Novel pyrroline-5-carboxylate reductase 2 (PYCR2) mutation in an Iranian patient with hypomyelinating leukodystrophy: findings of molecular and in silico investigations

Background Hypomyelinating leukodystrophy (HLD) is a specific group of leukodystrophies and is characterized by progressive postnatal growth delay that represents a type of clinically overlapping but genetically heterogeneous diseases with autosomal recessive inheritance. Loss-of-function mutations in PYCR2 are one of the main causes of HLD type 10 (HLD10), which is identified by cerebral hypomyelination, inadequate growth, brain atrophy, and movement abnormality. This study aimed to investigate the molecular etiology of HLD10 disorder in an Iranian patient from a consanguineous marriage family. Results The DNA samples were extracted from the patient, a 9-year-old girl, and her parents. Whole-exome sequencing was conducted for these samples and the results were eventually confirmed and segregated via Sanger sequencing. Our findings demonstrated a novel homozygous frameshift mutation in PYCR2 gene, c.135dup (NM_013328.4). The heterozygous state of this variant was confirmed in parents. Additionally, this mutation was predicted to exhibit damaging effects through protein sequence alteration. Conclusions Such findings are of importance for understanding the underlying pathogenicity mechanisms and for improving genetic counseling knowledge of HLD patients for families.