Further delineation of the phenotype and genotype in a newly identified PAN2-related disorder

Area of Science:

• Molecular Biology
• Genetics
• Developmental Biology

Background:

• mRNA decay is crucial for gene expression, with poly(A) tail shortening (deadenylation) playing a central role.
• The PAN2 gene encodes a key protein in the deadenylation pathway.
• Previous studies linked PAN2 loss-of-function variants to neurodevelopmental delay and congenital anomalies.

Purpose of the Study:

• To report two siblings with neurodevelopmental delay and congenital anomalies consistent with PAN2-related disorder.
• To identify the genetic cause in these siblings.
• To expand the understanding of the clinical and genotypic spectrum of PAN2-related disorder.

Main Methods:

• Clinical evaluation of two siblings presenting with neurodevelopmental delay and congenital anomalies.
• Whole-exome sequencing (WES) to identify genetic variants.
• Segregation analysis to confirm variant inheritance.

Main Results:

• The siblings presented with neurodevelopmental delay, multiple congenital anomalies, esophageal atresia (EA), and developmental dysplasia of the hip (DDH).
• WES identified a novel homozygous nonsense variant in PAN2 (c.1432C>T, p.Arg478Ter) in the affected sibling.
• Segregation analysis confirmed the variant was homozygous in the affected sibling and carried by unaffected family members.

Conclusions:

• This study expands the genotypic spectrum of PAN2-related disorder.
• Esophageal atresia and developmental dysplasia of the hip are suggested as additional clinical features of this emerging disorder.
• Further research is needed to fully elucidate the role of PAN2 in development and disease.