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

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

Luciana Musante  1 , Flavio Faletra  1 , Kolja Meier  2 , Hoda Tomoum  3 , Paria Najarzadeh Torbati  4 , Edward Blair  5 , Sally North  5 , Jutta Gärtner  2 , Susann Diegmann  2 , Mehran Beiraghi Toosi  6 , Farah Ashrafzadeh  7 , Ehsan Ghayoor Karimiani  4   8   9 , David Murphy  10 , Flora Maria Murru  1 , Caterina Zanus  1 , Andrea Magnolato  1 , Martina La Bianca  1 , Agnese Feresin  11 , Giorgia Girotto  1   11 , Paolo Gasparini  1   11 , Paola Costa  1 , Marco Carrozzi  1
Affiliations

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

Luciana Musante et al. Am J Med Genet A. 2022 Sep.

Erratum in

Abstract

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.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Pedigrees of the five unrelated families included in the study. Double bar, parental consanguinity; square, male; circle, female; filled, affected; unfilled unaffected; backslash, deceased
FIGURE 2
FIGURE 2
Schematic representation of TTC5 gene and protein. Type and location of TTC5 mutations identified in the patients reported in this study (black and bold) and previously published in the literature (gray) (Hu et al., ; Miyamoto et al., ; Rasheed et al., 2021). The position of the variants along the TTC5 gene, as well as the position of the corresponding protein changes, is indicated. The shown tetratricopeptide domains (TPR 1–6) and oligonucleotide binding domain (OB) are based on UniProtKB/Swiss‐Prot entry Q8N0Z6
See this image and copyright information in PMC

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