Novel fetal phenotype of TAF8 deficiency

Abstract

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.

Fig. 1. Causative genetic variant in TAF8.

A Pedigree of the extended Muslim family presenting a novel pathogenic genetic variant in TAF8. B Splicing sequence alignment in TAF8 orthologs shows high conservation of the c.45 + 5 G > A variant (highlighted in yellow) and almost complete conservation of the nearby residues (highlighted in light blue). C Schematic representation of TAF8 gene (bars = exons) and previously reported pathogenic variants including the novel variant c.45 + 5 G > A reported here for the first time.

Fig. 2. US, MRI, and pathological analysis of affected fetuses.

A Ultrasound of brain at 19 weeks of VI13 demonstrating hypoplastic cerebellum (measurement between two calipers +) and enlarged cisterna magna. B MRI images of the three fetuses studied (VI13, VI14, VI15): axial T2 (A1, A2) and axial T1 (A3)—flat open sylvian fissure with small frontal lobes. Sagittal T2 (B1–B3)—dysmorphic corpus callosum (short and thick). Abnormal brain stem with flat pons. Abnormal small vermis, open fastigium, no primary fissure. Coronal T2—small TCD (C1–C3), abnormal gyral pattern (arrow) (D1, D2). C Affected TAF8 deficiency, fetal brain, showing leptomeningeal glioneuronal heterotopia (arrows), magnification—×10. D Demonstrating partial agenesis of the CC (circle) and intact parts of the CC (arrows), magnification—×2.

Fig. 3. TAF8 protein and mRNA levels are reduced in an affected fetus.

A mRNA multiplex analysis of TAF8 in affected fetal (P) and normal control (N) fibroblasts. B WB analysis of TAF8 in affected fetal fibroblasts (P) and normal controls (N). ***p < 0.001 T-test, n = 3 in each group. C WB analysis of TAF8 at different developmental stages in mice. ***p < 0.001 one-way ANOVA test, n = 3 in each group.