Whole-exome sequencing as a powerful tool for identifying genetic causes in a patient with POLG-related disorders and phenylketonuria.

Objective This study's aim was to identify the genetic causes in a patient with phenylketonuria and hearing loss, liver disease, developmental and mental retardation, hypotonia, and external ophthalmoplegia. Methods Whole-exome sequencing and Sanger sequencing analysis were used to determine the genetic causes of manifestations in a young boy with hearing loss, liver disease, develop-mental and mental retardation, hypotonia, and external ophthalmoplegia. Results We found that the child harbored polymerase gamma (POLG) compound heterozygous mutations, c.2617G>A (p.E873K) and c.3550G>A (p.D1184N), and phenylalanine hydroxylase (PAH) compound heterozygous mutations, c.721C>T (p.R241C) and c.728G>A (p.R243Q). Among them, the POLG p.E873K mutation is a novel mutation and is not present in the Exome Aggregation Consortium database, Genome Aggregation database, and 1000 Genomes database. The two heterozygous mutations were each inherited from both of the child's parents. This finding suggested that the phenotype and the genotype were segregated. Conclusion Using whole-exome sequencing, we not only identified PAH mutations causing phenylketonuria, but also identified the genetic cause of the mitochondrial disease and found a novel POLG mutation. Our findings could be useful in helping future parents obtain healthy embryos through assisted reproductive technology.