Abstract
The Integrator complex subunit 1 (INTS1) is a component of the integrator complex that comprises 14 subunits and associates with RPB1 to catalyze endonucleolytic cleavage of nascent snRNAs and assist RNA polymerase II in promoter-proximal pause-release on protein-coding genes. We present five patients, including two sib pairs, with biallelic sequence variants in INTS1. The patients manifested absent or severely limited speech, an abnormal gait, hypotonia and cataracts. Exome sequencing revealed biallelic variants in INTS1 in all patients. One sib pair demonstrated a missense variant, p.(Arg77Cys), and a frameshift variant, p.(Arg1800Profs*20), another sib pair had a homozygous missense variant, p.(Pro1874Leu), and the fifth patient had a frameshift variant, p.(Leu1764Cysfs*16) and a missense variant, p.(Leu2164Pro). We also report additional clinical data on three previously described individuals with a homozygous, loss of function variant, p.(Ser1784*) in INTS1 that shared cognitive delays, cataracts and dysmorphic features with these patients. Several of the variants affected the protein C-terminus and preliminary modeling showed that the p.(Pro1874Leu) and p.(Leu2164Pro) variants may interfere with INTS1 helix folding. In view of the cataracts observed, we performed in-situ hybridization and demonstrated expression of ints1 in the zebrafish eye. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 to make larvae with biallelic insertion/deletion (indel) variants in ints1. The mutant larvae developed typically through gastrulation, but sections of the eye showed abnormal lens development. The distinctive phenotype associated with biallelic variants in INTS1 points to dysfunction of the integrator complex as a mechanism for intellectual disability, eye defects and craniofacial anomalies.
| Original language | American English |
|---|---|
| Pages (from-to) | 582-593 |
| Number of pages | 12 |
| Journal | European Journal of Human Genetics |
| Volume | 27 |
| Issue number | 4 |
| DOIs | |
| State | Published - 1 Apr 2019 |
Bibliographical note
Funding Information:Acknowledgements We are grateful to the families for their participation. This work was supported by National Eye Institute, National Institutes of Health [grant number R21EY022779–01 to A.S.]; Erasmus Medical Center [grant Mrace #104673 to G.M.]. This work was performed under the Care4Rare Canada Consortium funded by Genome Canada, the Canadian Institutes of Health Research (CIHR), the Ontario Genomics Institute, Ontario Research Fund, Génome Québec, and Children’s Hospital of Eastern Ontario Foundation. We also wish to acknowledge the contribution of the high-throughput sequencing platform of the McGill University and Génome Québec Innovation Centre, Montréal, Canada. R.E.L. and A.M.I. would like to thank Mary Anderson, Dr. Francois Bernier and Dr. Jillian Parboosingh for clinical and technical support, as well as helpful discussions.
Publisher Copyright:
© 2019, European Society of Human Genetics.