title: Proxy molecular diagnosis from whole-exome sequencing reveals Papillon-Lefevre syndrome caused by a missense mutation in CTSC.
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.
authors: Bristol Genetic Epidemiology Laboratories (BGEL), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom.
authors: A Mesut
authors: AM
authors: Erzurumluoglu
authors: College of Medicine, Pediatric Department, King Saud University, P.O. Box 50807, Riyadh, 11533, Kingdom of Saudi Arabia.
authors: Muslim M
authors: MM
authors: Alsaadi
authors: Bristol Genetic Epidemiology Laboratories (BGEL), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom.
authors: Santiago
authors: S
authors: Rodriguez
authors: College of Medicine, Pediatric Department, King Saud University, P.O. Box 50807, Riyadh, 11533, Kingdom of Saudi Arabia.
authors: Tahani S
authors: TS
authors: Alotaibi
authors: Bristol Genetic Epidemiology Laboratories (BGEL), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom.
authors: Philip A I
authors: PA
authors: Guthrie
authors: Bristol Genetic Epidemiology Laboratories (BGEL), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom.
authors: Sian
authors: S
authors: Lewis
authors: Bristol Genetic Epidemiology Laboratories (BGEL), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom.
authors: Aasiya
authors: A
authors: Ginwalla
authors: Bristol Genetic Epidemiology Laboratories (BGEL), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom; MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom.
authors: Tom R
authors: TR
authors: Gaunt
authors: Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Kingdom of Saudi Arabia.
authors: Khalid K
authors: KK
authors: Alharbi
authors: Department of Dermatology, King Saud University, P.O. Box 7805, Riyadh, 11472, Kingdom of Saudi Arabia.
authors: Fahad M
authors: FM
authors: Alsaif
authors: Department of Dermatology, King Saud University, P.O. Box 7805, Riyadh, 11472, Kingdom of Saudi Arabia.
authors: Basma M
authors: BM
authors: Alsaadi
authors: Bristol Genetic Epidemiology Laboratories (BGEL), University of Bristol, Oakfield House, Oakfield Grove, Bristol, BS8 2BN, United Kingdom.
authors: Ian N M
authors: IN
authors: Day
mesh_terms: D018912:Arabs / Q000331:legislation & jurisprudence; D020789:Cathepsin C / Q000235:genetics*; D003241:Consanguinity; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010214:Papillon-Lefevre Disease / Q000175:diagnosis* / Q000235:genetics; D010375:Pedigree; D012529:Saudi Arabia; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C533918:CTSC protein, human; D020789:Cathepsin C