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Eur J Hum Genet. 2019 Jan 8. doi: 10.1038/s41431-018-0298-9. [Epub ahead of print]

Biallelic sequence variants in INTS1 in patients with developmental delays, cataracts, and craniofacial anomalies.

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Dept. Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA, 94143-2711, USA.
GeneDx, Gaithersburg, MD, 20877, USA.
Department of Clinical Genetics, ErasmusMC University Medical Center, 3015CN, Rotterdam, The Netherlands.
Division of Medical Genetics, A.I. du Pont Hospital for Children/Nemours, Wilmington, DE, 19803, USA.
Department of Ophthalmology, University of California, San Francisco, San Francisco, CA, 94143, USA.
Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada.
School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
Department of Biochemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel.
Dept. Pediatrics, Division of Genetics, University of California, San Francisco, San Francisco, CA, 94143-2711, USA.


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.


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