Trio exome reveals PSMC5-associated neurodevelopmental proteasomopathy in an 18-year-old male with mild ID, microcephaly, and facial dysmorphism

We describe an 18-year-old male, born to healthy, non-consanguineous parents with no relevant family history. He was delivered at 38 + 2/7 weeks of gestation after an unremarkable prenatal course, with normal birth weight, length, and head circumference. At birth, he presented with neonatal hypotonia resulting in feeding difficulties, a small patent foramen ovale (PFO), and left hip instability. He subsequently underwent orchidopexy for right cryptorchidism. Regarding motor milestones, independent sitting was achieved at 12 months and walking at 15 months (with kinesiotherapy support), with delayed fine motor development. Language was delayed: first words appeared at 3 years and first sentences at 10 years, and he exhibited stuttering. Behavioral features included compulsive and aggressive behavior, with suspicion of autism spectrum disorder (ASD) though never formally diagnosed. Neuropsychological evaluation revealed mild intellectual disability. No regression was noted. He also had myopia (–3 diopters bilaterally) and astigmatism as well as conductive mild unilateral hearing loss. Clinical examination at 18 years showed microcephaly (occipitofrontal circumference 51.5 cm) and bilateral fifth-finger clinodactyly. Dysmorphic features included a broad, flat forehead; upslanting palpebral fissures; a narrow nasal bridge; long, flat philtrum with thin upper lip; downturned corners of the mouth; and micrognathia. Brain MRI and EEG were normal. Trio exome sequencing identified a de novo variant in PSMC5 (NM_002805.6: c.653A>T, p.Glu218Val). No other relevant variants were detected, and SNP-array as well as FMR1 analysis were non-contributory.