SAT-LB17 Triplication of SHOX Downstream Region in Mild Short Stature

Abstract

Deletions of the downstream flanking regions of the SHOX gene that contain conserved non-coding cis-regulatory DNA elements are a known cause of Leri-Weill dyschondrosteosis or idiopathic short stature (ISS). Functional and comparative genomic studies have demonstrated the existence of four CNE enhancers downstream of SHOX which have transcriptional activity, and a fifth has recently been suggested at approximately X:970,000. Duplications of these downstream regions have also been described in patients with ISS, although with a variable phenotype. We present a family with ISS and the first ever reported SHOX downstream triplication. The index case was a 12-year-old Caucasian female of unrelated parents, born with normal weight and length, and normal hearing/vision and development. At the age of 12, her height was -1.87 SD (-1.35 SD adjusted for parental height). Her growth chart showed a height on the 90th centile at birth, slowly crossing centiles for the first 5 years to the 2nd centile, which she then followed. She had normal proportions and head circumference, and no dysmorphic features apart from inverted nipples. Baseline investigations for short stature were normal, including IGF1, karyotype and celiac screen. Bone age was 1.5 year delayed. Family history: arthritis in the father, early menopause in the mother. Analysis of SHOX and its flanking regions was carried out using Multiplex Ligation-dependent Probe Amplification (MLPA) and direct sequencing of all coding exons. MLPA analysis showed a SHOX downstream triplication with a minimum size of 66kb (X:963670-1029779) and a maximum size of 428kb (X:899389-1327688). The size of the duplication was further defined using array comparative genome hybridization (ACGH) analysis which showed the minimum size to be ~325kb (X:907457-1232802). This triplication includes the proposed regulatory element at ~ X:970,000. The triplication was subsequently shown to be present in the proband’s mother and brother who also have mild ISS. Further analysis of these and other family members is ongoing. The triplication is of a single-sized fragment, and the fragment size is identical to one that has been seen in duplicated form in several other patients, increasing the likelihood that the triplicated fragments are in tandem. The precise mechanism of the pathogenic effect of the triplication is unknown, but it likely exerts a negative effect on SHOXtranscription, reducing its expression and ultimately resulting in SHOX haploinsufficiency. In conclusion, we describe a family with mild ISS and a downstream triplication of the proposed X:970,000 SHOX downstream regulatory element. This provides further evidence for this previously proposed regulatory element downstream of SHOX and adds additional proof that increased dosage of this regulatory element region is a cause of short stature.