TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition

Am J Med Genet A. 2022 Sep;188(9):2652-2665. doi: 10.1002/ajmg.a.62852. Epub 2022 Jun 7.


Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co-activator complex activity, similarly to what was observed in Menke-Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5-binding region. Recently, TTC5-related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5-related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre- and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway.

Keywords: TTC5; biallelic mutations; deep phenotyping; severe NDD syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Exons
  • Humans
  • Intellectual Disability* / diagnosis
  • Intellectual Disability* / genetics
  • Male
  • Microcephaly* / genetics
  • Mutation
  • Phenotype
  • Syndrome
  • Transcription Factors / genetics


  • TTC5 protein, human
  • Transcription Factors