Pierpont syndrome associated with the p.Tyr446Cys missense mutation in TBL1XR1.

We present a 7-year old male with severe delays, hypotonia and dysmorphic features who had striking, deep palmar and plantar creases and pillowing of the soft tissues of the palms and soles. His facial features included a high anterior hairline, small eyes with narrowed palpebral fissures, a bulbous nasal tip with a short columella, and a large mouth with a thin upper vermilion, and small chin. He had a submucous cleft palate, bilateral cryptorchidism and hydronephrosis. Cranial imaging demonstrated an Arnold Chiari malformation that was also present in his maternal uncle by report. Exome sequencing revealed a de novo heterozygous sequence variant, p.Tyr446Cys, in TBL1XR1 that has previously been reported in six patients with Pierpont syndrome. This sequence variant occurs in the carboxy-terminal, WD40 domain of the protein. As TBL1XR1 is a critical component of the NCoR/SMRT co-repressor complex and the WD40 repeats are hypothesized to interact with histone H2B and H4, the mutation may impact protein interactions necessary for stabilizing the complex with chromatin. De novo missense and frameshift mutations and deletions involving TBL1XR1 have been described in patients with intellectual disability and autism, but without any of the dysmorphic findings or malformations associated with Pierpont syndrome, implying a mutation-specific mechanism for the pathogenicity of p.Tyr446Cys. Our case is the first individual with this mutation to have a submucous cleft palate and hydronephrosis, although his severe delays, hypotonia, dysmorphic findings and emerging scoliosis appear consistent with previous reports. His distinctive facial and digital features are further evidence that p.Tyr446Cys results in a clinically recognizable, syndromic form of intellectual disability in contrast to other TBL1XR1 mutations.