SEPSECS – pontocerebellar hypoplasia type 2

SEPSECS encodes the O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase critical for selenoprotein biosynthesis and is designated HGNC:30605. Biallelic pathogenic variants in SEPSECS cause autosomal recessive pontocerebellar hypoplasia type 2, a condition marked by global developmental delay and progressive cerebellar atrophy. Clinical and experimental data converge to support a definitive gene–disease relationship that informs diagnosis, genetic counseling, and potential therapeutic strategies.

In a cohort study, recessive SEPSECS mutations were identified in 11 previously reported patients with pontocerebellar hypoplasia type 2, and two additional unrelated probands were characterized by whole-exome sequencing (total 13 probands) (PMID:26888482). Both new families harbored compound heterozygous variants: c.356A>G (p.Asn119Ser) and c.77delG (p.Arg26ProfsTer42) in one, and c.356A>G (p.Asn119Ser) with c.467G>A (p.Arg156Gln) in the other. All affected individuals presented with mild developmental delay in infancy despite normal early MRI, followed by progressive cerebellar atrophy on imaging and persistent motor impairment. Parental segregation confirmed recessive inheritance in each family.

The variant spectrum in pontocerebellar hypoplasia type 2 includes missense and predicted loss-of-function alleles, with recurrent use of p.Asn119Ser in multiple families. The exemplar variant c.356A>G (p.Asn119Ser) has been observed in trans with frameshift alleles, consistent with biallelic loss of SEPSECS activity.

Functional assays in patient fibroblasts and bacterial expression systems demonstrate partial but significant reduction of SEPSECS enzymatic activity, leading to decreased selenoprotein levels and increased oxidative protein damage in neural tissues (PMID:26115735). This partial loss-of-function mechanism aligns with the slowly progressive cerebellar degeneration observed clinically.

Mechanistically, defective Sec-tRNA[Ser]Sec biosynthesis disrupts neuronal redox homeostasis, sensitizing cerebellar neurons to oxidative stress. The concordance between in vitro activity assays, patient biochemical profiles, and neuroimaging phenotypes supports pathogenicity of biallelic SEPSECS variants.

Collectively, 13 probands across 11 families with confirmed biallelic segregation, a consistent phenotype of global developmental delay (HP:0001263) and cerebellar atrophy (HP:0001272), and supportive functional data establish a Strong ClinGen level of evidence for SEPSECS in pontocerebellar hypoplasia type 2. Routine inclusion of SEPSECS in diagnostic panels is recommended to facilitate early genetic diagnosis and family planning.

References

• Journal of human genetics • 2016 • Milder progressive cerebellar atrophy caused by biallelic SEPSECS mutations. PMID:26888482
• Neurology • 2015 • Selenoprotein biosynthesis defect causes progressive encephalopathy with elevated lactate. PMID:26115735

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