RESEARCH ARTICLE Familial Microduplication of 17q23.1–q23.2 Involving TBX4 is Associated With Congenital Clubfoot and Reduced Penetrance in Females Jess F. Peterson, 1,2 Lina Ghaloul-Gonzalez, 3 Suneeta Madan-Khetarpal, 3 Jessica Hartman, 3 Urvashi Surti, 1,2,4,5 Aleksandar Rajkovic, 1,2,4,5 and Svetlana A. Yatsenko 1,4,5 * 1 Pittsburgh Cytogenetics Laboratory, Center for Medical Genetics and Genomics, Magee-Womens Hospital of UPMC, Pittsburgh, Pennsylvania 2 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 3 Department of Medical Genetics, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 4 Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 5 Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Manuscript Received: 10 July 2013; Manuscript Accepted: 28 August 2013 Congenital clubfoot is a heterogeneous disorder that can result in functional disability, deformity, and pain if left untreated. Although the etiology is considered multifactorial in the majori- ty of cases, a 17q23.1–q23.2 duplication has been reported in families with congenital clubfoot characterized by variable ex- pressivity and incomplete penetrance. The candidate gene within the duplicated region is TBX4, a T-box transcription factor required for normal hind limb development. We describe a familial 2.15 Mb duplication in the 17q23.1–q23.2 region identi- fied in a mother, daughter, and two sons. The male proband was referred for genetic evaluation due to multiple congenital anom- alies including bilateral clubfoot, dysplastic hips, multiple heart defects, microcephaly, midfacial hypoplasia, brain anomalies on MRI scan, seizure disorder, optic nerve hypoplasia, hearing loss, and bilateral vocal cord paralysis. Cytogenetic testing on family members identified the 17q23.1–q23.2 duplication in both older siblings and the mother. In this family both male siblings had clubfoot, while females were phenotypically normal. Although TBX4 remains the candidate gene for congenital clubfoot involv- ing 17q23.1–q23.2 duplications, the explanation for variable expressivity and penetrance remains unknown. Ó 2013 Wiley Periodicals, Inc. Key words: 17q23; congenital clubfoot; TBX4; copy-number variations (CNVs); array comparative genomic hybridization (aCGH); incomplete penetrance; sex dimorphism INTRODUCTION Congenital unilateral or bilateral clubfoot (talipes equinovarus) is a relatively common condition with an incidence of 1–2 per 1,000 newborns that can result in long-term functional disability, deformity and pain if left untreated [Dobbs and Gurnett, 2012; Gray et al., 2012]. Talipes equinovarus is characterized by a downturned foot and high medial longitudinal arch. Congenital clubfoot treatment options range from stretching and casting to surgical intervention. Although the etiology of congenital club- foot remains largely unknown, both duplications and deletions involving the 17q23.1–q23.2 region have been associated with congenital clubfoot and other malformations [Alvarado et al., 2010; Lu et al., 2012]. The candidate gene located in 17q23.1–q23.2 includes TBX4, a T-box transcription factor re- quired for normal early hindlimb development [Dobbs and Gurnett, 2012; King et al., 2006; Menke et al., 2008; Minguillon et al., 2009; Duboc and Logan, 2011; Naiche et al., 2011]. How to Cite this Article: Peterson JF, Ghaloul-Gonzalez L, Madan- Khetarpal S, Hartman J, Surti U, Rajkovic A, Yatsenko SA. 2014. Familial microduplication of 17q23.1–q23.2 involving TBX4 is associated with congenital clubfoot and reduced penetrance in females. Am J Med Genet Part A 164A:364–369. Conflict of interest: none.  Correspondence to: Svetlana A. Yatsenko, M.D., Pittsburgh Cytogenetics Laboratory, Center for Medical Genetics and Genomics, Magee-Womens Hospital of UPMC, 300 Halket Street, Pittsburgh, PA 15213. E-mail: yatsenkosa@mail.magee.edu Article first published online in Wiley Online Library (wileyonlinelibrary.com): 25 November 2013 DOI 10.1002/ajmg.a.36238 Ó 2013 Wiley Periodicals, Inc. 364