title: Whole-exome sequencing reveals a recurrent mutation in the cathepsin C gene that causes Papillon-Lefevre syndrome in a Saudi family.
abstract: Papillon-Lefevre syndrome (PALS) is a rare, autosomal recessive disorder characterized by periodontitis and hyperkeratosis over the palms and soles. Mutations in the cathepsin C gene (CTSC) have been recognized as the cause of PALS since the late 1990s. More than 75 mutations in CTSC have been identified, and phenotypic variability between different mutations has been described. Next generation sequencing is widely used for efficient molecular diagnostics in various clinical practices. Here we investigated a large consanguineous Saudi family with four affected and four unaffected individuals. All of the affected individuals suffered from hyperkeratosis over the palms and soles and had anomalies of both primary and secondary dentition. For molecular diagnostics, we combined whole-exome sequencing and genome-wide homozygosity mapping procedures, and identified a recurrent homozygous missense mutation (c.899G>A; p.Gly300Asp) in exon 7 of CTSC. Validation of all eight family members by Sanger sequencing confirmed co-segregation of the pathogenic variant (c.899G>A) with the disease phenotype. This is the first report of whole-exome sequencing performed for molecular diagnosis of PALS in Saudi Arabia. Our findings provide further insights into the genotype-phenotype correlation of CTSC pathogenicity in PALS.
authors: Oral and Maxillofacial Prosthodontics Department, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors: Yaser Mohammad
authors: YM
authors: Alkhiary
authors: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia; Medical Genetics and Molecular Biology Unit, Biochemistry Department, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan.
authors: Musharraf
authors: M
authors: Jelani
authors: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
authors: Mona Mohammad
authors: MM
authors: Almramhi
authors: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia; Human Genetics Research Centre, Division of Biomedical Sciences (BMS), St. George's University of London (SGUL), London SW17 0RE, United Kingdom.
authors: Hussein Sheikh Ali
authors: HS
authors: Mohamoud
authors: Oral and Maxillofacial Prosthodontics Department, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
authors: Rayan
authors: R
authors: Al-Rehaili
authors: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia.
authors: Hams Saeed
authors: HS
authors: Al-Zahrani
authors: Department of Dermatology, King Abdulaziz University Hospital, Jeddah, Saudi Arabia.
authors: Rehab
authors: R
authors: Serafi
authors: Oral and Maxillofacial Prosthodontics Department, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Genetic Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.
authors: Huanming
authors: H
authors: Yang
authors: Princess Al-Jawhara Albrahim Center of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah, Saudi Arabia; BGI-Shenzhen, Shenzhen 518083, China.
authors: Jumana Yousuf
authors: JY
authors: Al-Aama
keywords: CTSC gene; Homozygosity mapping; Molecular diagnostics; Papillon–Lefevre syndrome; Saudi Arabia; Whole-exome sequencing