Meier‐GORLIN Syndrome Caused by Compound Heterozygous CDC6 Variants

Meier‐Gorlin syndrome (MGORS) is a rare primordial dwarfism syndrome characterized by the triad of pre‐ and postnatal growth restriction, microtia, and patellar aplasia or hypoplasia. Pathogenic variants in genes involved in DNA replication licensing and initiation have been implicated in MGORS, including the uncommon disease‐associated gene CDC6 , for which only two affected families have been reported to date. We report a male infant born at 37 weeks' gestation to a 40‐year‐old primigravida via cesarean delivery due to intrauterine growth restriction and fetal intolerance of labor. He presented with severe proportionate short stature (40 cm at birth; Z score −5.22), microcephaly, bilateral microtia, cryptorchidism, hypospadias, nonpalpable patellae, and characteristic facial features including a tiny mouth and short palpebral fissures. Cardiac evaluation was normal. He developed persistent respiratory insufficiency requiring prolonged respiratory support and remains hospitalized due to tracheobronchomalacia and chronic respiratory failure. A clinical diagnosis of MGORS was suspected. Targeted gene panel testing identified a heterozygous variant in CDC6 , c.920_927del (p.Ser307ThrfsTer9). Trio genome sequencing subsequently identified a second rare intronic variant, CDC6 c.461‐24A>G, and confirmed that the variants were in trans . A minigene splicing assay demonstrated retention of intron 3 associated with c.461‐24A>G, resulting in a predicted frameshift, p.Thr155LeufsTer8, and likely nonsense‐mediated decay. We report the third family with CDC6‐associated MGORS and provide functional evidence supporting the pathogenicity of a novel intronic CDC6 variant. These findings expand the mutational spectrum of CDC6 ‐related MGORS and highlight the importance of functional studies in the interpretation of noncanonical splice variants.