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

Skeletal dysplasias are a diverse group of genetically inherited bone disorders which may manifest with or without short stature. Extreme short stature can also result from different growth hormone deficiencies. Our research aimed to identify the genetic causes of recessively inherited short stature, with or without skeletal abnormalities in Pakistani families. We recruited participants from thirty-eight pedigrees with a history of these disorders. Radiological examinations were performed for a few patients. Some samples were first screened for variants in GHRHR and RMRP by Sanger sequencing. Next, exome sequencing was carried out for selected patients from each family. Exome data were annotated and all were analyzed using Franklin software while some data were also analyzed using the 3billion automated system. Candidate variants were confirmed by segregation analyses in each family. We identified ten novel homozygous variants in AARS2, COL2A1, ERCC6, EVC2, GHR, IHH, MYH3, NPR2, OBSL1 and TG segregating with the phenotypes in ten different families. In-silico analyses predicted these variants to be deleterious to the genes or the encoded proteins. AARS2 variants have not been previously described to cause short stature. Members of the other twenty-five families had variants in nine different genes. A GHRHR founder mutation accounted for short stature without skeletal abnormalities in 12 families. In contrast, significant genetic heterogeneity was observed in the group of families with short stature accompanied by skeletal dysplasia. In conclusion, our study has broadened the genotypic and phenotypic spectrum of multiple genes and the associated diseases with short stature and skeletal dysplasia.