See Table A. Genes and Databases for chromosome locus and protein.

See Molecular Genetics for information on variants detected in this gene.

Currently, about 10% of individuals with LWD do not have a demonstrable SHOX pathogenic variant and may either represent a false-negative result beyond the limits of current technology or represent phenocopies (true negatives).

Numbers vary between laboratories using different methodologies. Numbers also differ in patients from different ethnic origins.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon (e.g., those described by Mitka et al [2016] and Shima et al [2016]) to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Chen et al [2009] and Shima et al [2016]) may not be detected by these methods.

Gene-targeted deletion/duplication analysis should be able to detect all pathogenic deletions or duplications that are detected by CMA / SNP array, although it may also detect smaller deletions or duplications that are outside of the sensitivity of the specific CMA / SNP platform, depending on the probe and SNP coverage through the Xp22.32;Yp11.3 region on the CMA / SNP platform used.

Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including SHOX that cannot be detected by sequence analysis). The ability to determine the size of the deletion/duplication depends on the type of microarray used and the density of probes in the Xp22.32;Yp11.3 region. CMA designs in current clinical use target the Xp22.32;Yp11.3 region.

Balanced and unbalanced chromosome rearrangements disrupting SHOX have been detected in some individuals with SHOX deficiency [Shears et al 1998, Izumi et al 2007]; thus, chromosome analysis should be considered in those in whom SHOX deficiency is a strong possibility but whose molecular testing gave a normal result.