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A recurrent pathogenic variant in TPM2 reveals further phenotypic and genetic heterogeneity in multiple pterygium

Julie Vogt1, Atif Al-Saedi2, Tracey Willis3

  • 1West Midlands Regional Genetics Service, Birmingham Women's and Children's Hospital, Birmingham, UK.

Clinical Genetics
|February 25, 2020
PubMed

Insights

Genetic testing identified new mutations in the TPM2 gene causing Multiple Pterygium Syndrome (MPS). This expands understanding of MPS genetic causes and aids in diagnosing these complex developmental disorders.

Area of Science:

  • Genetics
  • Developmental Biology
  • Molecular Medicine

Background:

  • Multiple Pterygium Syndrome (MPS) encompasses a group of disorders with genetic heterogeneity, characterized by joint contractures and webbing.
  • While often autosomal recessive, MPS can also be X-linked or autosomal dominant, with genetic causes identified through advanced sequencing.
  • Previous research linked TPM2 gene mutations to various neuromuscular conditions and rare syndromes.

Purpose of the Study:

  • To investigate the genetic underpinnings of Multiple Pterygium Syndrome (MPS) in undiagnosed individuals.
  • To identify novel genetic variants associated with MPS phenotypes using advanced genomic technologies.
  • To expand the spectrum of TPM2-related disorders and inform diagnostic approaches for MPS.

Main Methods:

  • Utilized the Illumina TruSightOne clinical exome assay for genetic analysis.
  • Sequenced three unrelated individuals presenting with features of MPS-related conditions.
  • Performed segregation analysis with parental samples to confirm de novo mutation status.

Main Results:

  • Identified a recurrent heterozygous missense substitution in the TPM2 gene in all three unrelated individuals.
  • Confirmed the recurrent TPM2 substitution arose de novo in two patients through segregation analysis.
  • Observed overlapping yet variable clinical features among the affected individuals.

Conclusions:

  • The TPM2 gene is implicated in a broader range of Multiple Pterygium Syndrome phenotypes than previously recognized.
  • De novo mutations in TPM2 should be considered in the genetic diagnosis of isolated MPS cases.
  • This finding enhances the diagnostic yield for patients with complex congenital contracture syndromes.
Keywords:
TPM2arthrogryposisbeta tropomyosincamptodactylydistal contracturesmultiple pterygium syndrometrismus

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