Exploring genotype-phenotype correlation of a novel SHOX gene splicing variant: Langer mesomelic dysplasia or idiopathic short stature.

BACKGROUND

SHOX gene haploinsufficiency is a frequent cause of idiopathic short stature (ISS), while complete deficiency of this gene product causes the severe Langer mesomelic dysplasia (LMD). Mutations in the SHOX gene are among the well-known genetic factors responsible for short stature. This study investigated the genetic cause of LMD and ISS in two and five individuals in one family.

METHODS

Exome sequencing was conducted in the proband. Candidate variant was evaluated in silico for their impact. Sanger sequencing was employed for variant segregation analysis among available family members.

RESULTS

A novel SHOX gene splice donor variant (c.486 + 2T > C) was found in homozygous form in individuals with LMD, and in heterozygous form in individuals with ISS. The mutation is likely to disrupt normal splicing as it affects a nearly invariantly conserved nucleotide at a canonical splice location. The variant was absent from gnomAD. The mutation segregated perfectly with ISS, LMD, and normal stature in this family.

CONCLUSION

This study describes a new SHOX splice-site variant causing LMD and ISS, and demonstrates a strong genotype-phenotype correlation.