PSMC5-associated neurodevelopmental proteasomopathy in an 8-year-old male with syndromic ID, including short stature, cardiac defects, optic nerve hypoplasia and facial dysmorphism

We present an 8-year-old boy of European ethnicity, the younger of two children from unrelated parents. Features included mild chronic thrombocytopenia, short stature, bilateral optic nerve hypoplasia, mixed hearing loss and global developmental delay. He had sub-aortic stenosis and underwent shelf resection for this aged 3 years. He had an undescended testicle, noted age 7 years and a successful orchidopexy was performed. Other features of note were joint hypermobility, strabismus, myopia and some subtle facial dysmorphism; thin upper lip, triangular face, smooth philtrum and downturned corners of the mouth.
Skeletal survey did not show any convincing pattern of disproportionate shortening. MRI head performed aged 2 years which showed normal myelination.
His initial karyotype and array CGH were normal and further gene sequencing of PTPN11, GJB2 and GJB6 revealed no variants. He was enrolled in the DDD (Deciphering Developmental Disorders) study which revealed a variant of unknown significance in the TRAPPC2 gene, which was maternally inherited. This gene is known to cause SED tarda and given that this was not in keeping with his phenotype, it was dismissed as the cause for his phenotype.
Our patient then went on to be enrolled in the 100,000 Genomes Project (100KGP) and the primary analysis results identified no causative variants – the applied gene panels being ‘Intellectual Disability v2.395 and Inherited Bleeding Disorders v1.115. The 100KGP data was analysed via an interpretation portal in-house prior to seeing the family in clinic. A research variant in PSMC5 gene –heterozygous missense c.973C>T; p.Arg325Trp was discovered, denovo.