Abstract
INTRODUCTION: IMAGe syndrome, a rare disorder caused by maternally inherited CDKN1C pathogenic variants, is characterized by intrauterine growth retardation (IUGR), metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary abnormalities. We report a novel intronic CDKN1C variant in a 5-year-old Iranian girl with IMAGe syndrome. MATERIALS AND METHODS: Clinical evaluations showed severe IUGR (birth weight 1850 g), disproportionate short stature (height 88 cm, -4.4 Z score), metaphyseal dysplasia, adrenal insufficiency (ACTH 1110 pg/mL, low cortisol), and dysmorphic features (frontal bossing, low-set ears). Whole-exome sequencing (WES) was performed to identify causative genetic variants. RESULTS: WES revealed a heterozygous CDKN1C intronic variant, c.787+4A>T, absent from gnomAD, ExAC, and ClinVar. SpliceAI (score: 0.82) predicted disrupted splicing, potentially leading to a gain-of-function effect. The variant was consistently classified as a Variant of Uncertain Significance (VUS) according to ACMG/AMP 2015 guidelines with 2020 updates. No other pathogenic variants were identified in genes related to skeletal dysplasia, adrenal insufficiency, or growth retardation. Sanger sequencing confirmed maternal inheritance in the proband, her healthy mother, and grandfather, consistent with CDKN1C paternal imprinting. DISCUSSION: This case broadens the genetic spectrum of IMAGe syndrome by identifying the first reported intronic CDKN1C variant associated with this condition. WES is crucial for diagnosis, and RNA analysis is needed to confirm the variant's functional impact. Rapid diagnosis is essential for managing life-threatening adrenal insufficiency.