Tubulinopathies
Gene: TTL
TTL
Valentina Serpieri, University of Pavia
ESHG talk 1/6/24
FAM1 (Italy)
2 affected sisters born to consanguineous Pakistani parents
GDD, spastic tetraparesis, optic atrophy, brain anomalies resembling tubulinopathies (dysplasia of corpus callosum, basal ganglia, brainstem)
WES: homozygous TTL:c.1013G>A; p.Cys338Tyr in both affected sisters
Via genematcher
5 more families (9 individuals) w similar phenotypes and biallelic variants in TTL
FAM2 (Egypt): homozygous p.Arg46Pro
FAM3 (Egypt): homozygous p.Arg46Pro
FAM4 (Australia): homozygous p.Gln183Arg
FAM5 (France): homozygous p.Trp147*
FAM6 (Saudi Arabia): homozygous p.His243Tyr
TTL KO mice: death soon after birth, no overt malformations, but defects in organisation of cerebral layers
Functional work on patient fibroblasts
FAM1 – reduced quantity of TTL protein compared to control on Western blot, decreased function of TTL protein (increase in detyrosinated tubulin) compared to controls – infer LoF as mechanism
FAM3 – mentioned but no details
FAM4– mentioned but no details
Sources: OtherCreated: 4 Sep 2024, 2:22 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
complex neurodevelopmental disorder MONDO:0100038
Gene: ttl has been classified as Amber List (Moderate Evidence).
Gene: ttl has been classified as Amber List (Moderate Evidence).
Gene: ttl has been classified as Amber List (Moderate Evidence).
gene: TTL was added gene: TTL was added to Tubulinopathies. Sources: Other Mode of inheritance for gene: TTL was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TTL were set to complex neurodevelopmental disorder MONDO:0100038 Penetrance for gene: TTL were set to unknown Review for gene: TTL was set to AMBER