*; D005260:Female; D006201:Hair Diseases / Q000150:complications* / Q000235:genetics*; D006801:Humans; D007717:Knee / Q000002:abnormalities*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009264:Nails, Malformed / Q000150:complications* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics*; D040681:Structural Homology, Protein; D013576:Syndactyly / Q000150:complications* / Q000235:genetics*; D013577:Syndrome; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C417187:RIPK4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Bartsocas-Papas syndrome; CHAND syndrome; RIPK4; TP63; ectodermal dysplasia