Parent–child exome sequencing identifiesa de novo truncating mutation in TCF4 in non‐syndromic intellectual disability

To the Editor : Autosomal dominant mutations in the transcription factor TCF4 cause Pitt–Hopkins syndrome (PTHS; MIM#610954), which is characterized by severe intellectual disability (ID), facial dysmorphism, intermittent hyperventilation, epilepsy, and microcephaly (1–5). Here, we report a de novo nonsense mutation in TCF4 in a patient with mild-to-moderate non-syndromic ID (NSID) without the typical features of PTHS. In the context of a project that aims to identify de novo mutations in neurodevelopmental disorders, we sequenced the exomes of a patient with NSID and her parents. The exomes were captured from blood genomic DNA using the Agilent SureSelect 50Mb library (Agilent Technologies, Santa Clara, CA), and sequenced on the ABI-SOLiD4 system (Life Technologies Applied Biosystems, Foster City, CA) (single-end 50 bp reads, four exomes/slide). Read mapping, variant calling and annotation were performed as described (6). We achieved an average per-target base coverage of 20fold for the proband and her mother, and 22-fold for the father. A total of 11,241 coding/splicing variants were found in the proband. After removing synonymous, inherited, and common variants, and after visual inspection of the reads, we identified three variants, only one of which, c.C469T/p.R157X in TCF4, was confirmed as de novo by Sanger sequencing (Table 1). p.R157X was also identified in genomic DNA from the patient’s hair bulb and buccal cells as well as in total RNA from lymphoblastoid cells established using her blood (Fig. 1).