Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature.

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Abstract

Pseudoautosomal region 1 (PAR1) contains SHOX, in addition to seven highly conserved non-coding DNA elements (CNEs) with cis-regulatory activity. Microdeletions involving SHOX exons 1-6a and/or the CNEs result in idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). Here, we report six rare copy-number variations (CNVs) in PAR1 identified through copy-number analyzes of 245 ISS/LWD patients and 15 unaffected individuals. The six CNVs consisted of three microduplications encompassing SHOX and some of the CNEs, two microduplications in the SHOX 3'-region affecting one or four of the downstream CNEs, and a microdeletion involving SHOX exon 6b and its neighboring CNE. The amplified DNA fragments of two SHOX-containing duplications were detected at chromosomal regions adjacent to the original positions. The breakpoints of a SHOX-containing duplication resided within Alu repeats. A microduplication encompassing four downstream CNEs was identified in an unaffected father-daughter pair, whereas the other five CNVs were detected in ISS patients. These results suggest that microduplications involving SHOX cause ISS by disrupting the cis-regulatory machinery of this gene and that at least some of microduplications in PAR1 arise from Alu-mediated non-allelic homologous recombination. The pathogenicity of other rare PAR1-linked CNVs, such as CNE-containing microduplications and exon 6b-flanking microdeletions, merits further investigation.

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Short Stature due to SHOX Deficiency: Genotype, Phenotype, and Therapy

Gerhard Binder, Binder Gerhard (2011)

SHOX deficiency is a frequent cause of short stature. The short stature homeobox-containing gene resides in the telomeric PAR1 region on the short arm of both sex chromosomes and escapes X inactivation. For this review, abstracts of 207 publications presented by PubMed for the search term ‘SHOX’ were screened. Heterozygote SHOX mutations (80% deletions) were detected in 2–15% of individuals with formerly idiopathic short stature, in 50–90% of individuals with Leri-Weill dyschondrosteosis, and in almost 100% of girls with Turner syndrome. Mutational analysis is primarily performed by MLPA analysis followed by gene sequencing if necessary. SHOX is a nuclear protein that binds to DNA and acts as a transcriptional activator. Orthologs are present in many vertebrates but not in rodents. Gene expression starting as early as 33 days postconception in humans is predominant in the mid portion of the buds and in the first and second pharyngeal arches. In the growth plate, hypertrophic chondrocytes express SHOX where it seems to have antiproliferative potency. The penetrance of SHOX deficiency is high, but its clinical expression is very variable becoming more pronounced with age and being more severe in females. Growth failure starts early during the first years of life and the height deficit present at preschool age seems not to deteriorate further. The mean adult height is –2.2 SDS. Auxological analysis of the body proportions (mesomelia), the presence of minor abnormalities, and the search for subtle radiographic signs are important keys to the diagnosis which has to be confirmed by genetic analysis. The growth-promoting effect of GH therapy approved for individuals with SHOX mutations seems to be equal to the effect seen in Turner syndrome.

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Increased number of sex chromosomes affects height in a nonlinear fashion: a study of 305 patients with sex chromosome aneuploidy.

Anne Ottesen, Lise Aksglaede, Inger Garn … (2010)

Tall stature and eunuchoid body proportions characterize patients with 47,XXY Klinefelter syndrome, whereas patients with 45,X Turner syndrome are characterized by impaired growth. Growth is relatively well characterized in these two syndromes, while few studies describe the growth of patients with higher grade sex chromosome aneuploidies. It has been proposed that tall stature in sex chromosome aneuploidy is related to an overexpression of SHOX, although the copy number of SHOX has not been evaluated in previous studies. Our aims were therefore: (1) to assess stature in 305 patients with sex chromosome aneuploidy and (2) to determine the number of SHOX copies in a subgroup of these patients (n = 255) these patients and 74 healthy controls. Median height standard deviation scores in 46,XX males (n = 6) were -1.2 (-2.8 to 0.3), +0.9 (-2.2 to +4.6) in 47,XXY (n = 129), +1.3 (-1.8 to +4.9) in 47,XYY (n = 44), +1.1 (-1.9 to +3.4) in 48,XXYY (n = 45), +1.8 (-2.0 to +3.2) in 48,XXXY (n = 9), and -1.8 (-4.2 to -0.1) in 49,XXXXY (n = 10). Median height standard deviation scores in patients with 45,X (n = 6) were -2.6 (-4.1 to -1.6), +0.7 (-0.9 to +3.2) in 47,XXX (n = 40), -0.6 (-1.9 to +2.1) in 48,XXXX (n = 13), and -1.0 (-3.5 to -0.8) in 49,XXXXX (n = 3). Height increased with an increasing number of extra X or Y chromosomes, except in males with five, and in females with four or five sex chromosomes, consistent with a nonlinear effect on height. Copyright 2010 Wiley-Liss, Inc.

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Enhancer deletions of the SHOX gene as a frequent cause of short stature: the essential role of a 250 kb downstream regulatory domain

J J Chen, G Wildhardt, Z Zhong … (2009)

Background: Mutations and deletions of the homeobox transcription factor gene SHOX are known to cause short stature. The authors have analysed SHOX enhancer regions in a large cohort of short stature patients to study the importance of regulatory regions in developmentally relevant genes like SHOX. Methods: The authors tested for the presence of copy number variations in the pseudoautosomal region of the sex chromosomes in 735 individuals with idiopathic short stature and compared the results to 58 cases with Leri–Weill syndrome and 100 normal height controls, using fluorescence in situ hybridisation (FISH), single nucleotide polymorphism (SNP), microsatellites, and multiplex ligand dependent probe amplification (MLPA) analysis. Results: A total of 31/735 (4.2%) microdeletions were identified in the pseudoautosomal region in patients with idiopathic short stature; eight of these microdeletions (8/31; 26%) involved only enhancer sequences residing a considerable distance away from the gene. In 58 Leri–Weill syndrome patients, a total of 29 microdeletions were identified; almost half of these (13/29; 45%) involve enhancer sequences and leave the SHOX gene intact. These deletions were absent in 100 control persons. Conclusion: The authors conclude that enhancer deletions in the SHOX gene region are a relatively frequent cause of growth failure in patients with idiopathic short stature and Leri–Weill syndrome. The data highlights the growing recognition that regulatory sequences are of crucial importance in the genome when diagnosing and understanding the aetiology of disease.