PUBLICATION

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

Authors
Krall, M., Htun, S., Schnur, R.E., Brooks, A.S., Baker, L., de Alba Campomanes, A., Lamont, R.E., Gripp, K.W., Care 4 Rare Canada Consortium, Schneidman-Duhovny, D., Innes, A.M., Mancini, G.M.S., Slavotinek, A.M.
ID
ZDB-PUB-190110-2
Date
2019
Source
European journal of human genetics : EJHG   27(4): 582-593 (Journal)
Registered Authors
Htun, Stephanie, Lamont, Ryan, Slavotinek, Anne
Keywords
none
MeSH Terms
  • Adolescent
  • Adult
  • Animals
  • Cataract/genetics*
  • Cataract/physiopathology
  • Child
  • Child, Preschool
  • Craniofacial Abnormalities/genetics*
  • Craniofacial Abnormalities/physiopathology
  • Developmental Disabilities/genetics*
  • Developmental Disabilities/physiopathology
  • Female
  • Frameshift Mutation/genetics
  • Gastrulation/genetics
  • Humans
  • Infant
  • Lens, Crystalline/growth & development
  • Lens, Crystalline/pathology
  • Male
  • Mutation, Missense/genetics
  • Pedigree
  • Protein Folding
  • Whole Exome Sequencing
  • Wnt1 Protein/chemistry
  • Wnt1 Protein/genetics*
  • Young Adult
  • Zebrafish/genetics
PubMed
30622326 Full text @ Eur. J. Hum. Genet.
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.
Genes / Markers
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Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping