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

Area of Science:

• Genetics
• Endocrinology
• Rare Diseases

Background:

• IMAGe syndrome is a rare genetic disorder caused by pathogenic variants in the CDKN1C gene.
• It is characterized by intrauterine growth retardation (IUGR), metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary abnormalities.

Purpose of the Study:

• To report a novel intronic CDKN1C variant in a patient diagnosed with IMAGe syndrome.
• To highlight the importance of whole-exome sequencing (WES) in diagnosing rare genetic disorders.

Main Methods:

• Clinical evaluation of a 5-year-old Iranian girl with features of IMAGe syndrome.
• Whole-exome sequencing (WES) to identify causative genetic variants.
• SpliceAI prediction and ACMG/AMP guidelines for variant classification.

Main Results:

• A novel heterozygous intronic CDKN1C variant (c.787+4A>T) was identified, predicted to disrupt splicing.
• The variant was maternally inherited and classified as a Variant of Uncertain Significance (VUS).
• No other pathogenic variants were found in relevant genes.

Conclusions:

• This finding expands the genetic spectrum of IMAGe syndrome by reporting the first intronic CDKN1C variant.
• WES is crucial for diagnosis; RNA analysis is recommended for functional confirmation.
• Prompt diagnosis is vital for managing potentially life-threatening adrenal insufficiency.