Clinical and Genetic Characteristics with Dual-Positive Gene Variations

Li Wang^1*Xiaojing Yin¹Jinghe Shi²Pingyun Qiao²Fuwei Li²

• ¹Department of Neurology, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Children’s Hospital Affiliated of Zhengzhou University, Zhengzhou, China
• ²Department of Neurology, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Department of Neurology, Children’s Hospital Affiliated of Zhengzhou University, Zhengzhou, Henan Province, China

Objective: This study aims to examine the clinical and genetic characteristics associated with dual-positive gene variations. Methods: A retrospective analysis was performed on two pediatric patients diagnosed with dual-positive gene variations. Results: Patient 1, a 7-year-old female, presented with a low hairline, microcephaly, high-arched and thick eyebrows, a short nasal bridge, a thin and red upper lip, and a high palatal arch. She exhibited delayed language and motor development. Genetic analysis revealed de novo variations in the SMC3 and MECP2 genes. Patient 2, a 1.5-year-old male, exhibited high-arched eyebrows, long eyelashes, large ears, microcephaly, a single transverse palmar crease, a curved fifth finger, hand and foot tremors, external foot rotation, and an unsteady gait. He was unable to squat, and exhibited reduced muscle strength in the distal lower limbs. Electromyography indicated neurogenic damage. Additional findings included patent ductus arteriosus and a mildly abnormal auditory response. Genetic analysis identified a de novo variation in the SMC3 gene and a 1.38 Mb pathogenic haploid duplication at the PMP22 gene, which was also present in the proband's father. The PMP22 gene duplication was additionally observed in the proband's cousin,aunt, and grandfather. Conclusion: The study highlights the clinical manifestations and genetic variations associated with dual-positive gene variations, emphasizing the importance of genetic analysis in understanding the phenotypic spectrum and familial transmission of these conditions. We identified a rare pediatric case of Cornelia de Lange syndrome type 3 (CDLS3) associated with significant cognitive impairment attributable to variations in the SMC3 and MECP2 genes. Furthermore, the non-Rett syndrome phenotype linked to the MECP2 gene variation may exacerbate the cognitive deficits observed. Additionally, we encountered an unusual case of CDLS3 co-occurring with Charcot-Marie-Tooth disease type 1A. This highlights the importance of considering multiple genetic variations when the clinical phenotype cannot be solely explained by a single gene.