Multilocus pathogenic variants in MCM4, RYR1, and G6PD identified by trio-based whole-exome sequencing in a neonate...

Multilocus pathogenic variants are increasingly recognized in neonates with complex phenotypes and have important implications for diagnosis and clinical management. Reporting such cases helps expand the phenotypic spectrum and improve clinical understanding of blended genetic disorders.

We describe a rare case of a male neonate born at 38+5 weeks of gestation with a birth weight of 1.73 kg, consistent with small-for-gestational-age status. The infant presented with perinatal asphyxia requiring 37 minutes of resuscitation, followed by hypotonia, poor feeding, a weak cry, and reduced responsiveness. Laboratory investigations revealed anemia, hyperbilirubinemia, and G6PD deficiency. He received supportive care in the neonatal intensive care unit (NICU) and was discharged in stable condition with planned follow-up. Trio-based whole-exome sequencing (trio-WES) identified compound heterozygous missense variants in MCM4 (c.1829G>A and c.2179G>C), compound heterozygous variants in RYR1 (c.11608+1G>A and c.13660-29G>A), and a hemizygous pathogenic variant in G6PD (c.482G>T, p.Gly161Val), each inherited from one parent. To our knowledge, this combination of variants has not been previously reported. At 18-month follow-up, the infant exhibited delayed motor and language development, unsteady gait, and had 14 hospital visits due to recurrent respiratory infections.

This case highlights the potential for blended phenotypes caused by multilocus variation and underscores the diagnostic value of trio-WES in neonates with unexplained multisystem involvement. Long-term follow-up and multidisciplinary management remain essential for such patients.