Received on June 16, 2005
Accepted on October 10, 2005

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, and Department of Genome Research Center, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China
² Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China
³ Department of Surgery and Department of Pediatric Surgery, China Medical University, Shenyang, China
⁴ Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China and 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 Surgery, Beijing Children's Hospital, Beijing, China
⁸ Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada
⁹ St. Joseph's Hospital, CHC Phoenix Genetics Program, Phoenix, AZ
¹⁰ Surgical Unit, University Hospital, Maastricht, The Netherlands
¹¹ IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, and IEO, Istituto Europero di Oncologia, Milan, Italy

^* To whom correspondence should be addressed. 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 HLXB9 mutations by direct sequencing in 5 CS families, 6 sporadic cases, and 97 healthy Chinese individuals and potentially pathologic expansion of HLXB9 GCC repeats in patients, 4 general populations [Chinese, Japanese, Yoruba, and the Utah subset of the Centre du Etude Polymorphisme Humain (CEPH)] from the HapMap project, and 45 Chinese individuals.

Results: We identified 6 novel mutations, including 2 missense mutations affecting highly conserved residues (Ser185X, Trp215X, Ala26fs, Ala75fs, Met1Ile, and Arg273Cys). 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.