SHOX far‐downstream deletion in a patient with nonsyndromic short stature

Abstract

Haploinsufficiency of SHOX represents one of the major genetic causes of nonsyndromic short stature. To date, eight DNA elements around SHOX exons have been proposed as putative enhancer regions. Although six copy‐number variations (CNVs) downstream to the known enhancer regions have recently been identified in patients with short stature, the pathogenicity of these CNVs remains uncertain. Here, we identified a paternally derived SHOX far‐downstream deletion in a boy. The deletion involved a ~100 kb genomic interval at a position >60 kb away from the known enhancer regions. The boy exhibited moderate short stature with nonspecific skeletal changes. The height of the father was within the normal range but lower than the mid‐parental height. The deletion of the boy and the six previously reported CNVs mostly overlapped; however, all CNVs had unique breakpoints. The deletion of our case encompassed a ~30 kb genomic interval that has previously been associated with a 4C‐seq peak, as well as several SHOX‐regulatory SNPs/indels. These results indicate that the SHOX far‐downstream region contains a novel cis‐acting enhancer, whose deletion leads to nonsyndromic short stature of various degree. In addition, our data highlight genomic instability of SHOX‐flanking regions that underlies diverse nonrecurrent CNVs.

Shortened fetal long bones: A notable intrauterine phenotypic feature in SHOX‐associated skeletal dysplasia

“…3,16 Deletions of the SHOX gene and its regulatory elements located in the 50-250 kb downstream of the coding region are the most common genetic defects in SHOX-associated skeletal dysplasia individuals. 7,14,17,18 Of note, sporadic cases involving intragenic deletion, enhancer region deletion, and frameshift mutation have also been reported prenatally. 15,[19][20][21][22][23][24][25] According to our findings and the cases reported in the literature, whole gene deletions leading to SHOX haploinsufficiency were more frequently detected prenatally.…”

“…It is a causative gene associated with short‐stature phenotypes in Turner syndrome and functions in a dose‐dependent manner in limb development 3,16 . Deletions of the SHOX gene and its regulatory elements located in the 50–250 kb downstream of the coding region are the most common genetic defects in SHOX ‐associated skeletal dysplasia individuals 7,14,17,18 . Of note, sporadic cases involving intragenic deletion, enhancer region deletion, and frameshift mutation have also been reported prenatally 15,19–25 .…”

“…3,4 It has been confirmed that loss of function SHOX variants have a dosagedependent effect on linear growth and limb development. 2,[5][6][7] SHOX deletions are the most common variants that account for roughly 80% of pathogenic variants in this gene. 1 In 1997, the SHOX gene was identified as the causative gene for short stature phenotypes in patients with Turner syndrome.…”

“…The SHOX gene, located in the pseudoautosomal region 1 (PAR1) on the short arm of both sex chromosomes Xp22.33 and Yp11.3, encodes an essential homeodomain transcription factor involved in body patterning 3,4 . It has been confirmed that loss of function SHOX variants have a dosage‐dependent effect on linear growth and limb development 2,5–7 . SHOX deletions are the most common variants that account for roughly 80% of pathogenic variants in this gene 1 .…”

Efficacy and safety of GH treatment in Japanese children with short stature due to <i>SHOX</i> deficiency: a randomized phase 3 study

“…The SHOX coding region spans approximately 40 kb and is located 500–600 kb from the Xp/Yp telomere (GRCh37/hg19) ( 2 ). SHOX is associated with at least three enhancers in the upstream region and six in the downstream region ( 2 , 3 ). SHOX deficiency (loss-of-function abnormality) is caused by pathogenic sequence variants (SVs), such as nonsense, missense, and indel variants in the coding exons, and pathogenic copy number variants (CNVs), such as microdeletions and microduplications that disrupt the integrity of the SHOX coding/enhancer regions in subjects with an apparent normal karyotype ( 2 ).…”