Genes in panel
Regions in panel
Prev Next

Intellectual disability

Gene: TTC5

Amber List (moderate evidence)

TTC5 (tetratricopeptide repeat domain 5)
EnsemblGeneIds (GRCh38): ENSG00000136319
EnsemblGeneIds (GRCh37): ENSG00000136319
TTC5 is in 2 panels

3 reviews

Sarah Leigh (Genomics England Curator)

Green List (high evidence)

There is enough evidence for this gene to be rated GREEN at the next major review.
Created: 30 Jun 2020, 3:23 p.m. | Last Modified: 30 Jun 2020, 3:23 p.m.
Panel Version: 3.120
Comment on list classification: Not associated with a relevant phenotype in OMIM and as probable Gen2Phen gene for TTC5-associated neurodevelopmental disorder. At least 7 cases with biallelic variants.
Created: 30 Jun 2020, 3:21 p.m. | Last Modified: 30 Jun 2020, 3:21 p.m.
Panel Version: 3.120

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Seven families with bi-allelic variants reported.
Created: 3 Jun 2020, 11:04 a.m. | Last Modified: 3 Jun 2020, 11:04 a.m.
Panel Version: 3.80

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system

Publications

Variants in this GENE are reported as part of current diagnostic practice

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Hu et al (2019 - PMID: 29302074) reported briefly on 3 individuals from 2 consanguineous families (from Turkey and Iran) with biallelic TTC5 variants. Features included DD (3/3), ID (severe in 2/2 with relevant age), microcephaly (3/3), brain abnormalities, etc. A nonsense and a variant affecting splice site were identified by WES/WGS.

---

In a recent report, Rasheed et al (2020 - PMID: 32439809) report on the phenotype of 8 individuals - belonging to 5 consanguineous families - all 8 harboring homozygous TTC5 mutations.

Frequent features included hypotonia (6/8), motor and speech delay, moderate to severe ID (10/10 of relevant age - inclusion of less severely affected subjects was not considered by study design), brain MRI abnormalities (8/8). Other findings included microcephaly in some (6/11), behavioral abnormalities in few (autistic behavior in 2/8, aggression in 2/8), genitourinary anomalies (2/8), seizures (1/11). Facial phenotype incl. thin V-shaped upper lip, low-set ears (in most) and/or additional features.

TTC5 encodes a 440 aa protein, functioning as a scaffold to stabilise p300-JMY interactions. Apart from this role in nucleus, it has functions in the cytoplasm (inhibiting actin nucleataion, autophagosome formation, etc).

The gene has ubiquitous expression, highest in brain.

All variants were identified following WES - as the best candidates - in affected individuals with compatible Sanger studies in all affected family members and carrier parents.

2 missense and 2 nonsense variants were identified with the 2 missense SNVs localizing within TPR domains. qRT-PCR studies for a nonsense variant localizing 19 nt before the last exon, revealed fourfold decreased expression in affected individuals compared to carriers.

Families from Egypt shared a homozygous ~6.3 Mb haplotype block spanning TTC5, suggesting that p.(Arg263Ter) is likely a founder mutation.

The authors underscore some phenotypic (though not facial) similarities with Rubinstein-Taybi syndrome 2 due to EP300 mutations (in line with the role of TTC5).

Biallelic variants in genes encoding other members of the TTC family (containing a TPR motif), e.g. TTC8 or TTC15 cause disorders with neurologic manifestations (and DD/ID).
Sources: Literature
Created: 2 Jun 2020, 7:34 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system

Publications

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
Phenotypes
  • Central hypotonia
  • Global developmental delay
  • Intellectual disability
  • Abnormality of nervous system morphology
  • Microcephaly
  • Abnormality of the face
  • Behavioral abnormality
  • Abnormality of the genitourinary system
Tags
for-review
Clinvar variants
Variants in TTC5
Penetrance
Complete
Publications
Panels with this gene

History Filter Activity

30 Jun 2020, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: ttc5 has been classified as Amber List (Moderate Evidence).

30 Jun 2020, Gel status: 0

Added Tag

Sarah Leigh (Genomics England Curator)

Tag for-review tag was added to gene: TTC5.

2 Jun 2020, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance

Konstantinos Varvagiannis (Other)

gene: TTC5 was added gene: TTC5 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: TTC5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TTC5 were set to 29302074; 32439809 Phenotypes for gene: TTC5 were set to Central hypotonia; Global developmental delay; Intellectual disability; Abnormality of nervous system morphology; Microcephaly; Abnormality of the face; Behavioral abnormality; Abnormality of the genitourinary system Penetrance for gene: TTC5 were set to Complete Review for gene: TTC5 was set to GREEN