Deletions and Duplications of Developmental Pathway Genes in 5q31 Contribute to Abnormal

Although copy number changes of 5q31 have been rarelyreported, deletions have been associated with some commoncharacteristics,suchasshortstature,failuretothrive,develop-mental delay (DD)/intellectual disability (ID), club feet, dis-located hips, and dysmorphic features. We report on threeindividuals with deletions and two individuals with duplica-tions at 5q31, ranging from 3.6Mb to 8.1Mb and 830kb to3.4Mb in size, respectively. All five copy number changes areapparentlydenovoandinvolveseveralgenesthatareimportantin developmental pathways, including PITX1, SMAD5,andWNT8A. The individuals with deletions have characteristicfeatures including DD, short stature, club feet, cleft or highpalate, dysmorphic features, and skeletal anomalies. Haploin-sufficiencyofPITX1,atranscriptionfactorimportantforlimbdevelopment, is likely the cause for the club feet, skeletalanomalies, and cleft/high palate, while additional genes, in-cludingSMAD5andWNT8A,mayalsocontributetoadditionalphenotypicfeatures.Twopatientswithdeletionsalsopresentedwith corneal anomalies. To identify a causative gene for thecorneal anomalies, we sequenced candidate genes in a familywith apparent autosomal dominant keratoconus with sugges-tive linkage to5q31, but no mutations in candidate genes werefound.Theduplicationsaresmallerthanthedeletions,andthepatientswithduplicationshavenonspecificfeatures.Althoughdevelopmentislikelyaffectedbyincreaseddosageofthegenesintheregion,thedevelopmentaldisruptionappearslessseverethan that seen with deletion.