Novel de novo ARCN1 intronic variant causes rhizomelic short stature with microretrognathia and developmental delay

Timothy Tidwell, Malia Deshotel, Janice Palumbos, Chris Miller, Pinar Bayrak-Toydemir, John C Carey
Cold Spring Harbor Molecular Case Studies 2020 November 5
The archain 1 (ARCN1) gene encodes the coatomer subunit delta protein and is a component of the COPI coatomer complex, which is involved in retrograde vesical trafficking from the Golgi complex to the endoplasmic reticulum. Variants in ARCN1 have recently been associated with rhizomelic short stature with microcephaly, microretrognathia, and developmental delay. Here we report a 3.5- year-old boy with microcephaly, global developmental delay, and multiple congenital abnormalities and the ARCN1-related syndrome caused by a novel de novo intronic variant. Whole exome sequencing of the proband and his parents was utilized to determine the genetic origin of the patient's disorder and identified a de novo variant, NM_001655.5:c.654-15A>G, in the ARCN1 gene. Follow up functional characterization of mRNA from the patient demonstrated that this variant creates a splicing defect of the ARCN1 mRNA. ARCN1-related syndrome represents an emerging disorder of developmental delay, and this report represents the sixth described patient. Despite the few instances reported in literature, the phenotype is consistent between our patient and previously reported individuals.

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