Dysmorphic features, macrocephaly, intellectual disability and congenital heart defect due to TAF1 variant

*Correspondence: [e-mail].

Abstract

Case Presentation: The patient was the second child of healthy non-consanguineous parents. He was full-term, born in a cesarean birth due to congenital pulmonary valve stenosis. At birth, polydactyly and hydronephrosis were also noticed. He evolved with global development delay and severe oral-pharyngeal dysphagia. At the age of 4 years old, he developed focal seizures. His neurological examination showed axial hypotonia with appendicular mild hypertonia and tendon reflex were 3+/4 globally. He also presented with macrocephaly and facial dysmorphism such as downslanted palpebral fissures, high palate, low-set ears, pointed chin and long face. His MRI showed incomplete wide sylvian fissures and corpus callosum agenesis. His karyotype showed no alterations. Due to these findings, an exome was performed and a pathogenic variant c.4315C>G;p.(Leu1439Val) was described in the TAF1 gene, located in the X chromosome.

Discussion: TAF1 intellectual disability (ID) syndrome is caused by pathogenic variants in the X-linked gene TATA-box binding protein associated factor 1 (TAF1), which is involved in RNA polymerase II transcription. All variants reported to date are missense variants since TAF1 is known as a very constrained human gene because of its essential role in normal cellular functioning. It is suggested that the complete loss of TAF1 in hemi or homozygous loss-of-function variants may cause embryonic lethality. Main features are global developmental delay, ID, dysmorphic features, and neurological abnormalities. Characteristic dysmorphology includes: a long face, a high palate, a pointed chin, anteverted nares, prominent supraorbital ridges, down-slanted palpebral fissures, sagging cheeks, long philtrum and low-set and protruding ears - but facial gestalt is not highly specific to a recognizable pattern. Because of considerable pleiotropy and phenotypic variability, features such as brain morphological abnormalities, seizures and heart malformations have been reported. Some studies have suggested that TAF1 also plays an important role in early cardiac and cortical development.

Final Comments: Throughout this data, we aim to raise awareness to this genotype-phenotype and recommend that TAF1 ID should be considered in male patients presenting with global developmental delay or ID, corpus callosum abnormalities, dysmorphic typical features and congenital heart defects. TAF1 ID is usually associated with microcephaly, but our case describes macrocephaly as a novel feature to this syndrome.

Publication History

Article published online:
12 May 2025