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TSEN2 has emerged as an important gene implicated in pontocerebellar hypoplasia, a neurodegenerative disorder primarily characterized by cerebellar and pontine hypoplasia, progressive microcephaly, hypotonia, and seizures. The disease follows an autosomal recessive inheritance pattern, with affected individuals typically harboring biallelic mutations that disrupt normal TSEN2 function.
In an initial case report, a male patient presented with progressive microcephaly (HP:0000253), severe hypotonia, and myoclonic-tonic seizures. Molecular analysis uncovered two TSEN2 variants, including a novel nonsense mutation, c.691C>T (p.Gln231Ter) (PMID:23562994), which was shown to lead to premature termination likely resulting in loss-of-function. This observation was reinforced by similar biallelic findings in additional probands.
Further evidence from a multi‐patient study described an intronic founder mutation in TSEN2 that leads to aberrant splicing. In this study, six affected individuals from four consanguineous families demonstrated a consistent clinical picture combining craniofacial and central nervous system malformations with features of pontocerebellar hypoplasia (PMID:34964109). These studies collectively provide robust genetic data across multiple families and variant types, underlining the pathogenic role of TSEN2 in the disease.
Genetic studies have revealed a diverse variant spectrum in TSEN2, including missense, nonsense, and frameshift changes. The recurrent identification of the nonsense variant c.691C>T (p.Gln231Ter) in affected individuals underscores its diagnostic relevance. Segregation analyses in these reports further support a causative role as affected family members consistently demonstrated biallelic variants.
Functional assessments, including RT-PCR and RNA sequencing, have confirmed that TSEN2 mutations lead to abnormal splicing and impaired tRNA processing. Zebrafish morpholino experiments recapitulated key aspects of the human phenotype, providing experimental support that loss-of-function is the underlying mechanism of TSEN2-associated pontocerebellar hypoplasia (PMID:34964109).
Although TSEN2 has also been implicated in syndromes with overlapping features such as atypical hemolytic uremic syndrome, the clinical presentation in the context of pontocerebellar hypoplasia remains distinct. The totality of genetic and functional evidence, integrated from both single-case reports and multi-patient studies, supports a strong gene–disease association.
In summary, comprehensive clinical, genetic, and functional evaluations strongly link TSEN2 mutations to pontocerebellar hypoplasia. This association is crucial for advancing diagnostic precision, facilitating commercial test development, and guiding future research and publication in the field.
Key Take‑home message: TSEN2 is a strong candidate gene for pontocerebellar hypoplasia, and its evaluation should be integral to genetic diagnostic workflows for neurodegenerative disorders of early childhood.
Gene–Disease AssociationStrongMultiple independent studies report biallelic TSEN2 mutations in patients with pontocerebellar hypoplasia. Evidence from case reports and multi‐patient analyses, including at least 7 probands (PMID:23562994) and segregation in consanguineous families (PMID:34964109), supports this association. Genetic EvidenceStrongSeveral classes of deleterious TSEN2 variants, including the nonsense mutation c.691C>T (p.Gln231Ter), have been identified in affected individuals across independent studies. The replication of these findings in multiple families confirms the gene’s pathogenic role. Functional EvidenceModerateFunctional assays, including RT-PCR, RNA sequencing, and zebrafish models, have demonstrated that TSEN2 mutations lead to defective splicing and impaired tRNA processing, consistent with a loss-of-function mechanism. |