A homozygote variant in the tRNA splicing endonuclease subunit 54 causes pontocerebellar hypoplasia in a consanguineous Iranian family

BACKGROUND: Homozygous loss‐of‐function mutations in TSEN54 (tRNA splicing endonuclease subunit 54; OMIM: 608755) cause different types of pontocerebellar hypoplasias (PCH) including PCH2, PCH4, and PCH5. The study aimed to determine the possible genetic factors contributing to PCH phenotypes in two affected male infants in an Iranian family. METHODS: We subjected two affected individuals in a consanguineous Iranian family. To systematically investigate the susceptible gene(s), whole‐exome sequencing was performed on the proband and a novel identified variant was confirmed by Sanger sequencing. We also analyzed 26 relatives in three generations using PCR‐restriction fragment length polymorphism (PCR‐RFLP) followed and confirmed by Sanger sequencing. RESULTS: Physical and medical examinations confirmed PCH in the patients. Besides, the proband showed bilateral moderate sensorineural hearing loss and structural heart defects as the novel phenotypes. The molecular findings also verified that two affected individuals were homozygote for the novel synonymous variant, NM_207346.2: c.1170G>A; p.(Val390Val), in TSEN54. PCR‐RFLP and Sanger sequencing elucidated that the parents and 16 relatives were heterozygote for the novel variant. CONCLUSION: We identified a novel synonymous variant, c.1170G>A, in TSEN54 associated with PCH in an Iranian family. Based on this study, we strongly suggest using “TSENopathies” to show the overlapped phenotypes among different types of PCH resulted from TSEN causative mutations.