Novel fetal phenotype of TAF8 deficiency

TAF8 is part of the transcription factor TFIID complex. TFIID is crucial for recruiting the transcription factor complex containing RNA polymerase II. TAF8 deficiency was recently reported as causing a severe neurodevelopmental disorder in eight patients. We have ascertained three Muslim Arab couples with fetal brain malformations. Clinical, imaging, pathological, biochemical, and molecular analyses were performed. Pre-natal ultrasound performed in four pregnancies revealed massive cerebellar atrophy, microcephaly, cerebral and corpus callosum (CC) anomalies. Pre-natal MRI studies of two of the affected fetuses confirmed microcephaly, small vermis, abnormal sulcation pattern with malformation, and shortening of CC. The fetuses were found to carry a novel likely pathogenic homozygous variant (c.45 + 5 G > A) of TAF8, predicted to affect splicing and presenting autosomal recessive inheritance. Post-mortem examinations confirmed the imaging studies in one fetus. Dysmorphic features including hypertelorism, wide nasal bridge, clinodactyly, and hirsutism were present. Western blotting analysis in fibroblasts of an affected fetus demonstrated a significant reduction of TAF8 protein. We determined high expression levels of TAF8 which progressively diminish in fetal brains of WT mice. We report for the first time the fetal presentation of TAF8 deficiency due to a novel genetic variant, and study TAF8 presence during fetal and neonatal periods in mouse brains. Our study may contribute to understanding the role of TAF8 in the developing human brain.