Molecular diagnosis due to a hemizygous TAF1 Variant

This case report describes an 8-year-old male with a complex clinical presentation characterized by global developmental delay and refractory epilepsy. His medical history is significant for a term birth complicated by umbilical cord avulsion during a water delivery. His birth measurements were a weight of 2600g, a body length of 49cm, and a head circumference of 34.5cm, with APGAR scores of 6, 8, and 8 at one, five, and ten minutes, respectively. A postaxial hexadactyly was noted at birth and subsequently underwent surgical correction. The patient exhibited profound developmental delays, achieving independent ambulation at 6 years of age and remaining nonverbal. He developed epilepsy at one year of age with seizures that have been refractory to treatment with cannabidiol (CBD) and clobazam. His co-morbidities include gastrointestinal dysfunction and exocrine pancreatic insufficiency. There was no known family history of similar disorders.

Given the constellation of symptoms, whole-genome sequencing was performed. This revealed a hemizygous missense variant in the TAF1 gene (NM_004606.5:c.1726C>T;p.(P576S)). The patient's mother was identified as a heterozygous carrier of this variant. No other family members had similar known disorders. Pathogenic variants in TAF1 are known to cause an X-linked intellectual disability syndrome. This specific variant had been previously reported in a family with developmental delay, as described by O'Rawe et al. in 2015. Subsequent studies have expanded the phenotypic spectrum associated with TAF1 mutations to include seizures and polydactyly, consistent with this patient's presentation.