Whole exome sequencing identifies genetic basis of two challenging cases with metabolic disorders

Case I. We report a 3-year-old boy from non-consanguineous parents. No signs were seen at birth. Later, he was suspected of the mucopolysaccharidosis (MPS) owing to the appearance of the symptoms such as short stature, coarse face, corneal opacity, frequent upper respiratory tract infections and otitis media. The metabolic test had been revealed the alpha L iduronidase deficiency. The NGS for MPS genes did not reveal any causative variant. Afterward, whole exome sequencing (WES) was performed. Not any promising variant remained in the filtered file. Coverage analysis of the binary alignment map (BAM) file identified a pathogenic start-loss variant ENST00000247933.9:c.1A> C (p.Met1Leu) in the IDUA gene. The variant was missing from vcf file due to low read and depth. Mutation confirmation test confirmed the homozygous variant in the proband and both parents were carrier for c.1A> C variant.Case II. We present an 18-month-old male patient from consanguineous parents. Immediately from the second day after birth, the symptoms were manifested by weakness, anemia, respiratory problems and apnea, developmental delay, and seizure. He also had a sib who deceased at 40 days after birth may due to metabolic disorder. Following the appearance of the signs and symptoms, the metabolic test was carried out and shown an elevated level of blood ammonia. Moreover, urine examination exhibited an increased amount of 3-hydroxypropionic acid, glutaric acid, 3-hydroxyisovaleric acid, and methylcitric acid which are probably corresponding to propionic academia. To identify the causative variant, WES was performed and data were analyzed. Surprisingly, there was not any pathogenic variant in propionic academia causing genes (PCCA and PCCB) or related disorders’ genes. Considering the probably low coverage, we analyzed the PCCA and PCCB regions in the BAM file. The PCCB gene was completely covered and there was not any pathogenic mutation in the region. However, in the PCCA gene between exons 12 to 21 we identified that were not covered. This region with the size of approximately 220kb probably was deleted and we successfully identified by WES technique.

کلیدواژه ها:

: Mucopolysaccharidosis ، IDUA gene ، Propionic academia ، PCCA gene ، Whole exome sequencing