Novel De Novo TBL1XR1 Variant Causing PIERPONT Syndrome in an Indian Child: A Case Report and Genotype–Phenotype Review of Reported Patients

Abstract

AbstractThe transducin β-like-1 X-linked-receptor-1 gene (TBL1XR1) encodes for the TBL1XR1 protein which is involved in transcription. Single-nucleotide variants (SNVs) in the TBL1XR1 gene have been reported to be associated with Pierpont's syndrome (PS) which exhibits numerous features including global developmental delay (GDD), intellectual disability (ID), varying neurobehavioral and psychiatric manifestations with/without autism spectrum disorder (ASD), abnormal fat distribution in the distal extremities, short stature (SS), head circumference abnormalities, hearing loss (HL), and facial dysmorphisms. Eight PS patients, having a de novo mutation resulting in p.Tyr446Cys, showed no manifestations of ASD. The three other PS patients, having mutations resulting in p.Tyr446His, p.Cys325Tyr and p.Gly237Asp, respectively, and without the p.Tyr446Cys alteration, were in addition associated with neurobehavioral abnormalities, including ASD, hyperactivity, and self-mutilation tendencies. Here, via trio whole exome sequencing, we describe a 12th PS patient, the first from the Indian subcontinent, reflecting a novel TBL1XR1 p.His348Arg alteration. The proband is a 4.5-year-old male having GDD, speech delay, facial dysmorphisms, abnormal digital fat pads, hypotonia, microcephaly, patent ductus arteriosus, and ASD features. Our report strengthens the hypothesis that TBL1XR1 variants coding for the TBL1XR1 protein other than p.Tyr446Cys might be more commonly associated with a neurobehavioral phenotype and autistic tendencies.