Characterization of familial short stature with or without skeletal dysplasia in a Pakistani cohort reveals founder mutations as well as novel variants.

GHRHR, AARS2

Homozygous variants in somatotropic axis genes (GHRHR, GHR) and skeletal growth genes; GHRHR founder mutation

This study covers 38 Pakistani families with recessively inherited short stature, with or without skeletal dysplasia, investigated by targeted Sanger sequencing (GHRHR, RMRP) and then exome sequencing, with candidate variants confirmed by segregation in each family. Ten novel homozygous variants were identified in ten families, in AARS2, COL2A1, ERCC6, EVC2, GHR, IHH, MYH3, NPR2, OBSL1 and TG; AARS2 variants had never been described as a cause of short stature. Members of 25 other families carried variants in nine different genes, including a GHRHR founder mutation accounting for short stature without skeletal abnormalities in 12 families. By contrast, the group with skeletal dysplasia showed marked genetic heterogeneity.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The GHRHR founder mutation (12 families) is the directly actionable finding: in this population, isolated recessive short stature warrants testing for it first, all the more so as growth hormone deficiency is treatable. The novel variants rest only on in silico predictions and within-family segregation, without functional evidence. The association between AARS2 and short stature, seen in a single family, needs confirmation.

Analysis by Dr Thibaut Benquey