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Updated: Jan 16, 2026
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
Exploring genotype-phenotype correlation of a novel SHOX gene splicing variant: Langer mesomelic dysplasia or
Moein Kohkalani1, Seyyed Amin Seyyed Rezaei1, Maryam Naghinejad1
1Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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.
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