Short Report An analysis of PAX1 in the development of vertebral malformations Giampietro PF, Raggio CL, Reynolds CE, Shukla SK, McPherson E, Ghebranious N, Jacobsen FS, Kumar V, Faciszewski T, Pauli RM, Rasmussen K, Burmester JK, Zaleski C, Merchant S, David D, Weber JL, Glurich I, Blank RD. An analysis of PAX1 in the development of vertebral malformations. Clin Genet 2005: 68: 448–453. # Blackwell Munksgaard, 2005 Due to the sporadic occurrence of congenital vertebral malformations, traditional linkage approaches to identify genes associated with human vertebral development are not possible. We therefore identified PAX1 as a candidate gene in vertebral malformations and congenital scoliosis due to its mutation in the undulated mouse. We performed DNA sequence analysis of the PAX1 gene in a series of 48 patients with congenital vertebral malformations, collectively spanning the entire vertebral column length. DNA sequence coding variants were identified in the heterozygous state in exon 4 in two male patients with thoracic vertebral malformations. One patient had T9 hypoplasia, T12 hemivertebrae and absent T10 pedicle, incomplete fusion of T7 posterior elements, ventricular septal defect, and polydactyly. This patient had a C CC (Pro)!C TC (Leu) change at amino acid 410. This variant was not observed in 180 chromosomes tested in the National Institute of Environmental Health Sciences (NIEHS) single nucleotide polymorphism (SNP) database and occurred at a frequency of 0.3% in a diversity panel of 1066 human samples. The second patient had a T11 wedge vertebra and a missense mutation at amino acid 413 corresponding to C CA (Pro)!C TA (Leu). This particular variant has been reported to occur in one of 164 chromosomes in the NIEHS SNP database and was found to occur with a similar frequency of 0.8% in a diversity panel of 1066 human samples. Although each patient’s mother was clinically asymptomatic and heterozygous for the respective variant allele, the possibility that these sequence variants have clinical significance is not excluded. PF Giampietro a , CL Raggio b , CE Reynolds c , SK Shukla c , E McPherson a , N Ghebranious d , FS Jacobsen e , V Kumar f , T Faciszewski g , RM Pauli h , K Rasmussen a , JK Burmester i , C Zaleski a , S Merchant a,* , D David i , JL Weber i , I Glurich i and RD Blank j a Medical Genetic Services, Marshfield Clinic, Marshfield, WI; b Pediatric Orthopedics, Hospital for Special Surgery, New York, NY; c Clinical Research Center, Marshfield Clinic Research Foundation; d Molecular Diagnostics Genotyping Laboratory; e Orphopaedic Surgery; f Pediatric; g Orthopedic Spine Surgery, Marshfield Clinic, Marshfield; h Clinical Genetics Center, University of Wisconsin, Madison; i Center for Human Genetics, Marshfield Clinic Research Foundation, Marshfield; and j Endocrinology Section, Department of Medicine, University of Wisconsin and William S. Middleton Veterans’ Administration Medical Center, Madison, WI, USA Key words: CEPH diversity panel – PAX1 – polymorphism – vertebral malformation Corresponding author: Dr Philip F. Giampietro, Medical Genetic Services, Marshfield Clinic, 1000 North Oak Avenue 3C1, Marshfield, WI 54449, USA. Tel.: þ1 715 221 7400; fax: þ1 715 389 4399; e-mail: giampietro.philip@marshfieldclinic.org Received 1 June 2005, revised and accepted for publication 12 August 2005 Congenital vertebral malformations may cause kyphosis and/or scoliosis, resulting in back and neck pain, disability, cosmetic disfigurement, and functional distress. The true incidence of verteb- ral malformations is unknown, although esti- mates indicate a prevalence of approximately 0.5–1/1000 (1, 2). Vertebral malformations may represent an isolated finding, occur in association with other renal, cardiac, or spinal cord malfor- mations, or occur as part of an underlying chro- mosomal abnormality or syndrome. These include hemifacial microsomia, Alagille, Jarcho– Levin, Klippel–Feil, Goldenhar, Joubert, basal cell nevus, trisomy 18, diabetic embryopathy, and VACTERL (vertebral, anal, cardiac, *Present address: Medical Genetics Clinic, University of Alberta Hospital, Edmonton, Alberta, Canada. Clin Genet 2005: 68: 448–453 Copyright # Blackwell Munksgaard 2005 Printed in Singapore. All rights reserved CLINICAL GENETICS doi: 10.1111/j.1399-0004.2005.00520.x 448