Exome Sequencing Analysis and Clinical Features of a Chinese Patient with 3M Syndrome and A Review of Literature.

Background: 3M syndrome is a rare autosomal recessive genetic disorder characterized by significant intrauterine and postnatal growth restriction. There is limited research on its genetic basis within the Chinese population.

Methods: We performed trio-based whole-exome sequencing to identify the pathogenic gene in the affected child and collected and organized clinical and imaging data. Relevant information was reviewed through a literature search.

Results: In this study, we present a case involving prenatal diagnostic abnormalities and postnatal confirmation of 3M syndrome, including detailed documentation of clinical features and associated genetic variants. Notably, during prenatal ultrasound examination, the fetus exhibited increased nuchal translucency (NT) and delayed limb development. Postnatally, whole-exome sequencing revealed the compound heterozygous mutations in the CUL7 gene: c.3646-2A>G and c.3355+5G>A. The splicing mutation c.3646-2A>G is a novel pathogenic mutation, while the c.3355+5G>A mutation has been previously reported. In-silico analysis predicted strong pathogenicity for both splicing mutations. Through follow-up, we observed that the patient's height and weight are below the first percentile, with abnormal skeletal development and distinctive facial features. Based on literature review of reported cases, these mutations disrupt the normal function of CUL7-OBSL1-CCDC8 complex in the ubiquitin-proteasome pathway, leading to impaired growth regulation.

Discussion: This study identified a novel splicing mutation in the CUL7 gene in a patient with 3M syndrome, expanding the genetic spectrum of this disorder and contributing novel insights for clinical diagnosis and management.