TBL1XR1 – Pierpont syndrome

Pierpont syndrome (MONDO:0011213) is a rare autosomal dominant disorder characterized by global developmental delay, hearing impairment, distinctive facial features, and abnormal fat deposition in the distal limbs. TBL1XR1 (HGNC:29529) encodes a WD40 repeat–containing corepressor component of the SMRT/NCoR complex, and heterozygous missense mutations in TBL1XR1 have been implicated as the exclusive genetic cause of Pierpont syndrome.

Initial whole-exome and Sanger sequencing in six unrelated individuals identified a recurrent de novo heterozygous missense variant, c.1337A>G (p.Tyr446Cys), in all patients, each presenting with developmental delay, characteristic palmar and plantar creases, hearing loss, and dysmorphic facial gestalt (PMID:26769062). Segregation of the p.Tyr446Cys variant with Pierpont syndrome features was observed in one affected maternal uncle (PMID:28687524).

Subsequent case reports expanded the genetic and phenotypic spectrum: a seventh proband carrying p.Tyr446Cys exhibited additional features including microphthalmia, pendular nystagmus, cryptorchidism, and dermal sinus (PMID:28562391); a de novo c.977G>A (p.Ser326Asn) variant near the WD40 domain caused classical Pierpont features in another patient (PMID:36843287); and two novel WD40 variants—c.974G>A (p.Cys325Tyr) and c.1336T>C (p.Tyr446His)—were reported in two further unrelated individuals (PMID:30365874).

The spectrum of pathogenic TBL1XR1 alleles includes primarily missense variants clustering in the C-terminal WD40 repeats, with no loss-of-function mutations associated with Pierpont syndrome, indicating a mutation-specific, dominant-negative mechanism. In vitro, p.Tyr446Cys assembles into the NCoR/SMRT complex but alters protein interaction dynamics (PMID:26769062). A Tbl1xr1^Y446C/Y446C knock-in mouse model recapitulated key Pierpont features—growth delay, altered adipose composition, and impaired hearing—providing in vivo functional corroboration (PMID:35416977).

Collectively, more than ten de novo WD40 domain missense variants in at least eight unrelated families meet criteria for a strong gene–disease relationship. Diagnostic testing for TBL1XR1 hotspot variants, particularly c.1337A>G (p.Tyr446Cys), is clinically informative for confirming Pierpont syndrome, guiding genetic counseling, and enabling anticipatory management.

Key Take-home: Heterozygous WD40 repeat missense mutations in TBL1XR1 define an autosomal dominant Pierpont syndrome with a specific clinical and mechanistic profile.

References

• Journal of medical genetics • 2016 • A specific mutation in TBL1XR1 causes Pierpont syndrome. PMID:26769062
• Clinical dysmorphology • 2017 • Pierpont syndrome: report of a new patient. PMID:28562391
• European journal of medical genetics • 2017 • Pierpont syndrome associated with the p.Tyr446Cys missense mutation in TBL1XR1. PMID:28687524
• Human molecular genetics • 2022 • An animal model for Pierpont syndrome: a mouse bearing the Tbl1xr1Y446C/Y446C mutation. PMID:35416977
• American journal of medical genetics. Part A • 2023 • A novel de novo pathogenic variant in TBL1XR1 as a new proposed cause of Pierpont syndrome. PMID:36843287

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