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.