Chromosome 19p13.3 deletion in a child with peutz-jeghers syndrome, congenital heart defect, high myopia, learning difficulties and dysmorphic features: clinical and molecular characterization of a new contiguous gene syndrome

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Genetics and Molecular Biology Online Ahead of Print Copyright © 2011, Sociedade Brasileira de Genética. Printed in Brazil

Chromosome 19p13.3 deletion in a child with Peutz-Jeghers syndrome, congenital heart defect, high myopia, learning difficulties and dysmorphic features: Clinical and molecular characterization of a new contiguous gene syndrome
Josiane Souza1, Fábio Faucz1,Vanessa Sotomaior1, Aguinaldo Bonalumi Filho1, Jill Rosenfeld2 and Salmo Raskin1,3 Núcleo de Investigação Molecular Avançada, Programa de Pós-Graduação em Ciências da Saúde, Centro de Ciencias Biológicas e da Saúde, Pontificia Universidade Catolica do Paraná, Curitiba, PR, Brazil. 2 Signature Genomics, Spokane, Washington, USA. 3 GENETIKA – Centro de Aconselhamento e Laboratorio de Genetica,Curitiba, PR, Brazil. Abstract
The Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome characterized by mucocutaneous pigmentation, gastrointestinal polyps and the increased risk of multiple cancers. The causative point mutation in the STK11 gene of most patients accounts for about 30% of the cases of partial and complete gene deletion. This is a report on a girlwith PJS features, learning difficulties, dysmorphic features and cardiac malformation, bearing a de novo 1.1 Mb deletion at 19p13.3. This deletion encompasses at least 47 genes, including STK11. This is the first report on 19p13.3 deletion associated with a PJS phenotype, as well as other atypical manifestations, thereby implying a new contiguous gene syndrome. Key words: 19p13.3 deletion,comparative genomic hybridization array, contiguous gene syndrome, Peutz-Jeghers syndrome, STK11 gene. Received: April 15, 2011; Accepted: July 14, 2011.

The Peutz-Jeghers syndrome (PJS) is a rare autosomal-dominant disease characterized by gastrointestinal polyposis and mucocutaneous pigmentation. It is associated with a predisposition for various types of benign and malignant gastrointestinal andextra-intestinal tumors (Giardiello and Trimbath, 2006). In 1998, point mutations in the STK11(LKB1) gene were described as inducing PJS (Hemminki et al., 1998; Jenne et al., 1998). STK11, mapped at 19p13.3, encodes a serine-threonine protein kinase that acts as a regulator of cell-cycle metabolism and cell polarity, with evidence of tumor suppressor functions (Forcet et al., 2005). Germline pointmutations in STK11 have been identified in most patients with PJS, with partial or whole gene deletion in approximately 30% of these (Aretz et al., 2005; Resta et al., 2010). Some PJS individuals with deletions of up to 250 kb, encompassing STK11 and neighboring genes, have been described (Le Meur et al., 2004; Resta et al., 2010). Only one patient with a large deletion, between 220-250 kb,presented other features in addition to PJS
Send correspondence to Salmo Raskin. GENETIKA - Centro de Aconselhamento e Laboratorio de Genetica, Rua Saldanha Marinho 1782, Bairro Bigorrilho, 80730-180 Curitiba, PR, Brazil. E-mail:

characteristics, namely learning disability and scoliosis (Le Meur et al., 2004). Carriers of larger deletions at 19p13.3, but without PJSfeatures, have been reported (Archer et al., 2005; Hurgoiu and Suciu, 1984). Here, a patient with PJS, as well as other atypical clinical manifestations due to a ~1.1 Mb deletion at 19p13.3, is described. The patient, a girl, was the second child of a non-consanguineous and healthy couple. The father was 30-yearsold, and the mother 28, at the time of birth. The first child, an apparently normal boy atbirth, was stillborn after a complicated delivery. The girl was delivered at term, by caesarean section, after an uncomplicated pregnancy. Birth weight was 2500 g, body length 44 cm, and Apgar scores 3 and 5. For the first 18 days, she required intensive care-unit intervention with supplemental oxygen. At five days of age, atrial and ventricular septal defects were diagnosed, which were surgically...