TTC5 – Autosomal Recessive Non-syndromic Intellectual Disability

Biallelic TTC5 variants have been identified as a cause of autosomal recessive non-syndromic intellectual disability in eight patients from five consanguineous families (PMID:32439809) and seven additional probands (PMID:35670379).

Inheritance is autosomal recessive, supported by segregation of homozygous variants in multiple consanguineous pedigrees without affected heterozygotes. Identity-by-descent mapping in two Egyptian families confirmed a founder allele for one variant (PMID:32439809).

Genetic evidence encompasses four homozygous TTC5 variants: two missense (c.629A>G (p.Tyr210Cys) and c.692C>T (p.Ala231Val)) and two nonsense (c.787C>T (p.Arg263Ter) and c.1883C>T (p.Arg395Ter)) across 15 probands. The c.787C>T (p.Arg263Ter) variant recurs as a founder allele in Egyptian families (PMID:32439809).

Functional assays demonstrate that missense variants within tetratricopeptide repeats disrupt TTC5–p300 interaction, and the c.1883C>T (p.Arg395Ter) transcript undergoes nonsense-mediated decay in patient-derived blood cells, indicating loss-of-function as the pathogenic mechanism (PMID:32439809).

Clinical phenotypes are marked by moderate-to-severe intellectual disability, delayed motor and verbal milestones, hypotonia (HP:0001252), cerebral atrophy (HP:0002059), microcephaly (HP:0000252), seizures (HP:0001250), cryptorchidism (HP:0000028), and characteristic facial dysmorphism (HP:0000271) in all reported cases (PMID:32439809; PMID:35670379).

No reports of conflicting or alternative genetic etiologies have been described. The congruence of genetic, segregation, and experimental data supports a strong gene-disease relationship.

Key take-home: TTC5 loss-of-function underlies a recognizable autosomal recessive intellectual disability syndrome, enabling targeted genetic testing and early diagnosis.

References

• Journal of Medical Genetics • 2021 • Bi-allelic TTC5 variants cause delayed developmental milestones and intellectual disability. PMID:32439809
• American Journal of Medical Genetics Part A • 2022 • TTC5 syndrome: Clinical and molecular spectrum of a severe and recognizable condition. PMID:35670379

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