title: Molecular analysis of the CTSK gene in a cohort of 33 Brazilian families with pycnodysostosis from a cluster in a Brazilian Northeast region.
abstract: BACKGROUND
  Pycnodysostosis is an autosomal recessive skeletal dysplasia, the prevalence of which is estimated to be low (1 per million). Nevertheless, in recent years we have found 27 affected individuals from 22 families in Ceará State, a region of the Brazilian Northeast, giving a local prevalence of 3 per million. This local prevalence associated with a high parental consanguinity, suggesting a possible founder effect, prompted us to perform a molecular investigation of these families to test this hypothesis.
  
  
  METHODS
  The CTSK gene was sequenced by the Sanger method in the patients and their parents. In addition to 18 families from Ceará, this study also included 15 families from other Brazilian regions. We also investigated the origin of each family from the birthplace of the parents and/or grandparents.
  
  
  RESULTS
  We have studied 39 patients, including 33 probands and 6 sibs, from 33 families with pycnodysostosis and identified six mutations, five previously described (c.436G>C, c.580G>A, c.721C>T, c.830C>T and c.953G>A) and one novel frameshift (c.83dupT). This frameshift variant seems to have a single origin in Ceará State, since the haplotype study using the polymorphic markers D1S2344, D1S442, D1S498 and D1S2715 suggested a common origin. Most of the mutations were found in homozygosity in the patients from Ceará (83.3 %) while in other states the mutations were found in homozygosity in half of patients. We have also shown that most of the families currently living outside of Ceará have northeastern ancestors, suggesting a dispersion of these mutations from the Brazilian Northeast.
  
  
  CONCLUSIONS
  The high frequency of pycnodysostosis in Ceará State is the consequence of the high inbreeding in that region. Several mutations, probably introduced a long time ago in Ceará, must have spread due to consanguineous marriages and internal population migration. However, the novel mutation seems to have a single origin in Ceará, suggestive of a founder effect.
authors: Skeletal Dysplasia Group, Department of Medical Genetics, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
authors: Thaís Fenz
authors: TF
authors: Araujo
authors: Children's Hospital Albert Sabin, Fortaleza, CE, Brazil.|Medical Sciences Faculty of Juazeiro do Norte (FMJ), Juazeiro do Norte, CE, Brazil.
authors: Erlane Marques
authors: EM
authors: Ribeiro
authors: Medical Sciences Faculty of Juazeiro do Norte (FMJ), Juazeiro do Norte, CE, Brazil.
authors: Anderson Pontes
authors: AP
authors: Arruda
authors: Skeletal Dysplasia Group, Department of Medical Genetics, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.|Perinatal Genetics Program, Department of Medical Genetics, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
authors: Carolina Araujo
authors: CA
authors: Moreno
authors: Federal University of Campina Grande, Campina Grande, PB, Brazil.
authors: Paula Frassinetti Vasconcelos
authors: PF
authors: de Medeiros
authors: Children's Clinic, City Hall of Guarulhos, Guarulhos, SP, Brazil.
authors: Renata Moldenhauer
authors: RM
authors: Minillo
authors: Medical Department, Federal University of de São Carlos (UFSCAR), São Carlos, SP, Brazil.
authors: Débora Gusmão
authors: DG
authors: Melo
authors: Medical Genetics Unit, Children's Institute, Medical Sciences Faculty, University of São Paulo (FCMUSP), São Paulo, SP, Brazil.
authors: Chong Ae
authors: CA
authors: Kim
authors: Children's Hospital Juvêncio Mattos, São Luís, MA, Brazil.
authors: Maria Juliana Rodovalho
authors: MJ
authors: Doriqui
authors: Medical Genetics Service, Clinical Hospital of Porto Alegre, Porto Alegre, RS, Brazil.
authors: Têmis Maria
authors: TM
authors: Felix
authors: Centro de Genética Médica da Universidade Federal de São Paulo, São Paulo, SP, Brazil.
authors: Rodrigo Ambrosio
authors: RA
authors: Fock
authors: Skeletal Dysplasia Group, Department of Medical Genetics, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil. denisepcavalcanti@gmail.com.|Perinatal Genetics Program, Department of Medical Genetics, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil. denisepcavalcanti@gmail.com.
authors: Denise Pontes
authors: http://orcid.org/0000-0001-6617-4730
authors: DP
authors: Cavalcanti
mesh_terms: D001938:Brazil; D056657:Cathepsin K / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D058631:Pycnodysostosis / Q000235:genetics*
chemical_list: C534130:CTSK protein, human; D056657:Cathepsin K
keywords: Cathepsin K; Inbreeding; Novel mutation; Pycnodysostosis