ClinVar

In 4 brothers from a family of American and European ancestry with pontocerebellar hypoplasia type 1B (PCH1B; 614678), Wan et al. (2012) identified a homozygous 395A-C transversion in exon 2 of the EXOSC3 gene, resulting in an asp132-to-ala (D132A) substitution in a highly conserved residue in the putative RNA-binding S1 domain, which may be important for intersubunit interaction within the exosome complex. The mutation was identified by genomewide scan and exome sequencing, and confirmed by Sanger sequencing. Sequencing of this gene identified the same homozygous mutation in affected individuals from 3 additional families with the disorder; 2 of these families were consanguineous. Haplotype analysis of 3 of the families with a homozygous D132A mutation was consistent with a remote common ancestor. Affected individuals in 3 additional families carried the D132A mutation in compound heterozygosity with another pathogenic mutation in the EXOSC3 gene (see, e.g., 606489.0002 and 606489.0003). All available parents were unaffected and heterozygous for 1 of the mutations, which were not found in 379 control individuals. The phenotype consisted of neonatal onset of severe hypotonia, often with respiratory insufficiency, and global developmental delay, without achieving any motor milestones or speech, and progressive microcephaly. Other features included oculomotor apraxia, progressive muscle wasting, and distal contractures. Brain MRI showed marked cerebellar and pontine atrophy. Postmortem examination showed severe loss of cerebellar and spinal motor neurons.

In 2 teenaged sibs of Bangladeshi descent with PCH1B, Zanni et al. (2013) identified compound heterozygous mutations in the EXOSC3 gene: D132A, and a c.238G-T transversion, resulting in a val80-to-phe (V80F; 606489.0006) substitution at a conserved residue in the N-terminal domain. The mutations were found by exome sequencing and filtered against the dbSNP (build 135) and 1000 Genomes Project databases; D132A was observed in 6 of 4,870 control exomes (allele frequency of 0.0012). The unaffected parents and 2 unaffected sibs were heterozygous for 1 of the mutations. Functional studies of the variants were not performed. The patients had a relatively mild form of the disorder, with delayed motor development, onset of spasticity in childhood, and mild to moderate intellectual disability, but without hypotonia or microcephaly. The report expanded the phenotypic spectrum associated with EXOSC3 mutations to include hereditary spastic paraplegia.