# An Intronic Variant in CDKN1C Gene Causing IMAGe Syndrome in an Iranian Girl

## TL;DR

A new genetic variant in the CDKN1C gene is linked to IMAGe syndrome in a young Iranian girl, emphasizing the role of whole-exome sequencing in diagnosing rare genetic disorders.

## Contribution

The first reported intronic CDKN1C variant associated with IMAGe syndrome is identified, expanding the genetic spectrum of the condition.

## Key findings

- A novel CDKN1C intronic variant (c.787+4A>T) was found in an Iranian girl with IMAGe syndrome.
- Whole-exome sequencing confirmed the variant's absence in major databases and predicted splicing disruption.
- The variant was maternally inherited and classified as a Variant of Uncertain Significance.

## Abstract

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.

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.

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.

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.

A novel intronic CDKN1C variant (c.787+4A>T) was identified in an Iranian girl with IMAGe syndrome, expanding its genetic spectrum. This finding highlights the importance of whole‐exome sequencing for diagnosing rare disorders and managing life‐threatening adrenal insufficiency.