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. 2025 Mar 8:1-11.
doi: 10.1159/000545037. Online ahead of print.

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

Sally Radovick  1 , Mariam Gangat  2 , Bethany Murphy  2 , Jennifer L Miller  3 , Youn Hee Jee  4   5   6
Affiliations

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

Sally Radovick et al. Horm Res Paediatr. .

Abstract

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.

Keywords: Familial growth hormone deficiency; GH1; Intron consensus sequence; Isolated growth hormone deficiency; Splicing enhancer sequence.

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Conflict of interest statement

Conflict of Interest Statement

Jennifer L Miller’s spouse is the majority owner of Element Bars, Inc., a snack food company. All other authors have nothing to disclose. The rest of the authors have no conflicts of interest to declare.

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