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Original research
Bi-allelic TTC5 variants cause delayed developmental milestones and intellectual disability
  1. Arisha Rasheed1,
  2. Evren Gumus2,3,
  3. Maha Zaki4,
  4. Katherine Johnson5,
  5. Humera Manzoor1,
  6. Geneva LaForce5,
  7. Danica Ross6,7,
  8. Jennifer McEvoy-Venneri6,7,
  9. Valentina Stanley7,
  10. Sangmoon Lee6,7,
  11. Abbir Virani6,7,
  12. Tawfeg Ben-Omran8,
  13. Joseph G Gleeson6,9,
  14. Sadaf Naz1,
  15. Ashleigh Schaffer5
  1. 1School of Biological Sciences, University of the Punjab Quaid-i-Azam Campus, Lahore, Pakistan
  2. 2Medical Genetics, Mugla Sitki Kocman University Faculty of Medicine, Mugla, Turkey
  3. 3Medical Genetics, Harran University Faculty of Medicine, Sanliurfa, Turkey
  4. 4Clinical Genetic Department, National Research Centre, Cairo, Egypt
  5. 5Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, United States
  6. 6Rady Children's Institute for Genomic Medicine, San Diego, California, USA
  7. 7Department of Neuroscience, University of California, San Diego, La Jolla, CA, United States
  8. 8Clinical and Metabolic Genetics Division, Department of Pediatrics, Weill-Cornell Medical College, Hamad Medical Corporation, Doha, Qatar
  9. 9Department of Neuroscience and Pediatrics, Howard Hughes Medical Insistute, University of California, San Diego, La Jolla, CA, United States
  1. Correspondence to Dr Ashleigh Schaffer, Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, United States; ashleigh.schaffer{at}; Dr Sadaf Naz, School of Biological Sciences, University of the Punjab, Quaid-i-Azam campus, Lahore, Pakistan;{at}


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.

  • genetics
  • molecular genetics
  • neurology
  • developmental

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  • AR, EG and MZ are joint first authors.

  • SN and AS are joint senior authors.

  • AR, EG and MZ contributed equally.

  • SN and AS contributed equally.

  • Contributors AS and SN designed the study and evaluated the data. AR, HM, EG, MZ, TB-O and JGG recruited the families, VS helped in evaluation of patients. GL, DR, JM-V, SL, AV and AS carried out experiments and evaluated the data. AR, EG, SN, KJ and AS drafted the manuscript. All authors approved the final draft before submission.

  • Funding The study was funded by family RDHM-05, Higher Education Commission, Pakistan #2877 to SN, the National Institutes of Health R00HD082337 to AS, R01NS048453, R01NS09800 and QNRF NPRP 6-1463-3-351 to JGG, SFARI 51486313 to JGG, UM1HG008900/Broad Institute Center for Mendelian Genomics U54HG006504/Yale Center for Mendelian Disorders, N01 268201700006I-0-26800029 to CIDR for genotyping. JGG is an investigator with the Howard Hughes Medical Institute.

  • Competing interests None declared.

  • Patient consent for publication Parental/guardian consent obtained.

  • Ethics approval Institutional Review Board of School of Biological Sciences, University of the Punjab, Lahore Pakistan (IRB No. 00005281), the Regional Ethics Committee of Harran University, Sanliurfa; Turkey, and the University of California, San Diego (140028).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data are available under reasonable request from the corresponding authors. The accession numbers for the TTC5 variants reported in this article are: LOVD:0000602976LOVD:0000604184 and dbGap:phs000288.v1.p1.