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Keywords: Exome sequencing; Genotype-phenotype correlations; Intellectual and developmental disability; Mendelian disorder; Nervous system

H. Cheng 1; S. Capponi 2; E. Wakeling 3; E. Marchi 4; Q. Li 5; M. Zhao 6; C. Weng 7; S. Piatek 8; H. Ahlfors 8; R. Kleyner 9; A. Rope 10; A. Lumaka 11; P. Lukusa 11; K. Devriendt 12; J. Vermeesch 12; J. Posey 1; E. Palmer 13; S. Moutton 14; P. Mark 15; L. Adès 16; S. Sandaradura 16; J. Lupski 1; T. Roscioli 17; P. Agrawal 18; A. Kline 19; K. Wang 6; H. Timmers 2; G. Lyon 4,9

1) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, USA; 2) Medical Faculty-University of Freiburg, Freiburg, Germany; 3) North West University Healthcare NHS Trust, Harrow, UK; 4) Institute for Basic Research in Developmental Disabilities (IBR), Staten Island, USA; 5) University of Toronto, Toronto, Canada; 6) Children's Hospital of Philadelphia, Philadelphia, USA; 7) Columbia University Medical Center, New York, USA; 8) Great Ormond Street Hospital, London, UK; 9) Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, USA; 10) Genome Medical, South San Francisco, USA; 11) University of Kinshasa, DR Congo; 12) University of Leuven, Leuven, Belgium; 13) University of New South Wales, Randwick, Australia; 14) Bordeaux University Hospital, Bordeaux, Bordeaux, France; 15) Spectrum Health, , Grand Rapids, USA; 16) The Children’s Hospital at Westmead, Sydney, Australia; 17) Sydney Children's Hospital, Randwick, Australia; 18) Boston Children's Hospital, Boston, USA; 19) Harvey Institute for Human Genetics at GBMC, Baltimore, USA.

Purpose: We recently described a new neurodevelopmental syndrome caused by mutations involving the X-linked gene, TAF1, in 11 families. These individuals with missense variants or a duplication involving TAF1 - encoding a subunit of basal factor TFIID for RNA polymerase II transcription - were shown to present early in life with hypotonia, developmental delay, and characteristic facial features, followed by later diagnoses of intellectual disability (ID) and/or autism spectrum disorder (ASD). We investigated TAF1 rare variant genotype/phenotype correlations, hypothesizing a broader clinical phenotypic spectrum for this disorder, by identifying additional families through a genotype-first approach.

Methods: Families were identified through an international collaboration and primarily clinically-based sequencing. Variants of interest were identified with a range of bioinformatic approaches, followed by molecular modelling for those variants falling within structurally characterized domains of TAF1. Phenotyping cluster analysis was also performed using Human Phenotype Ontology (HPO) terms.

Results: We studied a total of 27 families, each with a distinct variant in TAF1. We used familial segregation analysis, clinical phenotyping, bioinformatics, molecular modelling, and clustering approaches to determine whether these variants contribute to the clinical phenotypes. We determined that five of these variants are likely benign, ten of the de novo variants are likely pathogenic, and the remaining twelve maternally inherited variants remain of uncertain significance. Two of the de novo variants occurred in females with significant skewing of X-chromosome inactivation. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability in their presentation, including autism spectrum disorder, brain anomalies (e.g. ventriculomegaly and corpus callosum abnormalities), seizures, hearing loss, and cardiac malformations.

Conclusion: Our allelic series data reveal that likely damaging TAF1 variant alleles can result in a broad phenotypic spectrum for TAF1 syndrome, whilst also broadening the range of molecular defects in TAF1 observed in human neurodevelopmental disorders. It also illustrates the current difficulties in assigning pathogenicity to inherited missense variants.