Proxy molecular diagnosis from whole-exome sequencing reveals Papillon-Lefevre syndrome caused by a missense mutation in CTSC.

A Mesut Erzurumluoglu,Santiago Rodriguez,Basma M Alsaadi,Tahani S Alotaibi,Aasiya Ginwalla,Fahad M Alsaif,Tom R Gaunt,Ian N M Day,Sian Lewis,Philip A I Guthrie,Khalid K Alharbi,Muslim M Alsaadi

doi:10.1371/journal.pone.0121351

A Mesut Erzurumluoglu, Santiago Rodriguez + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0121351

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Journal: PloS one	Publication Date: Mar 23, 2015
Citations: 20	License type: CC BY 4.0

Affiliation: University of Bristol, King Saud University

Abstract

Papillon-Lefevre syndrome (PLS) is an autosomal recessive disorder characterised by severe early onset periodontitis and palmoplantar hyperkeratosis. A previously reported missense mutation in the CTSC gene (NM_001814.4:c.899G>A:p.(G300D)) was identified in a homozygous state in two siblings diagnosed with PLS in a consanguineous family of Arabic ancestry. The variant was initially identified in a heterozygous state in a PLS unaffected sibling whose whole exome had been sequenced as part of a previous Primary ciliary dyskinesia study. Using this information, a proxy molecular diagnosis was made on the PLS affected siblings after consent was given to study this second disorder found to be segregating within the family. The prevalence of the mutation was then assayed in the local population using a representative sample of 256 unrelated individuals. The variant was absent in all subjects indicating that the variant is rare in Saudi Arabia. This family study illustrates how whole-exome sequencing can generate findings and inferences beyond its primary goal.

Highlights

Papillon-Lefevre syndrome (PLS, MIM# 245000) is an autosomal recessive disorder characterised by severe early onset periodontitis and palmoplantar hyperkeratosis, which results in the premature loss of the primary and secondary dentitions [1]
Whole-exome sequencing of the Primary ciliary dyskinesia (PCD) affected sibling had previously been carried out and her CTSC gene was analysed in follow up to the PLS presentation of two of her siblings [1]. 8 single nucleotide variations (intronic variants: rs217116, rs217060, rs580743, rs217075, rs217076, rs217077; missense mutations: rs217086 and c.899G>A:p.(G300D)) and a single nucleotide insertion were identified in the CTSC gene
Frequency of over 7% in the 1000 Genomes Project and Exome Variant Server (EVS) which are too common to be causal of a rare Mendelian disease such as PLS

Summary

Introduction

Papillon-Lefevre syndrome (PLS, MIM# 245000) is an autosomal recessive disorder characterised by severe early onset periodontitis and palmoplantar hyperkeratosis, which results in the premature loss of the primary and secondary dentitions [1]. PLS is caused by mutations in the CTSC gene which displays remarkably high allelic heterogeneity with over. CTSC encodes the cathepsin C protein, a lysosomal exocysteine proteinase belonging to the peptidase C1 family [2]. We had investigated the family previously for a Primary ciliary dyskinesia (PCD) study where the whole-exome of the two children with PCD was sequenced (though the PCD causal variant remains unknown). We reasoned that with a one-third chance of each PCD (PLS unaffected) sibling with wholeexome sequencing (WES) data being a non-carrier for the PLS causal mutation, we would have an 8/9 chance (1/3 x 1/3 = 1/9 = chance of both not being a carrier) of identifying the PLS causal mutation (likely in CTSC) in a heterozygous state in at least one of the two available WES data. We discuss the ethical and research implications of this study

Materials and Methods

Participants and Genetic Data Analysis

Results