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Unravelling the disease mechanism for TSPYL1 deficiency.

We describe a lethal combined nervous and reproductive systems disease in three affected siblings of a consanguineous family. The phenotype was characterized by visceroautonomic dysfunction (neonatal bradycardia/apnea, feeding problems, hyperactive startle reflex), severe postnatal progressive neurological abnormalities (including abnormal neonatal cry, hypotonia, epilepsy, polyneuropathy, cerebral gray matter atrophy), visual impairment, testicular dysgenesis in males, and sudden death at infant age by brainstem-mediated cardiorespiratory arrest. Whole exome sequencing revealed a novel homozygous frameshift variant p.Val242GlufsTer52 in the TSPY-like 1 gene TSPYL1. The truncated TSPYL1 protein that lacks the nucleosome assembly protein (NAP) domain was retained in the Golgi of fibroblasts from the three patients while control fibroblasts express full length TSPYL1 in the nucleus. Proteomic analysis of nuclear extracts from fibroblasts identified 24 up- and 20 down-regulated proteins in the patients compared to five controls with 'regulation of cell cycle' as the highest scored biological pathway affected. TSPYL1 deficient cells had prolonged S and G2 phases with reduced cellular proliferation rates. Tspyl1 depletion in zebrafish mimicked the patients' phenotype with early lethality, defects in neurogenesis and cardiac dilation. In conclusion, this study reports the third pedigree with recessive TSPYL1 variants, confirming that TSPYL1 deficiency leads to a combined nervous and reproductive systems disease, and provides for the first time insights into the disease mechanism.