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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: clinchem.2005.056192v1 52/1/46    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Web of Science (4) Citing Articles via Google Scholar Google Scholar Articles by Garcia-Barceló, M. Articles by Tam, P. K.-h. Search for Related Content PubMed PubMed Citation Articles by Garcia-Barceló, M. Articles by Tam, P. K.-h. Related Collections Molecular Diagnostics and Genetics

Population Differences in the Polyalanine Domain and 6 New Mutations in HLXB9 in Patients with Currarino Syndrome

¹ Department of Surgery, ² Genome Research Center, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
³ Department of Pediatric Surgery, China Medical University, Shenyang, China.
⁴ Department of Surgery, Beijing Children’s Hospital, Beijing, China.
⁵ Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Canada.
⁶ Department of Pediatrics, Children’s Hospital of the King’s Daughters, Norfolk, VA.
⁷ Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada.
⁸ St. Joseph’s Hospital, CHC Phoenix Genetics Program, Phoenix, AZ.
⁹ Surgical Unit, University Hospital, Maastricht, The Netherlands.
¹⁰ IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, and IEO, Istituto Europero di Oncologia, Milan, Italy.

^aAddress correspondence to this author at: Division of Paediatric Surgery, Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong SAR, China. Fax 852-2817-3155; e-mail paultam{at}hkucc.hku.hk.

Background: The combination of partial absence of the sacrum, anorectal anomalies, and presacral mass constitutes Currarino syndrome (CS), which is associated with mutations in HLXB9.

Methods: We analyzed 5 CS families and 6 sporadic cases for HLXB9 mutations by direct sequencing. Potentially pathologic expansions of HLXB9 GCC repeats were analyzed in patients, 4 general populations [Chinese, Japanese, Yoruba, and Centre du Etude Polymorphisme Human (CEPH)] from the HapMap project, and 145 healthy Chinese.

Results: We identified 6 novel mutations affecting highly conserved residues (Ser185X, Trp215X, Ala26fs, Ala75fs, Met1Ile, and Arg273Cys). GCC allele and genotype distributions showed marked statistically significant differences. (GCC)₁₁ was the most common allele overall; its frequency ranged from 90% in CEPH to 68% in Yoruba and 50% in Chinese and Japanese populations. (GCC)₉ was almost as common as (GCC)₁₁ in Chinese and Japanese populations, whereas its frequency was <10% in Yoruba and CEPH populations. The Yoruba population had the highest frequency of the largest alleles [(GCC)₁₂ and (GCC)₁₃], which were almost absent in the other groups.

Conclusions: Lack of HLXB9 mutations in some patients and the presence of variable phenotypes suggest DNA alterations in HLXB9 noncoding regions and/or in other genes encoding HLXB9 regulatory molecules or protein partners. If HLXB9, like other homeobox genes, has a threshold beyond which triplet expansions are pathologic, those populations enriched with larger alleles would be at a higher risk. The data illustrate the importance of ethnicity adjustment if these polymorphic markers are to be used in association studies.