TWIST1 – Craniosynostosis

TWIST1 (https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:12428) encodes a basic helix-loop-helix transcription factor essential for cranial suture development. Heterozygous loss-of-function variants in TWIST1 cause autosomal dominant craniosynostosis (MONDO:0015469), with both syndromic and nonsyndromic presentations, through haploinsufficiency and impaired repression of osteogenic pathways.

Familial and sporadic cases demonstrate an autosomal dominant inheritance pattern, with multiple reports of segregation across affected relatives. For example, the c.115C>G (p.Arg39Gly) variant was identified in a child and two clinically unaffected relatives, indicating variable expressivity within families ([PMID:15880747]). Segregation analyses in multi-patient cohorts document at least five additional affected family members carrying TWIST1 variants (e.g., microdeletions and missense changes) segregating with craniosynostosis symptoms.

Over 80 distinct TWIST1 variants have been reported in >100 unrelated probands, including missense (e.g., c.407C>T (p.Pro136Leu) in eight of ten Saethre–Chotzen syndrome patients and two of 43 undiagnosed craniosynostosis cases ([PMID:9792856])), frameshift, nonsense, and exon-spanning deletions. Microdeletions ranging from 2.9 kb to >11.6 Mb and single-nucleotide changes within the bHLH domain disrupt protein structure, confirming a critical variant spectrum.

Functional studies confirm haploinsufficiency as the primary mechanism. Nonsense mutations yield unstable truncated proteins, and missense alterations in the helix domains abolish dimerization with E12/E47 and mislocalize TWIST1 to the cytoplasm ([PMID:10749989]). Variants in two glycine-rich repeat tract motifs do not alter CDKN1A repression, underscoring domain-specific effects ([PMID:15880747]). Mouse models heterozygous for Twist1 recapitulate coronal suture fusion, supporting pathogenic concordance.

Some glycine-tract length polymorphisms are observed in asymptomatic individuals, indicating that not all TWIST1 indels are pathogenic and warrant careful variant interpretation ([PMID:11748846]). No studies have refuted the core association between heterozygous TWIST1 loss-of-function and craniosynostosis.

Integrated genetic and experimental data establish a definitive gene–disease relationship. TWIST1 variant analysis is clinically actionable: it informs recurrence risk, guides prenatal diagnosis, and influences surgical planning for suture release. Genetic testing for TWIST1 should be standard in patients with coronal or multisuture craniosynostosis.

Key Take-home: Heterozygous TWIST1 haploinsufficiency is a definitive cause of autosomal dominant craniosynostosis, underpinned by robust familial segregation and functional concordance.

References

• American journal of human genetics • 1998 • A comprehensive screen for TWIST mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1. PMID:9792856
• Human molecular genetics • 2000 • Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location. PMID:10749989
• Human mutation • 2005 • Functional analysis of natural mutations in two TWIST protein motifs. PMID:15880747
• Human mutation • 2001 • A survey of TWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals. PMID:11748846

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