Neonatal Encephalopathy: Novel Phenotypes and Genotypes Identified by Genome Sequencing

Area of Science:

• Genetics
• Neonatal Medicine
• Genomic Analysis

Background:

• Neonatal encephalopathy (NE) affects 1-6/1,000 live term newborns, presenting as altered consciousness or seizures.
• Investigating the genetic underpinnings of NE is crucial for diagnosis and understanding disease mechanisms.

Purpose of the Study:

• To identify the genetic causes of neonatal encephalopathy (NE) in term newborns using genome sequencing (GS).

Main Methods:

• Genome sequencing (GS) was performed on 17 term newborns with NE and their parents (trio analysis).
• Bioinformatic pipelines, in silico prediction tools, protein 3D modeling, and functional characterization were employed to assess variant pathogenicity.
• Manual filters and specific analytical tools were developed to analyze the sequencing data.

Main Results:

• Twelve variants in 10 genes were identified in 17 newborns.
• Four pathogenic/likely pathogenic variants were found in known disease genes (PPP2R5D, BCOR, CFL2, SCN2A).
• Seven variants of uncertain significance (VUS) were identified in known and candidate genes (DST, STAB2, CELF4, SORCS2, CTNND2, ASTN1). Functional characterization confirmed pathogenicity for SORCS2 VUS and reclassified STAB2 variants.

Conclusions:

• Genome sequencing achieved a 41% diagnostic rate for NE in this prospective study.
• The study expanded the phenotypic spectrum of several known genetic syndromes to include NE.
• Three candidate genes (SORCS2, CELF4, ASTN1) were identified as potential causes of NE, highlighting the importance of functional characterization and protein modeling in genetic discovery.