PT  - JOURNAL ARTICLE
AU  - Rasheed, Arisha
AU  - Gumus, Evren
AU  - Zaki, Maha
AU  - Johnson, Katherine
AU  - Manzoor, Humera
AU  - LaForce, Geneva
AU  - Ross, Danica
AU  - McEvoy-Venneri, Jennifer
AU  - Stanley, Valentina
AU  - Lee, Sangmoon
AU  - Virani, Abbir
AU  - Ben-Omran, Tawfeg
AU  - Gleeson, Joseph G
AU  - Naz, Sadaf
AU  - Schaffer, Ashleigh
TI  - Bi-allelic <em>TTC5</em> variants cause delayed developmental milestones and intellectual disability
AID  - 10.1136/jmedgenet-2020-106849
DP  - 2021 Apr 01
TA  - Journal of Medical Genetics
PG  - 237--246
VI  - 58
IP  - 4
4099  - http://jmg.bmj.com/content/58/4/237.short
4100  - http://jmg.bmj.com/content/58/4/237.full
SO  - J Med Genet2021 Apr 01; 58
AB  - Background Intellectual disability syndromes (IDSs) with or without developmental delays affect up to 3% of the world population. We sought to clinically and genetically characterise a novel IDS segregating in five unrelated consanguineous families.Methods Clinical analyses were performed for eight patients with intellectual disability (ID). Whole-exome sequencing for selected participants followed by Sanger sequencing for all available family members was completed. Identity-by-descent (IBD) mapping was carried out for patients in two Egyptian families harbouring an identical variant. RNA was extracted from blood cells of Turkish participants, followed by cDNA synthesis and real-time PCR for TTC5.Results Phenotype comparisons of patients revealed shared clinical features of moderate-to-severe ID, corpus callosum agenesis, mild ventriculomegaly, simplified gyral pattern, cerebral atrophy, delayed motor and verbal milestones and hypotonia, presenting with an IDS. Four novel homozygous variants in TTC5: c.629A>G;p.(Tyr210Cys), c.692C>T;p.(Ala231Val), c.787C>T;p.(Arg263Ter) and c.1883C>T;p.(Arg395Ter) were identified in the eight patients from participating families. IBD mapping revealed that c.787C>T;p.(Arg263Ter) is a founder variant in Egypt. Missense variants c.629A>G;p.(Tyr210Cys) and c.692C>T;p.(Ala231Val) disrupt highly conserved residues of TTC5 within the fifth and sixth tetratricopeptide repeat motifs which are required for p300 interaction, while the nonsense variants are predicted to decrease TTC5 expression. Functional analysis of variant c.1883C>T;p.(Arg395Ter) showed reduced TTC5 transcript levels in accordance with nonsense-mediated decay.Conclusion Combining our clinical and molecular data with a recent case report, we identify the core and variable clinical features associated with TTC5 loss-of-function variants and reveal the requirement for TTC5 in human brain development and health.