A heritable microduplication encompassing TBL1XR1 causes a genomic sister‐disorder for the 3q26.32 microdeletion syndrome

Abstract

Recently, a new syndrome with intellectual disability (ID) and dysmorphic features due to deletions or point mutations within the TBL1XR1 gene located in the chromosomal band 3q26.32 has been described (MRD41, OMIM 616944). One recurrent point mutation in the TBL1XR1 gene has been identified as the cause of Pierpont syndrome (OMIM 602342), a distinct intellectual disability syndrome with plantar lipomatosis. In addition, different de novo point mutations in the TBL1XR1 gene have been found in patients with autism spectrum disorders (ASD) and intellectual disability. Here, we report four patients from two unrelated families in whom array-CGH analysis and real-time quantitative PCR of genomic DNA revealed a TBL1XR1-microduplication. Adjacent genes were not affected. The microduplication occurred as a de novo event in one patient, whereas the other three cases occurred in two generations of a second, unrelated family. We compare and contrast the clinical findings in TBL1XR1 microdeletion, point mutation, and microduplication cases and expand the TBL1XR1-associated phenotypic spectrum. ID, hearing loss, and ASD are common features of TBL1XR1-associated diseases. Our clinical observations add to the increasing evidence of the role of TBL1XR1 in brain development, and they simultaneously demonstrate that different genetic disease mechanisms affecting TBL1XR1 can lead to similar ID phenotypes. The TBL1XR1-microduplication syndrome is an intellectual disability/learning disability syndrome with associated incomplete penetrance ASD, hearing loss, and delay of puberty. Its phenotypic overlap indicates that it is a genomic sister-disorder to the 3q26.32 microdeletion syndrome.

On the verge of diagnosis: Detection, reporting, and investigation of de novo variants in novel genes identified by clinical sequencing

“…As an example, in case 3, two de novo variants were reported in two genes, TBL1XR1 and KIAA0100 , both with weak association with ASD at the time of testing (late 2015). In 2016–2017, few reports emerged with de novo missense and frameshift variants and deletions involving TBL1XR1 in patients with ID and autism, but without any of the dysmorphic findings or malformations (Laskowski et al., ; Riehmer et al., ; Wang et al., ). Moreover, a specific missense variant (p.Tyr446Cys) in TBL1XR1 was later associated with Pierpont syndrome in seven unrelated patients (Laskowski et al., ; Slavotinek et al., ).…”

Nuclear Receptor Coactivators (NCOAs) and Corepressors (NCORs) in the Brain

“…A girl with a 708 Kb microdeletion on chromosome 3q26.32 (176 221 801−176 929 584), encompassing only TBL1XR1, has an intellectual disability and brain malformation ( 87 ). 309Kb and 521Kb microduplications of TBL1XR1 leads to developmental delay, intellectual disability, ASD, and hearing loss ( 88 ). A de novo missense TBL1XR1 mutation [c.209 G > A (G70D)] is identified in a Japanese girl with West syndrome and ASD features ( 89 ).…”

Two decades of a protooncogene TBL1XR1: from a transcription modulator to cancer therapeutic target

“…Two decades have passed since the discovery of TBL1XR1 and in unraveling its cellular functions. In early years, researches frequently reported the variants of TBL1XR1 in neurodevelopmental disorders, such as Pierpont syndrome ( 12 – 14 ), autism spectrum disorders ( 15 , 16 ), West syndrome ( 17 , 18 ) and intellectual disability ( 19 ). Later it emerged as a potential biomarker of poor prognosis and tumorigenesis for different types of cancers.…”