TBL1XR1 mutations in Pierpont syndrome are not restricted to the recurrent p.Tyr446Cys mutation

Abstract

Pierpont syndrome is a rare and sporadic syndrome, including developmental delay, facial characteristics, and abnormal extremities. Recently, a recurrent de novo TBL1XR1 variant (c.1337A > G; p.Tyr446Cys) has been identified in eight patients by whole‐exome sequencing. A dominant‐negative effect of this mutation is strongly suspected, since patients with TBL1XR1 deletion and other variants predicting loss of function do not share the same phenotype. We report two patients with typical Pierpont‐like syndrome features. Exome sequencing allowed identifying a de novo heterozygous missense TBL1XR1 variant in both patients, different from those already reported: p.Cys325Tyr and p.Tyr446His. The localization of these mutations and clinical features of Pierpont‐like syndrome suggest that their functional consequences are comparable with the recurrent mutation previously described, and provided additional data to understand molecular mechanisms of TBL1XR1 anomalies.

TBL1XR1 associated intellectual disability, a new missense variant with dysmorphic features plus autism: Expanding the phenotypic spectrum

“…Our case has facial Pierpont syndrome characteristics, brachydactyly, fetal pads and growth delay, but not the distinctive marked grooves of hands and feet, subcalcaneal fat pads, scoliosis or hearing loss. Moreover his neurological phenotype with ID also includes a behavioral profile, ASD, not previously reported in published Pierpont cases with TBL1XR1 pathogenic variants, 9,[11][12][13] but described in patients with other SNVs in TBL1XR1 [1][2][3][4][5]8 (Table 1).…”

“…Recently two patients have been diagnosed with Pierpont syndrome by retro-phenotyping with two novel different missense mutations in the TBL1XR1 gene, 13 one of them localized in the same residue as the recurrent one. These patients share most of the clinical Pierpont features though one of them has not the characteristic finger/toe fetal pads and subcalcaneal fat pads, and both of them have no scoliosis or hearing loss (Table 1).…”

“…Pierpont syndrome (OMIM #602342) is a rare pattern of multiple congenital anomalies originally described in 1998 10 that comprises ID, distinctive facial characteristics (high forehead, deep-set eyes, narrow palpebral fissures, broad nasal ridge, small midface, anteverted nares, thin upper vermilion, and large and fleshy ears), abnormal fat distribution in distal limbs (marked grooves and pillowing of hands and feet, subcalcaneal fat pads), short stature, and hearing loss. Later, four patients with clinical Pierpont-like syndrome have been described, two of them with the same recurrent mutation, 11,12 one with a novel missense change at the same amino acid residue of the recurrent one, 13 and the last at a different position of the gene. 13 Also, microdeletions that encompass TBL1XR1 have been described: a 1.6 Mb deletion in a 6-year-old girl with ID and nonspecific dysmorphic features 14 ; a familial case, mother and daughter, with ID and dysmorphic features and a 0.7 Mb deletion 15 ; and a 7-year-old girl with ID, dysmorphic features and cardiac and brain malformations with a 1.3 Mb deletion.…”

“…Later, four patients with clinical Pierpont-like syndrome have been described, two of them with the same recurrent mutation, 11,12 one with a novel missense change at the same amino acid residue of the recurrent one, 13 and the last at a different position of the gene. 13 Also, microdeletions that encompass TBL1XR1 have been described: a 1.6 Mb deletion in a 6-year-old girl with ID and nonspecific dysmorphic features 14 ; a familial case, mother and daughter, with ID and dysmorphic features and a 0.7 Mb deletion 15 ; and a 7-year-old girl with ID, dysmorphic features and cardiac and brain malformations with a 1.3 Mb deletion. 16 In all cases, the only deleted gene has been TBL1XR1, and in the 1.6 Mb deletion case, the other gene, NAALADL2, that lost its last exon has not been related so far to ID.…”

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

“…A de novo missense TBL1XR1 mutation [c.209 G > A (G70D)] is identified in a Japanese girl with West syndrome and ASD features ( 89 ). Whole-exome sequencing of Pierpont syndrome patients identifies Y446C, C325Y, and Y446H variants in TBL1XR1 as potentially disease-causing ( 90-92 ). TBL1XR1 Y446S is found in autosomal dominant mental retardation ( 93 ).…”