A Novel Variant in an Intron Splicing Enhancer Associated with Familial Growth Hormone Deficiency.

INTRODUCTION

Variants in the intron splicing enhancer (ISE) of intron 3 in the GH1 gene are implicated in the etiology of isolated growth hormone deficiency type 2 (type II IGHD).

METHODS

Exome sequencing was performed to screen variants that co-segregated with IGHD in an extended family with type II IGHD. The causality of the candidate variant was assessed using bioinformatic tools and previous in vitro studies.

RESULTS

Exome sequencing identified a rare intronic variant (NM_000515.5, c.291+34 G>A) in the second XGGG repeat of ISE in intron 3 of GH1, which occurred de novo in the mother with IGHD and was passed onto her two affected children. The variant was previously shown in vitro to cause exon 3 skipping in 50% of the mRNAs and was predicted to create a new binding site for exonic splicing enhancer binding proteins (SR proteins).

CONCLUSION

Our familial case reiterates the importance of intronic variants in the splicing enhancer region as a cause of IGHD. Consideration should be given to sequencing the splicing enhancer region in intron 3 of GH1 for patients who undergo genetic testing for growth hormone deficiency.