Skinfold over toenail is pathognomonic for the popliteal pterygium syndrome in a Congolese family with large intrafamilial variability

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Abstract

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We report on three related Congolese popliteal pterygium syndrome (PPS) patients concordant only for the skinfold over the toenail. Mutation analysis revealed that the three affected individuals carried a heterozygous missense mutation in the Exon 4, NM_006147.2:c.250C>T; p.Arg84Cys. This is the first molecularly confirmed PPS family from central Africa.

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Most cited references 19

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Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.

Shinji Kondo, Brian Schutte, Rebecca Richardson … (2002)

Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32-q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies. Phenotypic overlap and linkage data suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.

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Actionable, pathogenic incidental findings in 1,000 participants' exomes.

Michael O Dorschner, Laura M Amendola, Emily H Turner … (2013)

The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants' pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome.

Renata L L Ferreira de Lima, Sarah A Hoper, Michella Ghassibe … (2009)

Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome. We performed direct sequence analysis of interferon regulatory factor 6 exons on samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome. We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. On the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect on interferon regulatory factor 6 function.

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Author and article information

Journal

Journal ID (nlm-ta): Clin Case Rep

Journal ID (iso-abbrev): Clin Case Rep

Journal ID (publisher-id): ccr3

Title: Clinical Case Reports

Publisher: Blackwell Publishing Ltd (Oxford, UK )

ISSN (Print): 2050-0904

ISSN (Electronic): 2050-0904

Publication date (Print): December 2014

Publication date (Electronic): 15 September 2014

Volume: 2

Issue: 6

Pages: 250-253

Affiliations

[1 ]Department of Pediatrics, Faculty of Medicine, University of Kinshasa Democratic Republic of the Congo

[2 ]Center for Human Genetics, Faculty of Medicine, University of Kinshasa Democratic Republic of the Congo

[3 ]Institut National de Recherche Biomédicale Democratic Republic of the Congo

[4 ]Center for Human Genetics, Catholic University of Leuven Belgium

[5 ]Department of Medical Imaging, Faculty of Medicine, University of Kinshasa Democratic Republic of the Congo

Author notes

Koenraad Devriendt, Centre for Human Genetics, University Hospitals, University of Leuven, Herestraat 49, Bus 602, 3000 Leuven, Belgium. Tel: + 32 16 34 59 03; Fax: + 32 16 34 60 60; Email: koenraad.devriendt@ 123456uzleuven.be

Funding Information This work was made possible in part by a grant GOA/2012/015.

Article

DOI: 10.1002/ccr3.101

PMC ID: 4270704

SO-VID: 2738f1b5-8066-4a71-b235-5f71dac50080

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This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

History

Date received : 07 April 2014

Date revision received : 25 May 2014

Date accepted : 25 May 2014

Skinfold over toenail is pathognomonic for the popliteal pterygium syndrome in a Congolese family with large intrafamilial variability

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Abstract

Key Clinical Message

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Most cited references 19

Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.

Actionable, pathogenic incidental findings in 1,000 participants' exomes.

Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome.

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