Araujo Thaís Fenz, Ribeiro Erlane Marques, Arruda Anderson Pontes, Moreno Carolina Araujo, de Medeiros Paula Frassinetti Vasconcelos, Minillo Renata Moldenhauer, Melo Débora Gusmão, Kim Chong Ae, Doriqui Maria Juliana Rodovalho, Felix Têmis Maria, Fock Rodrigo Ambrosio, Cavalcanti Denise Pontes
Skeletal Dysplasia Group, Department of Medical Genetics, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, Brazil.
Children's Hospital Albert Sabin, Fortaleza, CE, Brazil.
Eur J Med Res. 2016 Aug 24;21(1):33. doi: 10.1186/s40001-016-0228-7.
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.
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.
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.
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.
致密性成骨不全症是一种常染色体隐性遗传性骨骼发育不良疾病，据估计其患病率较低（每百万人口中约有1例）。然而，近年来我们在巴西东北部的塞阿拉州发现了来自22个家庭的27名患者，当地患病率达每百万人口中有3例。这种与高近亲结婚率相关的当地患病率提示可能存在奠基者效应，促使我们对这些家庭进行分子研究以验证这一假设。
采用桑格测序法对患者及其父母的CTSK基因进行测序。除了来自塞阿拉州的18个家庭外，本研究还纳入了来自巴西其他地区的15个家庭。我们还根据父母和/或祖父母的出生地调查了每个家庭的起源。
我们研究了来自33个致密性成骨不全症家庭的39名患者，包括33名先证者和6名同胞，鉴定出6种突变，其中5种是先前已描述的（c.436G>C、c.580G>A、c.721C>T、c.830C>T和c.953G>A），1种是新的移码突变（c.83dupT）。该移码突变似乎仅起源于塞阿拉州，因为使用多态性标记D1S2344、D1S442、D1S498和D1S2715进行的单倍型研究提示其起源相同。大多数突变在塞阿拉州的患者中以纯合子形式出现（83.3%），而在其他州，一半的患者中突变以纯合子形式出现。我们还表明，目前居住在塞阿拉州以外的大多数家庭都有东北部的祖先，这表明这些突变是从巴西东北部扩散而来的。
塞阿拉州致密性成骨不全症的高发病率是该地区高近亲结婚率的结果。可能在很久以前引入塞阿拉州的几种突变，一定是由于近亲结婚和人口内部迁移而传播开来的。然而，这种新突变似乎仅起源于塞阿拉州，提示存在奠基者效应。
